Publications by authors named "Charly Gaul"

110 Publications

Impact of Galcanezumab on Total Pain Burden: A Post Hoc Analysis of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study in Patients with Episodic Cluster Headache.

J Pain Res 2021 8;14:2059-2070. Epub 2021 Jul 8.

Eli Lilly and Company, Indianapolis, IN, USA.

Purpose: In a phase 3 study, galcanezumab significantly reduced the frequency of episodic cluster headache attacks across weeks 1-3 (primary endpoint) compared with placebo. However, multiple pain dimensions may contribute to the total burden of episodic cluster headache pain. This post hoc analysis assessed the impact of galcanezumab on the total pain burden of episodic cluster headache using a composite measure.

Patients And Methods: Patients with episodic cluster headache were randomized 1:1 to galcanezumab 300 mg or placebo once monthly for 8 weeks. Mean weekly total pain burden was calculated (daily cluster headache attack frequency × average duration × average pain severity summed over 7 days) using data collected in an electronic patient-reported outcomes diary. Change from baseline in weekly total pain burden across weeks 1-3 was compared between galcanezumab and placebo. To explore construct validity, mean weekly total pain burden scores were stratified by Patient Global Impression of Improvement (PGI-I) responses at the week 4 clinic visit.

Results: The reduction from baseline in mean weekly total pain burden was significantly greater with galcanezumab (N=49) than with placebo (N=57): the least squares mean difference was -11.18 severity-weighted hours (p=0.035). Median weekly total pain burden decreased as PGI-I ratings improved, from 33.6 to 5.0 severity-weighted hours for patients who felt "very much worse" and "very much better," respectively.

Conclusion: Galcanezumab significantly reduced mean weekly total pain burden compared with placebo in patients with episodic cluster headache. The composite pain measure demonstrated construct validity. Total pain burden may provide a holistic measure of the pain of episodic cluster headache.

Clinical Trials: ClinicalTrials.gov, NCT02397473.
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http://dx.doi.org/10.2147/JPR.S305066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275210PMC
July 2021

Impact of a 12-week open-label placebo treatment on headache days in episodic and chronic migraine: a study protocol for a parallel-group, multicentre, randomised controlled trial.

BMJ Open 2021 06 23;11(6):e045969. Epub 2021 Jun 23.

Department of Neurology, Center for Translational Neuro- and Behavioral Sciences, University Medicine Essen, Essen, Germany.

Introduction: Migraine is the most common neurological disorder and one of the major causes of years lived with disability. Its treatment (especially of chronic forms) is often challenging and accompanied with adverse effects. Although new therapeutic approaches have recently emerged (eg, calcitonin gene-related peptide antibodies), these are linked to strict prescribing guidelines and therefore limited to only a minority of patients. Recently, randomised controlled trials have demonstrated that open-label placebo treatments can lead to significant and clinically relevant improvements of chronic pain conditions.

Methods And Analysis: This multicentre, randomised controlled clinical trial following a parallel group between-subject design aims to systematically investigate the impact of a 12-week open-label placebo treatment on moderate to severe headache days (primary outcome) in patients with episodic and chronic migraine in addition to treatment as usual. Secondary outcomes comprise the number of migraine days, pain intensity, intake of acute medication, quality of life, disability, global impression of change, tolerability and a responder rate. To systematically address potential predictors of placebo responses in patients with migraine, this study assesses potential psychometric predictors, salivary cortisol and alpha-amylase awakening responses, catechol-o-methyltransferase Val158Met polymorphisms, as well as functional and structural brain connectivity (ie, resting state functional MRI, diffusion tensor imaging). The data analysis will be performed on basis of the general linear model considering repeated measures (mixed model).

Ethics And Dissemination: This protocol and all corresponding documents were approved with regard to their content and compliance with ethical regulations by the Ethics Committee of the Medical Faculty of the University Duisburg-Essen, Germany and the Ethics Committee of the Landesärztekammer Hessen. The results from this study will be actively disseminated through manuscript publications and conference presentations.

Trial Registration Number: German Clinical Trials Register (DRKS00021259).
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http://dx.doi.org/10.1136/bmjopen-2020-045969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230930PMC
June 2021

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

J Headache Pain 2021 Jun 2;22(1):50. Epub 2021 Jun 2.

Allergan, An AbbVie Company, Marlow, Buckinghamshire, UK.

Background: Chronic migraine (CM) is associated with substantial economic burden. Real-world data suggests that onabotulinumtoxinA treatment for CM reduces healthcare resource utilisation (HRU) and related costs.

Methods: REPOSE was a 2-year prospective, multicentre, non-interventional, observational study to describe the real-world use of onabotulinumtoxinA in adult patients with CM. This analysis examined the impact of onabotulinumtoxinA on HRU. Patients received onabotulinumtoxinA treatment approximately every 12 weeks according to their physicians' discretion, guided by the summary of product characteristics (SPC) and PREEMPT injection paradigm. HRU outcome measures were collected at baseline and all administration visits and included headache-related hospitalizations and healthcare professional (HCP) visits. Health economic data, including family doctor and specialist visits, inpatient treatment for headache, acupuncture, technical diagnostics, use of nonpharmacologic remedies, and work productivity were also collected for patients enrolled at German study centres.

Results: Overall, 641 patients were enrolled at 78 study centres across 7 countries (Germany, UK, Italy, Spain, Norway, Sweden, and Russia), 633 received ≥1 onabotulinumtoxinA dose, and 128 completed the 2-year study. Patients were, on average, aged 45 years, 85% were female, and 60% (n = 377) were from Germany. At the end of the 2-year observation period, significantly fewer patients reported headache-related hospitalizations (p < 0.02) and HCP visits (p < 0.001) within the past 3 months than in the 3 months before baseline. In the German population, reductions were observed across all health services at all follow-up visits compared with baseline. The percentage of patients who saw a family doctor decreased from 41.7% at baseline to 13.5% at administration visit 8 and visits to a medical specialist decreased from 61.7% to 5.2% of patients. Inpatient acute treatment and technical diagnostics declined from 6.4% and 19.7% of patients at baseline to 0.0% and 1.0% at administration 8, respectively. The use of nonpharmacologic remedies and medication for the acute treatment of migraine also decreased with continued onabotulinumtoxinA treatment. Work incapacity, disability, absenteeism, and impaired performance at school/work improved with onabotulinumtoxinA treatment for CM over the 2-year observation period.

Conclusions: Real-world evidence from REPOSE demonstrates that onabotulinumtoxinA treatment is associated with decreased HRU and supports the long-term benefits associated with the use of onabotulinumtoxinA for CM in clinical practice.

Trial Registration: NCT01686581 . Name of registry: ClinicalTrials.gov. URL of registry: Date of retrospective registration: September 18, 2012. Date of enrolment of first patient: July 23, 2012.
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http://dx.doi.org/10.1186/s10194-021-01260-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173963PMC
June 2021

The beneficial effect of positive treatment expectations on pharmacological migraine prophylaxis.

Pain 2021 May 13. Epub 2021 May 13.

Department of Neurology, Center for Translational Neuro- and Behavioural Sciences, University Medicine Essen, Essen, Germany Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro-and Behavioural Sciences, University Medicine Essen, Essen, Germany Migraine and Headache Clinic Königstein, Königstein, Germany.

Abstract: Migraine is one of the leading causes of years lived with disability and considered to be a major global health concern. Pharmacological preventive treatment often causes side effects that limit the adherence to longer-term treatment regimens. Both experimental and clinical evidence suggests that positive expectations can modulate pain and analgesic treatment effects. However, the role of expectations in migraine prophylactic treatment has not systematically been investigated. Here, we examined the influence of treatment expectation before commencing pharmacological preventive treatment on its efficacy and tolerability in N = 134 episodic (30%) and chronic migraine (70%) patients in a prospective, longitudinal observational study over the course of 6 months. The migraine prophylaxis reduced the number of headache and migraine days with acceptable tolerability. Positive treatment expectation was associated with a generally lower number of headache and migraine days and a stronger reduction in headache days over the course of the treatment in chronic but not in episodic migraine patients. Moreover, patients with prior treatment showed a stronger reduction in headache days with higher expectation as compared to patients without prior experience. Our results underscore the relevance of further exploring the role of treatment expectation and its systematic modulation in patients with migraine and other pain conditions.
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http://dx.doi.org/10.1097/j.pain.0000000000002341DOI Listing
May 2021

Effectiveness of medication in cluster headache.

BMC Neurol 2021 Apr 22;21(1):174. Epub 2021 Apr 22.

Institute of Information Systems, University of Applied Sciences Hof, Hof, Germany.

Background: The aim of this work is to analyze the reports on cluster headache attacks collected online in the citizen science project CLUE with respect to the effectiveness of drugs taken during the attacks. The collection of data within the framework of citizen science projects opens up the possibility of investigating the effectiveness of acute medication on the basis of a large number of individual attacks instead of a simple survey of patients.

Methods: Data from 8369 cluster headache attacks, containing information about acute medication taken and the assessment of its effect, were collected from 133 participants using an online platform and a smartphone app. Chi-square tests were used to investigate whether the effect of the three recommended acute drugs differs when distinguishing between participants with chronic or episodic cluster headache. Furthermore, it was investigated whether there are differences between smokers and non-smokers in the assessment of the effect of the acute medication.

Results: Our participants rated the effectiveness of sumatriptan 6 mg s.c. as significantly better than oxygen and zolmitriptan nasal spray. Oxygen is considered to be significantly better in episodic versus chronic cluster headache, and sumatriptan is considered to be significantly better in chronic versus episodic cluster headache. Smokers rate the effect of oxygen as significantly better than non-smokers.

Conclusions: Despite some methodological limitations, web-based data collection is able to support findings from clinical trials in a real world setting about effectiveness of acute cluster headache treatment in several situations.
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http://dx.doi.org/10.1186/s12883-021-02195-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061078PMC
April 2021

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Front Hum Neurosci 2020 23;14:568051. Epub 2021 Mar 23.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.
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http://dx.doi.org/10.3389/fnhum.2020.568051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040977PMC
March 2021

[Drug therapy of acute migraine attacks and prophylaxis of migraine].

MMW Fortschr Med 2021 03;163(4):38-42

Migräne- u. Kopfschmerzklinik Königstein, Königstein, Germany.

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http://dx.doi.org/10.1007/s15006-021-9606-3DOI Listing
March 2021

Status of clinical research in neurology in Germany-A national survey.

Eur J Neurol 2021 May 26;28(5):1446-1452. Epub 2021 Feb 26.

Department of Neurology with the Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

Background And Purpose: To provide an overview on the status of clinical research in neurology in Germany.

Methods: German university hospitals, nonuniversity hospitals, and neurological medical practices were surveyed regarding their clinical research activities during the period 2013 to 2017.

Results: Fifty percent of university hospitals, 10.6% of nonuniversity hospitals, and 5.2% of medical practices in Germany responded to our questionnaire. More than 80% of the clinical studies conducted have been phase III/IV and noninterventional trials (NISs), whereas <1% have been phase I and 3.5% investigator-initiated trials (IITs). University hospitals have conducted most of the phase II-IV trials. NISs have been predominantly performed by medical practices. Fifty-six percent of the university hospitals and less of the nonuniversity institutions confirmed the implementation of standard operating procedures (SOPs). In university hospitals, on average, 11 physicians had acquired a good clinical practice certificate. Overall, 43% of all trials have been performed in neuroimmunology.

Conclusions: The status of clinical research in neurology in Germany is predominated by NISs and late-phase trials, potentially due to a general lack of easily accessible funding, which leads to a highly competitive environment and fewer opportunities to perform early-phase clinical trials as well as IITs. Our results indicate that there is substantial need for structured support for creating and implementing SOPs to maintain quality standards and guarantee uniformity of performance. This survey assessed many aspects of clinical research and serves as guidance for providing ideas for structured improvement of clinical research in neurology in Germany.
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http://dx.doi.org/10.1111/ene.14763DOI Listing
May 2021

Pain localization in cluster headache patients: Onset, peak, and radiation.

Acta Neurol Scand 2021 Apr 1;143(4):441-449. Epub 2021 Feb 1.

Department of Orthopedics, Ruhr-University Bochum, Bochum, Germany.

Objective And Aim: To describe differences in pain locations for onset, peak, and radiation aspects of cluster headache (CH) attacks.

Methods And Materials: Data were collected for 23 months using a cross-sectional online survey composed of 117 questions on pain location, demographics, and clinical features. 5260 datapoints on 44 pain locations from 631 respondents were analyzed.

Results: During the onset and peak of attacks, pain is concentrated periorbitally. Pain locations outside the periorbital region were reported more frequently for radiation than for onset and peak of attacks. Dorsal (occipital, neck, shoulder) pain was reported more frequently in connection with onset and radiation than during peak: onset (13%) versus peak (6%), p < 0.001, and radiation (22%) versus peak (6%), p < 0.001. There was no significant difference in dorsal pain frequencies for onset (13%) vs. radiation (22%), p = 0.552. Furthermore, the frequency with which individual pain locations were reported differed significantly for onset, peak, and radiation in CH.

Conclusions: Analysis of the pain location data shows specific frequencies and distributions of pain location for three aspects of CH attacks. The frequency with which individual pain points were reported differed significantly for onset, peak, and radiation. In general, dorsal pain points were reported more frequently for onset and radiation than for peak pain. Pain locations beyond the eye (extraorbital points) were more frequently reported in connection with radiating pain. Our findings could serve as a basis for future research, correlating CH pain patterns with the outcome of treatment approaches.
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http://dx.doi.org/10.1111/ane.13396DOI Listing
April 2021

Prevention of migraine with monoclonal antibodies against CGRP or the CGRP receptor: Addition to the S1 guideline: Therapy of migraine attacks and prevention of migraine. Recommendations of the Germany Society of Neurology and the German Migraine and Headache Society.

Neurol Res Pract 2020 13;2:11. Epub 2020 Apr 13.

Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup Hospital, University Hospital of Copenhagen, Glostrup Hospital, Ringvejen, DK-2600 Glostrup, Denmark.

Monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor (Erenumab) or against CGRP (Eptinezumab, Fremanezumab, Galcanezumab) are new substances for the preventive treatment of migraine. They represent an extension of the therapeutic options, which already exist in migraine prevention. In randomized, placebo-controlled studies, the efficacy and good tolerability of these specific substances have been demonstrated in patients with episodic and chronic migraine. The following treatment recommendation presents a summary of the pivotal studies. Recommendations are provided for the targeted selection of patients as well as for the evaluation of therapeutic success and the duration of treatment. Finally, possible restrictions on the use of this new substance group are discussed. This guideline is an abridged and translated version of the guideline published by Diener H-C, May A et al., Prevention of migraine with monoclonal antibodies against CGRP or the CGRP receptor, Supplement to S1 Guideline Therapy of Migraine Attack and Prevention of Migraine, 2019, Deutsche Gesellschaft für Neurologie (eds.), Guidelines for Diagnostics and Therapy in Neurology. A complete version of this guideline can be found on the website of the Deutsche Gesellschaft für Neurologie (www.dgn.org/leitlinien) and the AWMF (Arbeitsgemeinschaft wissenschaftlicher Medizinischer Gesellschaften). This guideline has been approved by the German Neurological Society (DGN) and the German Migraine and Headache Society (GMHS) and was reviewed by the two societies.
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http://dx.doi.org/10.1186/s42466-020-00057-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650107PMC
April 2020

Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial.

Lancet Neurol 2021 01 24;20(1):29-37. Epub 2020 Nov 24.

Department of Neurology, University Hospital Essen, Germany.

Background: Prednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach.

Methods: This study was a multicentre, randomised, double-blind, placebo-controlled trial done in ten specialised headache centres in Germany. Patients with episodic cluster headaches who were aged between 18 and 65 years and within a current pain episode for not more than 30 days, received 100 mg oral prednisone for 5 days followed by tapering of 20 mg every 3 days, or matching placebo (17 days total exposure). All patients received oral verapamil for long-term prevention, starting with 40 mg three times daily and increasing to 120 mg three times daily by day 19; patients then continued with verapamil 120 mg throughout the study. Randomisation was computer-generated at a 1:1 ratio by use of an interactive web-response system, with stratification according to age, sex, and participating site. Participants, investigators, and those assessing outcomes were unaware of treatment allocation. The primary endpoint was the mean number of attacks within the first week of treatment with prednisone compared with placebo. An attack was defined as a unilateral headache with moderate-to-severe intensity of at least five on a numerical rating scale. All efficacy and safety analyses were done in the modified intention-to-treat (mITT) population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of prednisone or placebo. The study was stopped early due to slow recruitment and expired funding. The study was registered with EudraCT (2011-006204-13) and with the German Clinical Trials Register (DRKS00004716).

Findings: Between April 5, 2013, and Jan 11, 2018, 118 patients were enrolled in the study. Two patients dropped out immediately and 116 patients were randomly assigned (57 patients to prednisone and 59 patients to placebo); 109 patients were included in the mITT analysis (53 patients assigned to prednisone and 56 patients assigned to placebo). Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks within the first week compared with 9·5 (6·0) attacks in the placebo group (difference -2·4 attacks, 95% CI -4·8 to -0·03; p=0·002). Two serious adverse events occurred, both in the placebo group (inguinal hernia and severe deterioration of cluster headache). A total of 270 adverse events were observed: in the prednisone group, 37 (71%) of 52 patients reported 135 adverse events (most common were headache, palpitations, dizziness, and nausea) and in the placebo group, 39 (71%) of 55 patients had 135 adverse events (most common were nausea, dizziness, and headache).

Interpretation: Oral prednisone was an effective short-term preventive therapy in our population of patients with episodic cluster headache. Our findings support the use of prednisone as a first-line treatment in parallel to the up-titration of verapamil, although the efficacy of prednisone alongside other long-term prevention requires additional investigation.

Funding: German Federal Ministry for Education and Research.
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http://dx.doi.org/10.1016/S1474-4422(20)30363-XDOI Listing
January 2021

Treatment Outcomes in Patients Treated With Galcanezumab vs Placebo: Post Hoc Analyses From a Phase 3 Randomized Study in Patients With Episodic Cluster Headache.

Headache 2020 Nov 11;60(10):2254-2264. Epub 2020 Nov 11.

Eli Lilly and Company, Indianapolis, IN, USA.

Background: Cluster headache (CH) is a highly disabling primary headache disorder. To date, characterization of outcomes in the preventive treatment of episodic CH, including precise definitions of clinically meaningful attack frequency reduction and impact on acute treatment management, is lacking.

Methods: This was a Phase 3, randomized, double-blind, placebo-controlled study in patients (men or women aged 18-65 years) diagnosed with episodic CH as defined by the International Classification of Headache Disorders-3 beta criteria. In this post hoc analysis, we evaluated the median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attack frequency, and impact on acute medication use. An anchor-based assessment of clinically relevant attack frequency reduction using the Patient Global Impression of Improvement (PGI-I) scores at Week 4 was also assessed.

Results: The median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attacks was consistently shorter (9-10 days sooner) with galcanezumab vs placebo (median [95% confidence interval, 95% CI]: ≥50%, 5 days [4.0 to 7.0] vs 14 days [6.0 to 19.0]; ≥75%, 11 days [7.0 to 16.0] vs 21 days [13.0 to 26.0]; 100%, 22 days [16.0 to 37.0] vs 32 days [23.0 to 34.0]). Mean reduction from baseline in the overall frequency of weekly pooled acute medication use across Weeks 1-3 was significantly greater with galcanezumab vs placebo (11.0 vs 5.5; odds ratio, OR [95% CI]: 5.52 [1.02, 10.01]; P value = .017). Patients reporting "much better" on the PGI-I experienced a median weekly CH attack reduction of approximately 43% from baseline across Weeks 1-3. The overall odds of achieving an attack reduction threshold of 43% across Weeks 1-3 was significantly higher with galcanezumab vs placebo (Weeks 1-3: OR [95% CI], 2.60 [1.3 to 5.3]).

Conclusions: Faster median time-to-first occurrence of response rates, lower frequency of pooled acute medications use, and a greater proportion of patients achieving a response anchored by patient-reported improvement were observed for galcanezumab vs placebo.
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http://dx.doi.org/10.1111/head.14011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756634PMC
November 2020

[Cluster headaches-proven and novel approaches : A critical evaluation of treatment studies].

Authors:
Charly Gaul

Schmerz 2020 Dec 6;34(6):511-516. Epub 2020 Nov 6.

Migräne- und Kopfschmerzklinik Königstein, Ölmühlweg 31, 61462, Königstein im Taunus, Deutschland.

Trigeminal autonomic cephalalgias are characterized by unilateral headaches accompanied by cranial autonomic symptoms and a sense of restlessness. Clinical trials have been conducted on acute therapy and prophylaxis of cluster headache in recent years. Since the other trigeminal autonomic cephalalgias are rare, it is virtually impossible to conduct controlled clinical trials for their investigation. Recent trials provide data on the efficacy of prednisolone, galcanezumab, fremanzeumab and noninvasive vagal nerve stimulation. Methodological difficulties arise in terms of patient recruitment for clinical trials, clinical endpoints and potential differences in the pathophysiology of episodic and chronic cluster headache.
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http://dx.doi.org/10.1007/s00482-020-00512-7DOI Listing
December 2020

Types of Triggers in Migraine - Factor Structure of the Headache Triggers Sensitivity and Avoidance Questionnaire and Development of a New Short Form (HTSAQ-SF).

Headache 2020 Oct 11;60(9):1920-1929. Epub 2020 Jul 11.

Department of Psychology, Johannes Gutenberg-University of Mainz, Mainz, Germany.

Objective: To examine the factor structure of the Headache Triggers Sensitivity and Avoidance Questionnaire (HTSAQ) and its German version (HTSAQ-G), in order to identify potential different types of triggers. Furthermore, a short form of the questionnaire was developed.

Background: The HTSAQ includes 24 of the most commonly reported headache triggers (eg, stress, odors, lack of sleep). Both the HTSAQ and HTSAQ-G appeared to be reliable and valid measures of sensitivity to and avoidance of headache triggers.

Methods: In a cross-country collaboration, data from 2 cross-sectional studies including N = 391 individuals diagnosed with migraine from Australia (n = 222) and Germany (n = 169) were analyzed. The factor structure of the questionnaire was examined using exploratory and confirmatory factor analysis. Finally, a short form of the HTSAQ was constructed and evaluated regarding psychometric properties.

Results: Factor analytic results showed a differentiation between internal and external headache triggers, and different patterns of strategies in coping with triggers. The scales of both the original questionnaire as well as the developed short form showed good reliability (Cronbach's α = 0.76 to 0.96). As expected, negative correlations (r = -0.10 to -0.30, P = .006 to .044) with acceptance of pain were observed. Participants with chronic migraine showed significantly higher triggers sensitivity and avoidance of triggers than those with episodic migraine (t(389) = -9.12, P < .001, Cohens d = 0.93).

Conclusions: Both the long and short forms of the questionnaire appear to be reliable and valid measures. The development of the short form of the questionnaire simplifies the use of the HTSAQ in clinical practice. Further research should focus on other primary headache disorders, such as tension-type headache or cluster headache.
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http://dx.doi.org/10.1111/head.13896DOI Listing
October 2020

Triptan efficacy does not predict onabotulinumtoxinA efficacy but improves with onabotulinumtoxinA response in chronic migraine patients.

Sci Rep 2020 07 9;10(1):11382. Epub 2020 Jul 9.

Department of Neurology, Klinikum Großhadern, Ludwig Maximilians University Munich, Marchioninistr. 15, 81377, Munich, Germany.

Chronic migraine (CM) is a highly disabling primary headache. Botulinum toxin (onabotulinumtoxinA) is effective for treatment of CM, with ~ 50% of patients responding after 24 weeks. A response predictor would prevent unnecessary treatments. Inhibiting calcitonin gene related peptide (CGRP) release from trigeminal nociceptive fibres is one of the modes of acting discussed for onabotulinumtoxinA in CM. Therefore, we hypothesized that the response to triptans might predict response to onabotulinumtoxinA. Contrariwise, onabotulinumtoxinA treatment might affect triptan efficacy. 49 CM patients scheduled for their first onabotulinumtoxinA treatment were included. Before (T0) and three months after (T1) onabotulinumtoxinA treatment, patients rated triptan efficacy and indicated number of headache days/month. At T1, patients additionally rated onabotulinumtoxinA efficacy. Headache days/month were on average reduced by 7.1 ± 7.0 days from T0 to T1 (p < 0.001). Triptan efficacy ratings at T0 did not predict onabotulinumtoxinA efficacy ratings at T1 (p = 0.19) or reduction of headache days (p = 0.37). However, triptan efficacy significantly improved from T0 to T1 in onabotulinumtoxinA responders (p < 0.001) but not in non-responders (p = 1.00). Triptan efficacy did not predict response to onabotulinumtoxinA in CM. However, triptan efficacy increased after successful onabotulinumtoxinA treatment. This supports the hypothesis that efficacy of acute migraine treatment with triptans improves with effective migraine prophylaxis.
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http://dx.doi.org/10.1038/s41598-020-68149-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347633PMC
July 2020

Determination of psychosocial factors in cluster headache - construction and psychometric properties of the Cluster Headache Scales (CHS).

Cephalalgia 2020 10 2;40(11):1240-1249. Epub 2020 Jun 2.

Migraine and Headache Clinic Königstein, Königstein, Germany.

Background: Cluster headache (CH) is clinically associated with considerable psychosocial burden. However, instruments to assess and characterize psychosocial factors in cluster headache more specifically are lacking. This study aimed to develop a self-report questionnaire, which assesses the broadest possible spectrum of psychosocial factors in cluster headache, the Cluster Headache Scales (CHS).

Method: Items of the Cluster Headache Scales were constructed based on a literature review and semi-structured interviews with several experts (including persons with cluster headache). A cross-sectional online survey was conducted to determine the psychometric properties and the factor structure of the Cluster Headache Scales. Data was analyzed using exploratory factor analysis as well as exploratory structural equation modelling (ESEM).

Results: In total, n = 342 subjects with cluster headache (mean age 47.8, 63% male, 51% with episodic cluster headache) were included. Factor analysis yielded eight clearly interpretable factors: Medical care, medication side effects, fear of attacks, disability, (auto)aggression, coping, physical activity, and financial burden, which are assessed via 36 items. The internal consistencies of the subscales were acceptable to excellent and ranged between Cronbach's alpha = .76 and .93. The pattern of correlations with related instruments provides first evidence for convergent validity.

Conclusion: The CHS represents a reliable and valid self-report instrument for the assessment of psychosocial factors in persons with cluster headache, which appears useful for both clinical practice as well as research. The study was registered at the German Clinical Trials Register (www.drks.de, ID-Number: DRKS00016502).
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http://dx.doi.org/10.1177/0333102420928076DOI Listing
October 2020

Use of outpatient medical care by headache patients in Germany: a population-based cross-sectional study.

J Headache Pain 2020 May 11;21(1):49. Epub 2020 May 11.

Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany.

Background: Headache sufferers in need of professional health care often do not utilize the care available, and factors influencing headache-specific physician consultation are not yet understood. Objectives of this study are (1) to assess self-reported headache-specific physician consultations and (2) to identify headache-related and sociodemographic predictors.

Methods: Data of a random sample of the general population in Germany aged ≥14 years were analyzed (N = 2461). A multivariate binary logistic regression was conducted to identify a parsimonious model to predict physician consultation.

Results: 50.7% of the participants with headache reported at least one headache-specific physician consultation during lifetime. Of these, 53.6% had seen one, 26.1% two, and 20.3% more than two physicians because of their headaches. The odds of physician consultation increased with the number of headache days per month (HDM) [(reference HDM < 1) HDM 1-3 (OR = 2.29), HDM 4-14 (OR = 2.41), and HDM ≥15 (OR = 4.83)] and increasing Headache Impact Test score (HIT-6) [(reference "no or little impact") moderate impact (OR = 1.74), substantial impact (OR = 3.01), and severe impact (OR = 5.08)]. Middle-aged participants were more likely to have consulted than younger and older ones [(reference 14-34 years) 35-54 years (OR = 1.90), 55-74 years (OR = 1.96), ≥75 years (OR = 1.02)]. The odds of physician consultation among self-employed subjects were lower than among employed manual workers (OR = 0.48). The living environment (rural versus urban) did not have an influence on the consultation frequency.

Conclusion: The results indicate that apart from burden-related factors (headache frequency; headache impact), health care utilization patterns are also influenced by patients' occupational status and age. Further research is needed to analyze whether the lower consultation rate means that the self-employed have a higher risk of chronification or that they have more effective self-management strategies regarding headache.
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http://dx.doi.org/10.1186/s10194-020-01099-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212612PMC
May 2020

Peripheral nerve stimulation registry for intractable migraine headache (RELIEF): a real-life perspective on the utility of occipital nerve stimulation for chronic migraine.

Acta Neurochir (Wien) 2020 12 6;162(12):3201-3211. Epub 2020 May 6.

Migraine and Headache Clinic, Königstein Klinik, Königstein, Germany.

Background: Migraine is common and ranked as the first cause of disability in people under fifty. Despite significant advances in its pharmacological treatment, it often remains intractable. Neuromodulation is one option considered in the management of those patients.

Objective: To assess the safety and efficacy of neuromodulation in the treatment of intractable chronic migraine using the Abbott occipital nerve stimulator.

Methods: Recruitment took place in 18 centres in 6 countries. Patients over the age of 18 who had failed three or more preventative drugs, had at least moderate disability based on MIDAS or HIT-6 score and were implanted with an Abbott neurostimulator were included in the study. Patients were followed up for a maximum of 24 months. Data were collected on adverse events, headache relief, headache days, quality of life, migraine disability, satisfaction and quality of life.

Results: One hundred twelve patients were included, 79 female and 33 male, with 45 patients reaching the maximum follow-up of 24 months. At 3 months, 33.7% were satisfied or very satisfied with the procedure with 43.0% reporting improved or greatly improved quality of life. 67.5% indicated that they would undergo the procedure again with satisfaction peaking at 9 months when 49.3% were satisfied or very satisfied with the procedure. At 24 months, 46.7% of available patients were satisfied or very satisfied with the procedure-18% of enrolled patients. The adverse events were however frequent with incidences of 37%, 47% and 31% respectively for hardware-, biological and stimulation-related side effects.

Conclusion: Neuromodulation can be beneficial for selected patients with intractable chronic migraine although frequent complications have been consistently reported across studies. Further research focusing on development of better hardware and technique optimisation and in particular reliable randomised trials with significantly longer follow-ups are warranted in this field.
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http://dx.doi.org/10.1007/s00701-020-04372-zDOI Listing
December 2020

Do doctors treat themselves differently than their patients? Study on the self-treatment of migraine among German neurologists and pain specialists.

Cephalalgia 2020 07 17;40(8):788-796. Epub 2020 Feb 17.

Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital of Schleswig-Holstein, Germany.

Aim: To investigate whether the self-treatment of migraine among neurologists and pain specialists corresponds to national medical guidelines and treatment of patients.

Methods: An email cross-sectional survey was sent to members of the German Society for Neurology, German Pain Society and German Migraine and Headache Society containing questions on demographics, professional experience and specialization and - in case participants suffered from migraine - questions about their migraine and its treatment.

Results: 175/418 (41.9%) participants suffered from migraine (m: 29.3%; f: 55.2%, 45.9 ± 10.7 years). For acute migraine attacks, 96.6 % of them use a first-line treatment according to the medical guidelines. Seventeen (9.7%) are currently taking a migraine prophylaxis, 52.9% of these use a recommended first-line prophylaxis. In all, 21.7% are not taking a prophylactic treatment despite an indication (based on number of monthly migraine days) for it, due to fear of side-effects, low intensity of migraine attacks and a sufficient effect of acute medication. This group of participants was younger, less experienced and specialized and was mainly employed (vs. self-employed) compared to those taking a prophylaxis. A total of 96.6% reported treating their patients in line with current guidelines; 14.3% would treat themselves differently when they were their own patients.

Conclusion: The self-treatment of acute migraine attacks for the most part complies with the guidelines but, regarding the indication for a prophylaxis, a more divergent treatment approach was observed among younger, less experienced physicians. For the majority of physicians there is no difference between self-treatment and treatment of migraine patients.
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http://dx.doi.org/10.1177/0333102420907593DOI Listing
July 2020

More Attacks and Analgesic Use in Old Age: Self-Reported Headache Across the Lifespan in a German Sample.

Front Neurol 2019 17;10:1000. Epub 2019 Oct 17.

Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany.

Reliable population-based data on the prevalence and characteristics of primary headache across the lifespan are essential. However, robust data are lacking. We utilized questionnaire data from a random general population sample in Germany, that comprised 2,478 participants aged ≥14 years. A standardized questionnaire addressing headache and headache treatment was filled in during the face-to-face survey. The 6-month prevalence of self-reported headache in the total sample amounted to 39.0% (known diagnosis of migraine 7.2%; tension-type headache 12.4%; another diagnosis or unknown diagnosis 23.4%). Age-specific prevalence rates were 37.9% (14-34 years), 44.6% (35-54 years), 38.5% (55-74 years), and 26.9% (≥75 years). Compared to age group 14-34, participants aged 35-54 were more ( = 1.29, 95%- 1.05-1.60, = 0.018) and those aged ≥75 were less ( = 0.55, 95%- 0.40-0.76, < 0.001) likely to have any headache. Of the participants with headache, 79.5% reported headache on <4 days per month, 15.6% on 4-14 days per month and 4.9% on >14 days per month. The frequency of headache did not differ significantly between age groups in men [ = 1.45, > 0.05], but in women [ = 21.57, < 0.001]: women aged ≥75 years were over-represented in the group reporting 4-14 headache days per month. The analgesic use (days per month) differed significantly between age groups among participants with headache on <4 days per month and on >14 days per month: 1.8 (14-34 years), 2.5 (35-54 years), 3.2 (55-74 years), and 3.4 (≥75 years), respectively 7.9 (14-34 years), 11.4 (35-54 years), 18.4 (55-74 years), and 22.8 (≥75 years). In general, the prevalence of headache decreases with age. However, older women suffer from more frequent attacks and older participants take analgesics on more days per month than younger participants. This might put them at risk of medication overuse which may lead to medication overuse headache. More research is needed to understand these specifics in headache frequency and treatment behavior in older people.
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http://dx.doi.org/10.3389/fneur.2019.01000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843053PMC
October 2019

The relation between emotion regulation and migraine: A cross-cultural study on the moderating effect of culture.

Cephalalgia 2020 04 5;40(4):384-392. Epub 2019 Nov 5.

Migraine and Headache Clinic Königstein, Königstein im Taunus, Germany.

Background: Effects of emotion suppression on physical health might be contingent on culture. Existing research on emotion regulation has mainly included western participants. Herewith the question arises, whether this gained expertise is transferable to an Asian culture.

Objectives: This cross-sectional study evaluated to what extent the regulation of emotions is related to migraine and if the relation between emotion regulation and migraine complaints differs between a Western and an Asian population. Therefore, the main characteristics and symptoms of patients with migraine from both Germany and Japan are compared.

Methods: 261 Japanese and 347 German headache patients participated in this online study and completed self-report measures of emotion regulation (suppression and reappraisal) and headache complaints.

Results: Cultural groups did not differ regarding their demographic data, intake of medication and number of days with headache. German participants showed significantly higher levels of anxiety and lower levels of emotion suppression compared to Japanese patients. Emotion regulation is not correlated with headache complaints either in the Japanese or in the German patient group.

Conclusion: Although group differences were found with respect to anxiety and emotion suppression, subsequent regression analysis revealed these differences were unrelated to headache complaints. As our baseline analysis focused on group means, approaches that examine individual reaction patterns to stress and accompanying sensory stimulus processing may prove to be more fruitful and illuminating.
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http://dx.doi.org/10.1177/0333102419885394DOI Listing
April 2020

Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial.

Cephalalgia 2019 Oct 15;39(12):1475-1487. Epub 2019 Sep 15.

Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data.

Methods: This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6-8 hours apart).

Results: Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) ( = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53;  = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common.

Conclusions: Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The "sham" device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844.
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http://dx.doi.org/10.1177/0333102419876920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791025PMC
October 2019

Differential efficacy of non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A meta-analysis.

Cephalalgia 2019 Jul 10;39(8):967-977. Epub 2019 Jun 10.

2 NIHR-Wellcome Trust King's Clinical Research Facility, King's College London, UK.

Background: Two randomized, double-blind, sham-controlled trials (ACT1, ACT2) evaluated non-invasive vagus nerve stimulation (nVNS) as acute treatment for cluster headache. We analyzed pooled ACT1/ACT2 data to increase statistical power and gain insight into the differential efficacy of nVNS in episodic and chronic cluster headache.

Methods: Data extracted from ACT1 and ACT2 were pooled using a fixed-effects model. Main outcome measures were the primary endpoints of each study. This was the proportion of participants whose first treated attack improved from moderate (2), severe (3), or very severe (4) pain intensity to mild (1) or nil (0) for ACT1 and the proportion of treated attacks whose pain intensity improved from 2-4 to 0 for ACT2.

Results: The pooled population included 225 participants (episodic: n = 112; chronic: n = 113) from ACT1 (n = 133) and ACT2 (n = 92) in the nVNS (n = 108) and sham (n = 117) groups. Interaction was shown between treatment group and cluster headache subtype ( < 0.05). nVNS was superior to sham in episodic but not chronic cluster headache (both endpoints  < 0.01). Only four patients discontinued the studies due to adverse events.

Conclusions: nVNS is a well-tolerated and effective acute treatment for episodic cluster headache.

Trial Registration: The studies were registered at clinicaltrials.gov (ACT1: NCT01792817; ACT2: NCT01958125).
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http://dx.doi.org/10.1177/0333102419856607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637721PMC
July 2019

Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine.

Brain 2019 07;142(7):1894-1904

Migraine and Headache Clinic, Koenigstein im Taunus, Germany.

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.
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http://dx.doi.org/10.1093/brain/awz134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620826PMC
July 2019

An Integrative Cognitive Behavioral Therapy Program for Adults With Migraine: A Feasibility Study.

Headache 2019 05 10;59(5):741-755. Epub 2019 Apr 10.

Department of Psychology, University of Mainz, Mainz, Germany.

Objective: To present a novel cognitive behavioral therapy program that was developed exclusively for adults with migraine, and to assess the feasibility of this program.

Background: Unlike previous efforts, we combined different approaches of behavioral therapy into one program: relaxation therapy, cognitive behavioral therapy, trigger management.

Methods: The treatment program consists of 7 sessions (including psychoeducation, lifestyle counseling, coping with fear of attacks, trigger management, and stress management). The research was conducted in a single-group study with N = 9 completers (age: M = 41.6, SD = 17.6 years; N = 8 female, N = 1 male; N = 5 migraine without aura, N = 2 migraine with aura, N = 2 chronic migraine). After each of the group therapy sessions, evaluation questionnaires were filled out, and individual qualitative interviews were conducted after completion of the program.

Results: The treatment program was very well accepted. Every session was rated as comprehensible, and overall satisfaction with the sessions was high. Participants greatly appreciated having access to a specific treatment, exclusively addressing migraine.

Conclusions: The idea of combining several approaches of behavioral therapy into a specific treatment program for migraine seems to be feasible and promising. A randomized controlled trial to determine the efficacy of our program is currently running.
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http://dx.doi.org/10.1111/head.13532DOI Listing
May 2019

[Headache - an Update 2018].

Laryngorhinootologie 2019 Mar 7;98(3):192-217. Epub 2019 Mar 7.

Epidemiological studies have shown a clear correlation between migraine and vascular disease in more and more patients. Pathophysiological studies show the relevance of the hypothalamus in the generation of migraine attacks. Glutamate seems to play an important role here. New contrast-enhanced MRI studies support the assumption that the blood-brain barrier remains intact during migraine attacks. The selection of a triptan still remains unique. Neurostimulation has also been included in the acute treatment of migraine. Monoclonal humanized antibodies against CGRP (calcitonin gene-related peptides) and a fully human antibody against the CGRP receptor are effective in the prophylaxis of both episodic and chronic migraine. Tricyclic antidepressants showed efficacy in tension-type headache and is superior compared to SSRIs (selective serotonin reuptake inhibitors). Electronic diaries can reduce the risk of relapse after a medication break in the event of overuse of headache medication. In patients with episodic cluster headache, successful transient therapy with transcutaneous stimulation of the vagus nerve may be required. In trigeminal neuralgia, a significant comorbidity with depression and anxiety disorders was found.
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http://dx.doi.org/10.1055/a-0823-4814DOI Listing
March 2019

An open-label prospective study of the real-life use of onabotulinumtoxinA for the treatment of chronic migraine: the REPOSE study.

J Headache Pain 2019 Mar 7;20(1):26. Epub 2019 Mar 7.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Background: The PREEMPT Studies established onabotulinumtoxinA as preventive treatment for adults with chronic migraine (CM). The purpose of the REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilisation, and Patient-reported OutcomeS observed in practice (REPOSE) Study was to observe real-life, long-term (24-month) use of onabotulinumtoxinA in adults with CM and report on the utilisation, effectiveness, safety, and tolerability.

Methods: The REPOSE Study was a European, open-label, multicentre, prospective, noninterventional study. Patients received onabotulinumtoxinA approximately every 12 weeks according to their physician's usual practice, guided by the summary of product characteristics (SPC). Patients were observed for 24 months after initiating onabotulinumtoxinA treatment. Outcome measures were collected at baseline and all administration visits and included onabotulinumtoxinA injection practices, headache-day frequency, Migraine-Specific Quality-of-Life Questionnaire (MSQ), EuroQol 5-Dimension Questionnaire (EQ-5D), and adverse drug reactions (ADRs) to evaluate safety/tolerability.

Results: Of 641 patients enrolled, 633 received ≥1 dose of onabotulinumtoxinA for a total of 3499 treatment sessions. At baseline, mean (SD) age was 45.4 (11.7) years; patients were predominantly women (85.3%). Injection practices closely followed the SPC in mean dosage (155.1 U) and injection sites per session (31.4), with the exception of a prolongation of the recommended 12-week dosing interval, with 79.1% of patients receiving ≥1 treatment session that was > 13 weeks after the previous treatment session. Headache-day frequency was reduced from a baseline mean (SD) of 20.6 (5.4) to 7.4 (6.6) days at administration visit 8 (P < 0.001). Each MSQ domain (restrictive, preventive, and emotional) was significantly reduced from baseline through each administration visit (P < 0.001). The median EQ-5D total and health state scores were significantly improved from baseline through each administration visit (P < 0.001). Overall, 18.3% of patients reported an ADR; most were mild to moderate intensity, with only 1.3% of patients reporting a serious ADR. Eyelid ptosis (5.4%), neck pain (2.8%), and musculoskeletal stiffness (2.7%) were the most frequently reported.

Conclusions: Long-term, real-world preventive treatment of CM with onabotulinumtoxinA showed effectiveness with a sustained reduction in headache-day frequency and significant improvement in quality-of-life measures. ADRs were mild to moderate, with no new safety concerns identified.

Trial Registration: Trial registration number: NCT01686581. Name of registry: ClinicalTrials.gov. URL of registry: https://clinicaltrials.gov/ct2/show/NCT01686581 . Date of retrospective registration: September 18, 2012. Date of enrolment of first patient: July 23, 2012.
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http://dx.doi.org/10.1186/s10194-019-0976-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734221PMC
March 2019

Topical Ambroxol 20% for the Treatment of Classical Trigeminal Neuralgia - A New Option? Initial Clinical Case Observations.

Headache 2019 03 17;59(3):418-429. Epub 2019 Jan 17.

Migraine and Headache Clinic, Königstein, Germany.

Background: Trigeminal neuralgia is difficult to treat and shows upregulation of sodium channels. The expectorant ambroxol acts as a strong local anesthetic, about 40 times stronger than lidocaine. It preferentially inhibits the channel subtype Na 1.8, expressed especially in nociceptive C-fibers. It seemed reasonable to try ambroxol for the treatment with neuropathic facial pain unresponsive to other standard options.

Material And Methods: Medical records of patients suffering from classical trigeminal neuralgia (n = 5) and successful pain reduction following topical ambroxol 20% cream in addition to standard treatment are reported.

Results: All patients reported pain attacks with pain intensity between 4 and 10 NRS (numeric pain scale). In all cases they could be triggered, 3 patients reported additional spontaneous pain. Attacks were reduced in all 5 patients. Pain reduction achieved following ambroxol 20% cream was 2-8 points (NRS) earliest within 15-30 minutes and lasted for 4-6 hours mostly. This was reproducible in all cases; in one case pain was eliminated after 1 week. No patient reported side effects or skin changes; oral medication was reduced in 2 patients.

Conclusion: For the first time, a clinically significant pain relief following topical ambroxol 20% cream in patients with trigeminal neuralgia is reported. In view of the positive side effect profile, topical ambroxol for patients with such a highly impaired quality of life should be investigated further as a matter of urgency.
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http://dx.doi.org/10.1111/head.13475DOI Listing
March 2019

Distribution of migraine attacks over the days of the week: Preliminary results from a web-based questionnaire.

Acta Neurol Scand 2019 Apr 28;139(4):340-345. Epub 2019 Jan 28.

Institute of Information Systems, University of Applied Sciences Hof, Hof, Germany.

Objectives: The purpose of this work is the analysis of migraine attack reports collected online within the project Migraine Radar in respect to the distribution of the migraine attacks over the week on a single-participant level.

Materials & Methods: Recording data using a web app as well as smartphone apps made it possible to collect data of 44 639 migraine attacks of 1085 participants who reported seven or more attacks over a participation period of at least 90 days. This allows the investigation of attack distributions on a single-participant level. Considering the day of the week with the highest attack frequency for each participant-the mode of the individual distribution-allows identifying participants suffering from weekend migraines. Namely, a weekend pattern is assumed if the mode falls on a Saturday or Sunday.

Results: For 15.9% of the participants, the attacks were not distributed equally (P < 0.05) over the days of the week. Instead, participants show different individual patterns for the distribution of their migraine attacks. Furthermore, the modes of the individual distributions are not distributed equally over the week. In fact, Saturday seems to be the predominant day for migraine attacks for a greater proportion of participants (195 of 1085).

Conclusions: Concerning the individual attack distributions, we found that participants show individual attack patterns and weekend migraine can be determined for a subgroup of participants, while other participants show accumulations of their attacks on other days of the week.
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http://dx.doi.org/10.1111/ane.13065DOI Listing
April 2019

Chronic Headache Due to Overuse of Analgesics and Anti-Migraine Agents.

Dtsch Arztebl Int 2018 06;115(22):365-370

Department of Neurology and West German Headache Center, Essen; Department of Neurology and West German Headache Center, Essen; Department of Psychiatry and Psychotherapy, University Hospital and Faculty of Medicine, Tübingen; LEAD Graduate School & Research Network, University of Tübingen; Migraine and Headache Clinic Königstein.

Background: The frequent or regular use of analgesics and anti-migraine drugs can make headache more frequent and induce the transformation of episodic to chronic headache. Chronic headache due to medication overuse is defined as headache that is present on ≥ 15 days per month for at least three months in a patient who previously suffered from primary headaches, and who takes analgesics on ≥ 15 days per month or anti-migraine drugs (triptans or ergot alkaloids), opioid drugs, or combined analgesics on ≥ 10 days per month.

Methods: This review is based on pertinent articles published up to December 2017 that were retrieved by a selective search in PubMed employing the terms "medication overuse AND headache" and "medication overuse headache."

Results: The prevalence of medication overuse headache in the general population in Germany is 0.7% -1%. This disorder is more common in women and in persons suffering from comorbid mental disorders or other painful conditions. The treatment of medication overuse headache consists of three steps. Patient education and counseling are given with the goal of reducing the intake of medication for acute headache treatment. The ensuing headache prophylaxis is with topiramate, amitriptyline, or onabotulinum toxin A. If these treatment strategies fail, a drug holiday is recommended. This can be in the outpatient, day clinic, or inpatient setting, depending on the severity of the condition and its comorbidities.

Conclusion: Patients who frequently take acute medication to treat headache episodes must be identified early in order to avoid headache chronification and medication overuse headache. The suggested treatment algorithm is still in need of validation by randomized trials.
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http://dx.doi.org/10.3238/arztebl.2018.0365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039717PMC
June 2018
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