Publications by authors named "Lars Bendtsen"

80 Publications

Reply: The role of neurovascular contact in patients with multiple sclerosis.

Cephalalgia 2021 Jul 13:3331024211027358. Epub 2021 Jul 13.

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

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http://dx.doi.org/10.1177/03331024211027358DOI Listing
July 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

Health-related quality of life in tension-type headache: a population-based study.

Scand J Pain 2021 Jan 22. Epub 2021 Jan 22.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.

Objectives: Tension-type headache (TTH) is the most prevalent primary headache disorder. We assessed the cross-sectional impact of TTH on health related quality of life (HRQoL) in a general population. We also examined the association of HRQoL scores with headache frequency, disability, medication overuse, poor self-rated health, psychiatric comorbidity, and pain sensitivity in individuals with TTH.

Methods: A sample of 547 subjects completed a headache diagnostic interview, the SF-12 to calculate physical (PCS) and mental (MCS) health component scores, depression (major depression inventory [MDI]) and neuroticism (Eysenck Personality Questionnaire) measures. We defined the following headache diagnosis categories: pure TTH, pure migraine, and coexistent headache (TTH + migraine). Cases were further classified into chronic (≥15) or episodic (<15 headache days/month).

Results: Using generalized linear models (GLM) adjusted for age, sex and education, both PCS-12 and MCS-12 scores varied in groups distinguished by migraine and TTH status; scores were lower for individuals with coexistent headache (TTH + migraine; n=83), followed by pure TTH (n=97) and pure migraine (n=43) compared to the no headache group (n=324) (p≤0.001). In analyses considering chronicity, PCS-12 scores were lower in chronic coexistent headache followed by pure chronic TTH (CTTH), episodic migraine +/- episodic TTH (ETTH) and pure ETTH than in the no headache group (p≤0.001). MCS-12 scores were lower in pure CTTH, followed by chronic coexistent headache, episodic migraine +/- ETTH and pure ETTH compared to the no headache group (p≤0.001). Multiple regression models showed that in TTH, lower PCS-12 scores were associated with age (p=0.04), female sex (p=0.02), and poor self-rated health (p≤0.001). Lower MCS-12 scores in TTH were associated with depression (p≤0.001).

Conclusions: In a population sample, TTH, and to higher degree CTTH, are associated with decreased HRQoL.
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http://dx.doi.org/10.1515/sjpain-2020-0166DOI Listing
January 2021

Calcitonin gene related peptide in migraine: current therapeutics, future implications and potential off-target effects.

J Neurol Neurosurg Psychiatry 2021 Jan 25. Epub 2021 Jan 25.

Neurology, Alfred Health, Melbourne, Victoria, Australia.

Migraine is the second largest cause of years lost to disability globally among all diseases, with a worldwide prevalence over 1 billion. Despite the global burden of migraine, few classes of therapeutics have been specifically developed to combat migraine. After 30 years of translational research, calcitonin gene-related peptide (CGRP) inhibitors have emerged as a promising new tool in the prevention of migraine. Like all new therapeutics; however, we have limited real-world experience and CGRP has several known systemic actions that warrant consideration. This article provides a narrative review of the evidence for CGRP antagonists and summarises the known and potential side effects that should be considered.
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http://dx.doi.org/10.1136/jnnp-2020-324674DOI Listing
January 2021

Dependence-like behaviour in patients treated for medication overuse headache: A prospective open-label randomized controlled trial.

Eur J Pain 2021 04 7;25(4):852-861. Epub 2021 Jan 7.

Danish Headache Centre, Rigshospitalet, Glostrup, Denmark.

Background: Dependence-like behaviour may complicate withdrawal and increase risk of relapse of medication overuse headache (MOH). The most effective treatment for reducing dependence-like behaviour is unknown.

Objectives: To compare patient-reported outcomes among three treatment strategies for MOH. The primary outcome was change in Severity of Dependence Scale (SDS) score from baseline to 6 months.

Methods: Patients with MOH were randomized to (1) withdrawal combined with preventive medication from start (W+P), (2) preventive medication without withdrawal (P), or (3) withdrawal with optional preventive medication 2 months after withdrawal (W). At baseline, 2, and 6 months, patients filled out SDS (used for measurements of dependence-like behaviour and treatment feasibility), Headache Under-Response of Treatment (HURT) and WHO Quality of Life BREF questionnaires.

Results: Out of 120 patients with MOH, 100 completed the 6-month follow-up and filled out questionnaires. The W+P arm was the most effective in treating MOH. After 6 months, the SDS score was reduced by 3.69 (95% CI 3.23-4.49) in the W+P arm, by 3.19 (95% CI 2.43-3.96) in the W arm, and by 1.65 (95% CI 0.96-2.33) in the P arm (p = 0.04). At baseline and after 2 months, the P arm was considered the most feasible treatment, but at 6-month follow-up, there was no difference in feasibility score, change in HURT score, or quality of life.

Conclusions: Dependence-like behaviour was reduced most in the two withdrawal arms. Withdrawal combined with preventive medication is recommended for the treatment of MOH.

Significance: Withdrawal combined with preventive medication from start is the treatment strategy that reduces dependence-like behaviour the most in MOH patients. Patients initially considered preventive treatment without withdrawal as the most feasible treatment. However, no difference in feasibility between the three arms was found at 6-month follow-up. Withdrawal combined with preventive medication is recommended for treatment of MOH.
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http://dx.doi.org/10.1002/ejp.1715DOI Listing
April 2021

Neurovascular contact plays no role in trigeminal neuralgia secondary to multiple sclerosis.

Cephalalgia 2021 Apr 28;41(5):593-603. Epub 2020 Nov 28.

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

Introduction: A demyelinating plaque and neurovascular contact with morphological changes have both been suggested to contribute to the etiology of trigeminal neuralgia secondary to multiple sclerosis (TN-MS). The aim of this study was to confirm or refute whether neurovascular contact with morphological changes is involved in the etiology of TN-MS.

Methods: We prospectively enrolled consecutive TN-MS patients from the Danish Headache Center. Clinical characteristics were collected systematically. MRI scans were done using a 3.0 Tesla imager and were evaluated by the same experienced blinded neuroradiologist.

Results: Sixty-three patients were included. Fifty-four patients were included in the MRI analysis. There was a low prevalence of neurovascular contact with morphological changes on both the symptomatic side (6 (14%)) and the asymptomatic side (4 (9%)),  = 0.157. Demyelinating brainstem plaques along the trigeminal afferents were more prevalent on the symptomatic side compared to the asymptomatic side (31 (58%) vs. 12 (22%),  < 0.001). A demyelinating plaque was highly associated with the symptomatic side (odds ratio = 10.6,  = 0.002).

Conclusion: The primary cause of TN-MS is demyelination along the intrapontine trigeminal afferents. As opposed to classical trigeminal neuralgia, neurovascular contact does not play a role in the etiology of TN-MS. Microvascular decompression should generally not be offered to patients with TN-MS.The study was registered at ClinicalTrials.gov (number NCT04371575).
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http://dx.doi.org/10.1177/0333102420974356DOI Listing
April 2021

Evidence of localized and widespread pressure pain hypersensitivity in patients with tension-type headache: A systematic review and meta-analysis.

Cephalalgia 2021 02 22;41(2):256-273. Epub 2020 Sep 22.

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

Objective: This meta-analysis evaluates pressure pain sensitivity values in symptomatic and distant pain-free areas comparing individuals with tension-type headache to controls.

Databases And Data Treatment: Electronic databases were searched for cross-sectional or prospective case-control studies comparing pressure pain thresholds in patients with tension-type headache to headache-free controls. Data were extracted by three reviewers. The methodological quality was assessed by the Newcastle-Ottawa Quality Assessment Scale. Meta-analyses of trigeminal, extra-trigeminal (neck) and distant pain-free areas in tension-type headache were compared to headache-free controls. Frequency of tension-type headache and gender were taken into account.

Results: Twenty studies were included. Patients with tension-type headache exhibited lower pressure pain thresholds than headache-free controls: Trigeminal (MD -49.11 kPa, 95% CI -66.05 to -32.17), cervical spine (MD -88.17 kPa, 95% CI -108.43 to -67.92) and distant pain-free areas (MD -98.43 kPa, 95% CI -136.78 to -60.09). Differences were significant for chronic, episodic, and mixed episodic and chronic tension-type headache within the trigeminal and neck (symptomatic areas), but only significant for chronic tension-type headache (MD -102.86, 95% CI -139.47 to -66.25 kPa) for distant pain-free areas. In general, women had lower pressure pain thresholds than men. The methodological quality ranged from fair (45%) to good (40%). The results showed a high heterogeneity and publication bias.

Conclusion: This first meta-analysis addressing pressure pain thresholds differences in symptomatic and distant pain-free areas between patients with tension-type headache and controls found low to moderate evidence supporting the presence of pressure pain hypersensitivity in the trigeminal and neck areas in tension-type headache in comparison with headache-free controls. Sensitivity to pressure pain was widespread only in chronic, not episodic, tension-type headache (moderate evidence). https://doi.org/10.17605/OSF.IO/R29HY.
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http://dx.doi.org/10.1177/0333102420958384DOI Listing
February 2021

Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia.

Lancet Neurol 2020 09;19(9):784-796

Department of Neurology, Danish Headache Center, Rigshospitalet, Glostrup, Denmark.

Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted.
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http://dx.doi.org/10.1016/S1474-4422(20)30233-7DOI Listing
September 2020

Comparison of 3 Treatment Strategies for Medication Overuse Headache: A Randomized Clinical Trial.

JAMA Neurol 2020 09;77(9):1069-1078

Danish Headache Center, Rigshospitalet, Glostrup, Denmark.

Importance: Medication overuse headache (MOH) is a disabling, globally prevalent disorder representing a well-known and debated clinical problem. Evidence for the most effective treatment strategy is needed.

Objective: To compare 3 treatment strategies for MOH.

Design, Setting, And Participants: This open-label, randomized clinical trial with 6 months of follow-up was conducted in the tertiary sector at the Danish Headache Center, Glostrup, from October 25, 2016, to June 28, 2019. Of 483 patients with MOH referred during the inclusion period, 195 met the criteria consisting of migraine and/or tension-type headache, 18 years or older, eligibility for outpatient treatment, no severe physical or psychiatric disorder, no other addiction, and not pregnant or breastfeeding. Of these, 75 refused participation and 120 were included. Data were analyzed from July 3 to September 6, 2019.

Interventions: Random assignment (1:1:1 allocation) to 1 of the 3 outpatient treatments consisting of (1) withdrawal plus preventive treatment, (2) preventive treatment without withdrawal, or (3) withdrawal with optional preventive treatment 2 months after withdrawal.

Main Outcomes And Measures: The primary outcome was change in headache days per month after 6 months. Predefined secondary outcomes were change in monthly migraine days, use of short-term medication, pain intensity, number of responders, patients with remission to episodic headache, and cured MOH.

Results: Of 120 patients, 102 (mean [SD] age, 43.9 [11.8] years; 81 women [79.4%]) completed the 6-month follow-up. Headache days per month were reduced by 12.3 (95% CI, 9.3-15.3) in the withdrawal plus preventive group, by 9.9 (95% CI, 7.2-12.6) in the preventive group, and by 8.5 (95% CI, 5.6-11.5) in the withdrawal group (P = .20). No difference was found in reduction of migraine days per month, use of short-term medication, or headache intensity. In the withdrawal plus preventive group, 23 of 31 patients (74.2%) reverted to episodic headache, compared with 21 of 35 (60.0%) in the preventive group and 15 of 36 (41.7%) in the withdrawal group (P = .03). Moreover, 30 of 31 patients (96.8%) in the withdrawal plus preventive group were cured of MOH, compared with 26 of 35 (74.3%) in the preventive group and 32 of 36 (88.9%) in the withdrawal group (P = .03). These findings corresponded to a 30% (relative risk, 1.3; 95% CI, 1.1-1.6) increased chance of MOH cure in the withdrawal plus preventive group compared with the preventive group (P = .03).

Conclusion And Relevance: All 3 treatment strategies were effective, but based on these findings, withdrawal therapy combined with preventive medication from the start of withdrawal is recommended as treatment for MOH.

Trial Registration: ClinicalTrials.gov Identifier: NCT02993289.
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http://dx.doi.org/10.1001/jamaneurol.2020.1179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251504PMC
September 2020

Correction to: European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention.

J Headache Pain 2019 May 23;20(1):58. Epub 2019 May 23.

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

AbstractFollowing publication of the original article [1], the authors notified us of some misreported data due to the publication of the EVOLVE-2 trial (Cephalalgia. 2018;38:1442-1454), which substantially changed the level of evidence of galcanezumab for the prevention of episodic migraine. All changes are marked in bold and with red in Figure 1 and Figure 2. Please note that the final recommendations remain unchanged.
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http://dx.doi.org/10.1186/s10194-019-0972-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734242PMC
May 2019

Favourable prognosis of trigeminal neuralgia when enrolled in a multidisciplinary management program - a two-year prospective real-life study.

J Headache Pain 2019 Mar 4;20(1):23. Epub 2019 Mar 4.

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

Background: Prognosis of medically treated trigeminal neuralgia patients is assumed to be poor, but the evidence is lacking. Thus, prospective real-life studies of medical management of trigeminal neuralgia are warranted.

Methods: This was an observational study. Patients were consecutively enrolled in a structured management program at a specialist centre for facial pain. Optimisation of medical treatment, physiotherapy, psychotherapy, and advice from trained nurses, were parts of the program. Medically intractable patients were referred for neurosurgery. Data-collection was prospective using standardised schemes and patient surveys. The aim was to describe the two-year outcome of medical treatment at the specialist centre. The primary outcome was a 50% reduction in the overall burden of pain according to a Numerical Rating Scale (NRS) after two years.

Results: A total of 186 primary TN patients were enrolled in the program of which 103 patients remained medically managed and completed the two-year follow-up. Fifty patients were treated surgically within the first two years of follow-up. Half of the medically managed patients (53 (51%)), had more than a 50% reduction in the overall burden of pain over the two-year period. The overall burden of pain on NRS decreased from mean 5.34 to 3.00, p < 0.01. There was no significant association between primary outcome and sex, depression and/or anxiety, concomitant persistent pain, or neurovascular contact with morphological changes of the trigeminal nerve.

Conclusions: Patients with trigeminal neuralgia improve over a two-year period when enrolled in a structured medical management program. Optimisation of drug treatment, continuous advice and education and support by the multidisciplinary team, referral of the medically intractable patients for surgery or the natural history of the disease, can be some of the reasons for the improvement. The favourable prognosis provides hope and optimism for medically managed TN patients.

Trial Registration: Current study was observational, and patients were offered standard clinical care and laboratory workups according to current American Academy of Neurology and European Federation of Neurological Societies treatment guidelines. The study has been registered at ClincalTrials.gov. ID: NCT03838393 .
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http://dx.doi.org/10.1186/s10194-019-0973-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734423PMC
March 2019

Complete withdrawal is the most feasible treatment for medication-overuse headache: A randomized controlled open-label trial.

Eur J Pain 2019 07 15;23(6):1162-1170. Epub 2019 Mar 15.

Danish Headache Center, Rigshospitalet Glostrup, Copenhagen, Denmark.

Background: Complete stop of acute medication and/or migraine medication for treatment of medication-overuse headache (MOH) has previously been reported more effective in reducing headache days and migraine days per month compared with restricted intake of acute medication. However, it is unknown whether complete stop or restricted intake is the most feasible treatment for patients.

Objectives: To investigate whether feasibility of withdrawal in MOH is different between complete stop of acute medication and restricted intake, and whether reductions in headache-related medication dependence, anxiety and depression differ between the treatments.

Methods: Medication-overuse headache patients were included in a prospective, open-label, outpatient study and randomized to two months of withdrawal with either no analgesics or acute migraine medication (programme A) or acute medication restricted to 2 days/week (programme B). After 6 and 12 months, patients graded feasibility of withdrawal. Dependence was measured by Severity of Dependence Scale (SDS), while anxiety and depression were measured by Hospital Anxiety and Depression Scale (HADS).

Results: We included 72 MOH patients with primary migraine and/or tension-type headache. Forty-nine completed withdrawal and the SDS questionnaire at 12-month follow-up, and the feasibility of withdrawal was significantly higher in programme A compared to programme B (p < 0.001). At 12 months, the dependence was reduced by 44% in programme A compared to 26% in programme B (p = 0.053), while the anxiety score was reduced by 32% and 11%, respectively (p = 0.048).

Conclusions: Withdrawal with complete stop of acute medication was more feasible and most effective in reducing headache-related anxiety compared with restricted intake.

Significance: A complete stop of all analgesics is the most effective treatment for MOH regarding reduction in headache days but has often been regarded as too challenging for patients. However, in this study, complete stop appears to be more feasible compared with restricted intake of analgesics seen from the patients' perspective.
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http://dx.doi.org/10.1002/ejp.1383DOI Listing
July 2019

Complete withdrawal is the most effective approach to reduce disability in patients with medication-overuse headache: A randomized controlled open-label trial.

Cephalalgia 2019 06 7;39(7):863-872. Epub 2019 Feb 7.

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

Background: Medication-overuse headache leads to high disability and decreased quality of life, and the best approach for withdrawal has been debated.

Aim: To compare change in disability and quality of life between two withdrawal programs.

Methods: We randomized medication-overuse headache patients to program A (two months without acute analgesics or migraine medications) or program B (two months with acute medications restricted to two days/week) in a prospective, outpatient study. At 6 and 12 months, we measured disability and headache burden by the Headache Under-Response to Treatment index (HURT). We estimated quality of life by EUROHIS-QOL 8-item at 2-, 6-, and 12-month follow-up. Primary endpoint was disability change at 12 months.

Results: We included 72 medication-overuse headache patients with primary migraine and/or tension-type headache. Fifty nine completed withdrawal and 54 completed 12-month follow-up. At 12-month follow-up, 41 patients completed HURT and 38 completed EUROHIS-QOL 8-item. Disability reduction was 25% in program-A and 7% in program-B ( p = 0.027). Headache-burden reduction was 33% in program-A and 3% in program-B ( p = 0.005). Quality of life was increased by 8% in both programs without significant difference between the programs ( p = 0.30). At 2-month follow-up, quality of life increased significantly more in program-A than program-B ( p = 0.006).

Conclusion: Both withdrawal programs reduced disability and increased quality of life. Withdrawal without acute medication was the most effective in reducing disability in medication-overuse headache patients.

Trial Registration: Clinicaltrials.gov (NCT02903329).
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http://dx.doi.org/10.1177/0333102419828994DOI Listing
June 2019

European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention.

J Headache Pain 2019 Jan 16;20(1). Epub 2019 Jan 16.

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

Background And Aim: Monoclonal antibodies acting on the calcitonin gene-related peptide or on its receptor are new drugs to prevent migraine. Four monoclonal antibodies have been developed: one targeting the calcitonin gene-related peptide receptor (erenumab) and three targeting the calcitonin gene-related peptide (eptinezumab, fremanezumab, and galcanezumab). The aim of this document by the European Headache Federation (EHF) is to provide an evidence-based and expert-based guideline on the use of the monoclonal antibodies acting on the calcitonin gene-related peptide for migraine prevention.

Methods: The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed systematic review and analysis of the literature, assessed the quality of available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided.

Results: We found low to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in patients with episodic migraine and medium to high quality of evidence to recommend erenumab, fremanezumab, and galcanezumab in patients with chronic migraine. For several clinical questions, there was not enough evidence to provide recommendations using the GRADE approach and recommendations relied on experts' opinion.

Conclusion: Monoclonal antibodies acting on the calcitonin gene-related peptide are new drugs which can be recommended for migraine prevention. Real life data will be useful to improve the use of those drugs in clinical practice.
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http://dx.doi.org/10.1186/s10194-018-0955-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734227PMC
January 2019

Challenges recruiting to a proof-of-concept pharmaceutical trial for a rare disease: the trigeminal neuralgia experience.

Trials 2018 Dec 27;19(1):704. Epub 2018 Dec 27.

Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.

Background: This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia.

Methods: This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics.

Results: Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change.

Conclusions: Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges.

Trial Registration: ClinicalTrials.gov, NCT01540630 . EudraCT, 2010-023963-16. 07 Aug 2015.
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http://dx.doi.org/10.1186/s13063-018-3045-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307274PMC
December 2018

Circulating nociceptin and CGRP in medication-overuse headache.

Acta Neurol Scand 2019 Mar 11;139(3):269-275. Epub 2018 Dec 11.

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

Background: Previous studies found low serum levels of nociceptin in migraine patients but high serum levels of calcitonin gene-related peptide (CGRP). CGRP can elicit migraine-like headache. Medication-Overuse Headache (MOH) often has migraine features and can mimic chronic migraine. We therefore hypothesized that as in migraine, serum levels of nociceptin would be lower and CGRP serum levels higher in MOH patients compared with those in healthy volunteers. We hypothesized that the serum levels would normalize after detoxification.

Methods: Seventeen MOH patients, hereof 70.6% with chronic migraine and MOH, and 30 sex and age matched headache-free controls were included. MOH patients underwent a 2-month outpatient detoxification program and after 6 months, 10 patients and 19 controls were retested. Blood samples were analyzed blinded.

Results: We found no differences in the levels of nociceptin and CGRP between MOH patients and controls (P = 0.65 and P = 0.59). The mean headache frequency reduction was 43% and 70% of patients reverted to episodic headache after 6 months, but the levels of nociceptin and CGRP were unchanged (P = 0.71 and P = 0.82).

Conclusion: In contrast to previous findings in migraine patients, we found normal serum levels of nociceptin and CGRP in MOH patients. Thus, we find no evidence that the increased headache frequency of MOH patients could be caused by altered nociceptin and CGRP levels. This underlines the importance of identifying medication overuse in chronic headache and treating the MOH.
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http://dx.doi.org/10.1111/ane.13053DOI Listing
March 2019

Guideline on the use of onabotulinumtoxinA in chronic migraine: a consensus statement from the European Headache Federation.

J Headache Pain 2018 Sep 26;19(1):91. Epub 2018 Sep 26.

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

OnabotulinumtoxinA is being increasingly used in the management of chronic migraine (CM). Treatment with onabotulinumtoxinA poses challenges compared with traditional therapy with orally administered preventatives. The European Headache Federation identified an expert group that was asked to develop the present guideline to provide recommendations for the use of onabotulinumtoxinA in CM. The expert group recommend onabotulinumtoxinA as an effective and well-tolerated treatment of CM. Patients should preferably have tried two to three other migraine prophylactics before start of onabotulinumtoxinA. Patients with medication overuse should be withdrawn from the overused medication before initiation of onabotulinumtoxinA if feasible, if not onabotulinumtoxinA can be initiated from the start or before withdrawal. OnabotulinumtoxinA should be administered according to the PREEMPT injection protocol, i.e. injecting 155 U-195 U to 31-39 sites every 12-weeks. We recommend that patients are defined as non-responders, if they have less than 30% reduction in headache days per month during treatment with onabotulinumtoxinA. However other factors such as headache intensity, disability and patient preferences should also be considered when evaluating response. Treatment should be stopped, if the patient does not respond to the first two to three treatment cycles. Response to continued treatment with onabotulinumtoxinA should be evaluated by comparing the 4 weeks before with the 4 weeks after each treatment cycle. It is recommended that treatment is stopped in patients with a reduction to less than 10 headache days per month for 3 months and that patients are re-evaluated 4-5 months after stopping onabotulinumtoxinA to make sure that the patient has not returned to CM. Questions regarding efficacy and tolerability of onabotulinumtoxinA could be answered on the basis of scientific evidence. The other recommendations were mainly based on expert opinion. Future research on the treatment of CM with onabotulinumtoxinA may further improve the management of this highly disabling disorder.
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http://dx.doi.org/10.1186/s10194-018-0921-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755553PMC
September 2018

Economic benefits of treating medication-overuse headache - results from the multicenter COMOESTAS project.

Cephalalgia 2019 02 8;39(2):274-285. Epub 2018 Jul 8.

7 Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Background: Medication-overuse headache is a costly disease for individuals and society.

Objective: To estimate the impact of medication-overuse headache treatment on direct and indirect headache-related health care costs.

Methods: This prospective longitudinal study was part of the COMOESTAS project (COntinuous MOnitoring of Medication Overuse Headache in Europe and Latin America: development and STAndardization of an Alert and decision support System). Patients with medication-overuse headache were included from four European and two Latin American headache centers. Costs of acute medication, costs of health care services, and measurements of productivity were calculated at baseline and at 6-month follow-up Treatment consisted of overused drug withdrawal with optional preventive medication.

Results: A total of 475 patients (71%) completed treatment and were followed up for 6 months. Direct health care costs were on average reduced significantly by 52% ( p < 0.001) for the total study population. Significant reductions were seen in both number of consumed tablets (-71%, p < 0.001) and number of visits to physicians (-43%, p < 0.001). Fifty percent of patients reduced their number of consumed tablets ≥ 80%. Headache-related productivity loss, calculated either as absence from work or ≥ 50% reduction of productivity during the workday, were reduced by 21% and 34%, respectively ( p < 0.001).

Conclusion: Standardized treatment of medication-overuse headache in six countries significantly reduced direct health care costs and increased productivity. This emphasizes the importance of increasing awareness of the value of treating medication-overuse headache.

Trial Registration: The trial was registered at ClinicalTrials.gov (no. NCT02435056).
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http://dx.doi.org/10.1177/0333102418786265DOI Listing
February 2019

Psychological, clinical, and therapeutic predictors of the outcome of detoxification in a large clinical population of medication-overuse headache: A six-month follow-up of the COMOESTAS Project.

Cephalalgia 2019 01 27;39(1):135-147. Epub 2018 Jun 27.

1 Headache Science Centre, IRCCS Mondino Foundation, Pavia, Italy.

Aim: To identify factors that may be predictors of the outcome of a detoxification treatment in medication-overuse headache.

Methods: Consecutive patients entering a detoxification program in six centres in Europe and Latin America were evaluated and followed up for 6 months. We evaluated anxious and depressive symptomatology (though patients with severe psychiatric comorbidity were excluded), quality of life, headache-related disability, headache characteristics, and prophylaxis upon discharge.

Results: Of the 492 patients who completed the six-month follow up, 407 ceased overuse following the detoxification (non overusers), another 23 ceased overuse following detoxification but relapsed during the follow-up. In the 407 non-overusers, headache acquired an episodic pattern in 287 subjects (responders). At the multivariate analyses, lower depression scores (odds ratio = 0.891; p = 0.001) predicted ceasing overuse. The primary headache diagnosis - migraine with respect to tension-type headache (odds ratio = 0.224; p = 0.001) or migraine plus tension-type headache (odds ratio = 0.467; p = 0.002) - and the preventive treatment with flunarizine (compared to no such treatment) (odds ratio = 0.891; p = 0.001) predicted being a responder. A longer duration of chronic headache (odds ratio = 1.053; p = 0.032) predicted relapse into overuse. Quality of life and disability were not associated with any of the outcomes.

Conclusions: Though exploratory in nature, these findings point to specific factors that are associated with a positive outcome of medication-overuse headache management, while identifying others that may be associated with a negative outcome. Evaluation of the presence/absence of these factors may help to optimize the management of this challenging groups of chronic headache sufferers.
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http://dx.doi.org/10.1177/0333102418783317DOI Listing
January 2019

Prognostic factors for outcome of microvascular decompression in trigeminal neuralgia: A prospective systematic study using independent assessors.

Cephalalgia 2019 02 13;39(2):197-208. Epub 2018 Jun 13.

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

Introduction: There is a lack of high-quality prospective, systematic studies using independent assessors of outcome of microvascular decompression as treatment for trigeminal neuralgia.

Methods: Clinical characteristics and outcome data were recorded prospectively from consecutive classical trigeminal neuralgia patients, using standardized interviews. Degree of neurovascular contact was evaluated by a 3.0 Tesla MRI blinded to symptomatic side. Patients were assessed before and 12 months after surgery by a neurologist.

Results: Twenty-six men and 33 women completed 12 months follow-up. Forty-one patients (69%) had an excellent outcome (no pain, no medication). Ten (18%) patients had a good outcome. Eight (12%) patients had no improvement or had worsening of pain. MRI showed neurovascular contact with morphological changes in 34 patients (58%). Odds ratio between neurovascular contact with morphological changes and excellent outcome was 4.4 (Cl 1.16-16.26), p = 0.029. Odds ratio between male sex and excellent outcome was 11.38 (Cl 2.12-59.52), p = 0.004. No significant association was found between excellent outcome and concomitant persistent pain, current age or disease duration.

Conclusion: Neurovascular contact with morphological changes and male sex are positive predictive factors for outcome of microvascular decompression. The findings enable clinicians to better inform patients before surgery.
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http://dx.doi.org/10.1177/0333102418783294DOI Listing
February 2019

Complete detoxification is the most effective treatment of medication-overuse headache: A randomized controlled open-label trial.

Cephalalgia 2018 02 19;38(2):225-236. Epub 2017 Oct 19.

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

Background There is lack of evidence on how to detoxify medication-overuse headache. Aim To compare the effect of complete stop of acute medication with restricted intake. Methods Medication-overuse headache patients were included in a prospective, outpatient study and randomized to two months' detoxification with either a) no analgesics or acute migraine-medication (program A), or b) acute medication restricted to two days/week (program B). Detoxification was followed by preventives if indicated. Patients were followed up at 2, 6 and 12 months. Percentage reduction in headache days/month after 6 months was the primary outcome. Results We included 72 medication-overuse headache patients with a primary migraine and/or tension-type headache diagnosis. Fifty-nine completed detoxification, 58 (81%) were followed up at month 6 and 53 (74%) at month 12. At month 6, program A reduced headache days/month by 46% (95% CI 34-58) compared with 22% (95% CI 11-34) in program-B ( p = 0.005), and 70% in program A versus 42% in program B were reverted to episodic headache ( p = 0.04). Migraine-days/month were reduced by 7.2 in program A ( p < 0.001) and 3.6 in program B ( p = 0.002) after 6 months. Conclusion Both detoxification programs were very effective. Detoxification without analgesics or acute migraine-medication was the most effective program. Trial registration Clinicaltrials.gov (NCT02903329).
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http://dx.doi.org/10.1177/0333102417737779DOI Listing
February 2018

Reply.

Pain 2017 06;158(6):1177

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

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http://dx.doi.org/10.1097/j.pain.0000000000000868DOI Listing
June 2017

Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial.

Lancet Neurol 2017 Apr 17;16(4):291-300. Epub 2017 Feb 17.

Convergence Pharmaceuticals, Cambridge, UK.

Background: Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study.

Methods: We did a double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a trial in 25 secondary care centres in Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK. After a 7-day run-in phase, eligible patients aged 18-80 years with confirmed trigeminal neuralgia received open-label, BIIB074 150 mg three times per day, orally, for 21 days. Patients who met at least one response criteria were then randomly assigned (1:1) to BIIB074 or placebo for up to 28 days in a double-blind phase. We used an interactive web response system to assign patients with a computer-generated schedule, with stratification (presence or absence of existing pain medication). Patients, clinicians, and assessors were masked to treatment allocation. The primary endpoint was the difference between groups in the number of patients classified as treatment failure during the double blind phase assessed in the modified intention-to-treat population. We assessed safety in all patients who received one or more doses of BIIB074. This study is registered with ClinicalTrials.gov (NCT01540630) and EudraCT (2010-023963-16).

Findings: The first patient was enrolled on April 23, 2012, and the last patient completed the study on February 26, 2014. We enrolled 67 patients into the open-label phase; 44 completed open-label treatment, and 29 were randomly assigned to double-blind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures (p=0·0974). BIIB074 was well tolerated, with similar adverse events in the double-blind phase to placebo. Headache was the most common adverse event with BIIB074 in the open-label phase (in 13 [19%] of 67 patients), followed by dizziness (in six [9%] patients). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074 (in one [7%] of 15 patients for each event), and headache, dizziness, diarrhoea, and vomiting were the most frequent adverse events in patients assigned to placebo (in one [7%] of 14 patients for each event). No severe or serious adverse events were reported in the BIIB074 group during the double-blind phase. One patient assigned to placebo reported intestinal adhesions with obstruction as a severe and serious adverse event, which was considered as unrelated to study medication.

Interpretation: The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials.

Funding: Convergence Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(17)30005-4DOI Listing
April 2017

Trigeminal neuralgia - diagnosis and treatment.

Cephalalgia 2017 Jun 11;37(7):648-657. Epub 2017 Jan 11.

2 Department of Neurology and Psychiatry, Sapienza University, Rome, Italy.

Introduction Trigeminal neuralgia (TN) is characterized by touch-evoked unilateral brief shock-like paroxysmal pain in one or more divisions of the trigeminal nerve. In addition to the paroxysmal pain, some patients also have continuous pain. TN is divided into classical TN (CTN) and secondary TN (STN). Etiology and pathophysiology Demyelination of primary sensory trigeminal afferents in the root entry zone is the predominant pathophysiological mechanism. Most likely, demyelination paves the way for generation of ectopic impulses and ephaptic crosstalk. In a significant proportion of the patients, the demyelination is caused by a neurovascular conflict with morphological changes such as compression of the trigeminal root. However, there are also other unknown etiological factors, as only half of the CTN patients have morphological changes. STN is caused by multiple sclerosis or a space-occupying lesion affecting the trigeminal nerve. Differential diagnosis and treatment Important differential diagnoses include trigeminal autonomic cephalalgias, posttraumatic or postherpetic pain and other facial pains. First line treatment is prophylactic medication with sodium channel blockers, and second line treatment is neurosurgical intervention. Future perspectives Future studies should focus on genetics, unexplored etiological factors, sensory function, the neurosurgical outcome and complications, combination and neuromodulation treatment as well as development of new drugs with better tolerability.
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http://dx.doi.org/10.1177/0333102416687280DOI Listing
June 2017

Persistent idiopathic facial pain - a prospective systematic study of clinical characteristics and neuroanatomical findings at 3.0 Tesla MRI.

Cephalalgia 2017 Nov 27;37(13):1231-1240. Epub 2016 Oct 27.

1 Danish Headache Center, Department of Neurology, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Nordre Ringvej 67, 2600 Glostrup, Denmark.

Introduction Persistent idiopathic facial pain (PIFP) is a poorly understood chronic orofacial pain disorder and a differential diagnosis to trigeminal neuralgia. To address the lack of systematic studies in PIFP we here report clinical characteristics and neuroimaging findings in PIFP. Methods Data collection was prospective and standardized in consecutive PIFP patients. All patients underwent 3.0 MRI. Results In a cohort of 53 PIFP patients, the average age of onset was 44.1 years. PIFP was found in more women 40 (75%) than men 13 (25%), p < 0.001. There was a high prevalence of bilateral pain 7 (13%), hypoesthesia 23 (48%), depression 16 (30%) and other chronic pain conditions 17 (32%) and a low prevalence of stabbing pain 21 (40%), touch-evoked pain 14 (26%) and remission periods 10 (19%). The odds ratio between neurovascular contact and the painful side was 1.4 (95% Cl 0.4-4.4, p = 0.565) and the odds ratio between neurovascular contact with displacement of the trigeminal nerve and the painful side was 0.2 (95% Cl 0.0-2.1, p = 0.195). Conclusion PIFP is separated from trigeminal neuralgia both with respect to the clinical characteristics and neuroimaging findings, as NVC was not associated to PIFP.
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http://dx.doi.org/10.1177/0333102416675618DOI Listing
November 2017

[Clinical presentation and treatment of medication-overuse headache].

Ugeskr Laeger 2016 Sep;178(39)

Medication-overuse headache (MOH) is a disabling, costly and often overlooked disorder. The prevalence in Denmark is 1.8% equivalent to 80.000-100.000 adults. The aim is to increase awareness of clinical presentation and treatment options for patients with MOH when encountered in primary care setting, exemplified by three representative cases. Clinical presentation of MOH and three treatment approaches are discussed. MOH is a chronic disorder which is preventable and treatable.
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September 2016

Medication-overuse headache: a perspective review.

Ther Adv Drug Saf 2016 Aug 30;7(4):147-58. Epub 2016 Jun 30.

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

Medication-overuse headache (MOH) is a debilitating condition in which frequent and prolonged use of medication for the acute treatment of pain results in the worsening of the headache. The purpose of this paper is to review the most recent literature on MOH and discuss future avenues for research. MOH accounts for a substantial share of the global burden of disease. Prevalence is often reported as 1-2% but can be as high as 7% overall, with higher proportions among women and in those with a low socioeconomic position. Management consists of withdrawing pain medication, focusing on prophylactic and nonmedical treatments, and limiting acute symptomatic medication. Stress reduction and lifestyle interventions may support the change towards rational pain medication use. Support, follow up, and education are needed to help patients through the detoxification period. There is fertile ground for research in MOH epidemiology, pathophysiology, and neuroimaging. Randomized and long-term follow-up studies on MOH treatment protocols are needed. Further focused research could be of major importance for global health.
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http://dx.doi.org/10.1177/2042098616653390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959634PMC
August 2016

Lifelong contribution to headache science: A tribute to Professor Jes Olesen.

Cephalalgia 2017 12 27;37(2_suppl). Epub 2016 Jul 27.

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/10.1177/0333102416662582DOI Listing
December 2017

[Diagnostics and treatment of trigeminal neuralgia].

Ugeskr Laeger 2016 Jul;178(29)

Trigeminal neuralgia (TN) is characterized by unilateral evoked short-lasting intense pain paroxysms in the face. A concomitant persistent background pain is frequently present. Neurovascular contact causing displacement or atrophy of the trigeminal nerve is important to TN aetiology. TN can also be secondary to a space-occupying lesion or multiple sclerosis. Early high-quality magnetic resonance imaging is mandatory as a part of the work-up. First-choice treatment is medical. Medically refractory patients are referred to neurosurgery. Nationwide in Denmark, there is a need for structured and uniform treatment of TN.
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July 2016

Medication overuse headache in Europe and Latin America: general demographic and clinical characteristics, referral pathways and national distribution of painkillers in a descriptive, multinational, multicenter study.

J Headache Pain 2015 8;17:20. Epub 2016 Mar 8.

Danish Headache Center, Neurological Department, Glostrup Hospital, Glostrup, Denmark.

Background: Medication overuse headache (MOH) is a very disabling and costly disorder due to indirect costs, medication and healthcare utilization. The aim of the study was to describe general demographic and clinical characteristics of MOH, along with the national referral pathways and national painkillers distribution in several European and Latin American (LA) Countries.

Methods: This descriptive cross-sectional observational study included 669 patients with MOH referred to headache-centers in Europe and LA as a part of the COMOESTAS project. Information about acute medication and healthcare utilization were collected by extensive questionnaires, supplemented with structured patient interviews.

Results: Triptans were overused by 31 % European patients and by 6 % in LA (p < 0.001), whereas ergotamines were overused by 4 % in Europe and 72 % in LA (p < 0.001). Simple analgesics were overused by 54 % in Europe and by 33 % in LA (p < 0.001), while combination-analgesics were more equally overused (24 % in Europe and 29 % in LA). More European patients (57 %) compared with LA patients (27 %) visited general practitioners (p < 0.001), and 83 % of European patients compared to 38 % in LA consulted headache specialists (p < 0.001). A total of 20 % in Europe and 30 % in LA visited emergency rooms (p = 0.007).

Conclusion: There are marked variations between LA and Europe in healthcare pathways and in acute medication overuse regarding patients with MOH. This should be considered when planning prevention campaigns against MOH.
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http://dx.doi.org/10.1186/s10194-016-0612-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783306PMC
September 2016