DNA-methylation and immunological response in medication overuse headache.

OBJECTIVE: To investigate whether medication-overuse headache patients have differential DNA-methylation pattern. METHODS: We collected blood samples from 120 medication-overuse headache-patients, 57 controls (29 episodic migraine patients and 28 healthy controls) in a hypothesis-generating cross-sectional case-control pilot study; 100 of the medication-overuse headache-patients were followed for six months and samples were collected at two and six months for the longitudinal methylation analyses. Blood cell proportions of leucocytes (neutrophils, NK-cells, monocytes, CD8+ and CD4+ T-cells, and B-cells) and the neutrophile-lymphocyte ratio were estimated using methylation data as a measure for immunological analysis and a cell type-specific epigenome wide association study was conducted between medication-overuse headache-patients and controls, and longitudinally for reduction in headache days/month among medication-overuse headache-patients. RESULTS: We found a higher neutrophile-lymphocyte ratio in medication-overuse headache-patients compared to controls, indicating a higher immunological response in medication-overuse headache-patients (false discovery rate (adjusted p-value)<0.001). Reduction in headache days/month (9.8; 95% CI 8.1-11.5) was associated with lower neutrophile-lymphocyte ratio (false discovery rate adjusted p-value = 0.041).Three genes (CORIN, CCKBR and CLDN9) were hypermethylated in specific cell types in medication-overuse headache-patients compared to controls. No methylation differences were associated with reduction in headache days in medication-overuse headache-patients after six months. CONCLUSION: This pilot study was consistent with higher immunological response in medication-overuse headache-patients which decreased with a reduction in headache days in longitudinal analysis. medication-overuse headache-patients exhibited differential methylation in innate immune cells but did not exhibit longitudinal differences with alterations in headache days. Our study creates hypotheses for further biomarker searches.ClinicalTrials.gov Identifier: NCT02993289.

Fundus imaging and perimetry in patients with idiopathic intracranial hypertension-an intermethod and interrater validity study.

BACKGROUND AND PURPOSE: There is a need to improve the diagnostic process of patients suspected of papilledema. In patients with known or suspected idiopathic intracranial hypertension a fundus imaging and perimetric visual field assessment system (COMPASS) performed at a headache center was validated in comparison to an assessment (Topcon plus OCTOPUS) at a neuroophthalmological clinic. METHODS: For intermethod assessment, blinded fundus images and perimetry from COMPASS versus Topcon plus OCTOPUS were assessed by a neuroophthalmologist. For interrater assessment, fundus images and perimetry obtained by the COMPASS system were assessed by an untrained medical doctor, a trained neurologist and a trained medical student and compared to the neuroophthalmologist's assessments. RESULTS: For the intermethod variation of the presence of papilledema on fundus images, a kappa value of 0.60, sensitivity of 87% and specificity of 73% were found. The interrater variation of the presence of papilledema on fundus images showed kappa values ranging from 0.43 to 0.74, sensitivity values ranging from 70% to 96% and specificity values ranging from 46% to 93% when comparing the assessments made by the headache center staff with neuroophthalmologist's assessments. The COMPASS showed a 59% sensitivity and moderate agreement in detecting visual field defects compared with OCTOPUS. The visual field assessment showed only slight to fair agreement from 0.19 to 0.31 between assessments made by the headache center staff and the neuroophthalmologist. CONCLUSION: The COMPASS system can be used with reasonable sensitivity in the assessment of papilledema in patients suspected of idiopathic intracranial hypertension at a tertiary headache center.

Treatment experiences and clinical characteristics in migraine and tension-type headache patients before the first visit to a tertiary headache center.

OBJECTIVES: To investigate previous treatment and clinical characteristics in migraine and tension-type headache patients at their first visit to a tertiary headache center. METHODS: This was a cross-sectional study using data obtained from electronic questionnaires and medical charts. Migraine and tension-type headache patients were investigated at their first visit to the Danish Headache Center. RESULTS: Out of 382 patients the main diagnoses of primary headaches were: 36% with episodic migraine, 43% with chronic migraine, 3% with episodic tension-type headache and 17% with chronic tension-type headache. The majority had attempted non-pharmacological treatment options such as physiotherapy (episodic migraine: 53%, chronic migraine: 68%, episodic tension-type headache: 50%, chronic tension-type headache: 65%) and acupuncture: (episodic migraine: 45%, chronic migraine: 62%, episodic tension-type headache: 17%, chronic tension-type headache: 51%). The majority of migraine patients had tried no more than one triptan (episodic migraine: 71%, chronic migraine: 66%). In total, 35% of episodic migraine and 19% of chronic migraine patients as well as 50% of episodic tension-type headache and 41% of chronic tension-type headache patients had never tried preventive medication. The headache under-response to treatment (HURT) questionnaire score was higher in chronic migraine (score 15) and chronic tension-type headache (score 16) patients than the episodic forms (P < 0.004). CONCLUSIONS: Headache patients had attempted several non-pharmacological treatments prior to their first visit at a tertiary headache center in Denmark. The limited use of acute and preventive treatment before the first visit demonstrates a need for better treatment at the primary and secondary care level.

Manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education in migraine treatment. A systematic review and meta-analysis.

BACKGROUND: Many people suffering from migraine combine pharmacological and non-pharmacological treatments. The purpose of this systematic review is to provide an updated guideline for some widely used non-pharmacological treatment options for migraine. METHODS: We conducted a systematic literature review of randomized studies of adults with migraine treated with manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education. The main outcomes measured were days with headache and quality of life. Recommendations were formulated based on the Grade of Recommendation, Assessment, Development and Evaluation (GRADE) approach including patient preferences based on expert opinion and questionnaire data. RESULTS: The overall level of certainty of the evidence was low to very low. Manual therapy techniques and psychological treatment did not change the studied outcomes. Supervised physical activity might have a positive impact on quality of life, acupuncture on headache frequency, intensity, quality of life and the use of attack-medicine. Patient education might improve self-rated health and quality of life and increase the number of well-informed patients. CONCLUSION: Based on observed effects, the lack of serious adverse events, and patients' preferences, we make weak recommendations for considering the investigated interventions as a supplement to standard treatment.Protocol registration: Prospero CRD42020220132.

Telephone follow-up on treatment and patient satisfaction at a Danish tertiary headache center: A prospective study.

OBJECTIVE: We investigated whether telephone follow-up consultations could lead to appropriate adjustment of treatments and a higher degree of patient satisfaction among patients with migraine and tension-type headache (TTH). BACKGROUND: Migraine and TTH are disabling headache forms requiring optimized treatment. METHODS: In a prospective, non-randomized, quality control study with controls comparing telephone-interview intervention (TeII) with business-as-usual (BAU) treatment, we included newly referred patients with migraine and/or TTH. The TeII group was contacted by telephone by healthcare professionals at 8 and 16 weeks after the first visit addressing headache treatment. Electronic questionnaires were sent to all participants before the first visit and after 6 months. Predefined outcomes were number of patients with change in preventive and acute medication; change in headache frequency; migraine frequency; scores from the eight-item Headache Under-Response to Treatment (HURT-8) questionnaire, Insomnia Severity Index (ISI), and Hospital Anxiety and Depression Scale (HADS); and patient satisfaction after 6 months. RESULTS: From May 2020 to April 2021, there were 230 patients enrolled in the TeII program, whereof 96 patients were included in the analysis. For the BAU group, 91 patients with similar sex and age distribution were identified via medical-record reviews in the same period. More patients in the TeII group than in the BAU group had a change in acute medication (27/96 [28%] vs. five of 91 [6%], p < 0.001) and preventive medication (28/96 [29%] vs. 12/91 [13%], p = 0.006). Headache days per month decreased in the TeII group (-4.6, 95% confidence interval [CI] -6.5 to -2.7; p = 0.001) and the BAU group (-2.5, 95% CI -4.6 to -0.4; p = 0.018), without significant difference between the groups (p = 0.080). There was no difference in migraine frequency between the groups (TeII: 1.0 day, 95% CI, -1.3 to 1.0; BAU: 1.0 day, 95% CI, -2.5 to 0.5; p = 0.718) or HURT-8 score (TeII: 10.5, 95% CI 9.5-11.5; BAU: 13.0, 95% CI 11.7-14.2; p = 0.053). There were no changes in the ISI score (TeII: 1.0, interquartile range [IQR] 6; p = 0.152; BAU: 0.5, IQR 4.5; p = 0.824), HADS-Anxiety score (TeII: -5, IQR 5.3; p = 0.186; BAU: 1.0, IQR 4.0; p = 0.445), or HADS-Depression score (TeII: 0.0, IQR 3.0; p = 0.163; BAU: 0.0, IQR 2.0; p = 0.303) in any of the groups. There was a higher degree of patient satisfaction in the TeII group compared with the BAU group in treatment (median [IQR] score 4 [3-5] vs. 3 [3-4], p < 0.001), headache improvement (median [IQR] 3 [2-4] vs. 2 [1-3], p = 0.002), the headache program (median [IQR] 4 [3-5] vs. 3 [3-4], p < 0.001), and information (median [IQR] 4 [3-5] vs. 3 [3-4], p = 0.005). CONCLUSION: Patients with migraine and/or TTH benefit from a telephone follow-up approach within the first 6 months of their treatment course in terms of more efficient treatment and higher patient satisfaction.

Diagnostics and management of headache in general practice.

BACKGROUND: Headache disorders are globally prevalent and insufficient treatment contribute to low quality of life, increased disability, and socioeconomic costs. However, headache can to a large extent be treated appropriately by general practitioners. OBJECTIVE: To explore general practitioners' (GPs') management of patients with headache lasting ≥6 months. METHODS: In this retrospective descriptive cross-sectional study based on medical audit, all GPs practicing in Vejle municipality (population 116,992), Denmark, were invited to review their latest 20 patients with headache. Outcome measures were headache diagnostics, treatment, and referrals. Factors associated with referral to neurological treatment were examined by logistic regression. RESULTS: Of 26 invited practices, 19 participated reporting on 367 patients with lasting headache (71.4% women; mean-age 48.5 years). One hundred and sixty-one patients had migraine (44%; IQR: 28-60%), 140 (38%; IQR: 25-44%) had tension-type headache; 243 (66%; IQR: 50-79%) used simple analgesics, 147 (40%; IQR: 29-59%) triptans, 37 (10%; IQR: 0-14%) opioids, 93 (25%; IQR: 20-35%) were prescribed preventive medication; 176 (48%; IQR: 48-59%) were referred to neurologist, and 92 (25%; IQR: 10-37%) were referred to CT or MRI scan. Associated factors for referral were >1 headache diagnosis (aOR 1.75 [95% CI: 1.05-2.95]; P = 0.03), post-traumatic headache (aOR 2.53 [95% CI: 1.25-5.38]; P = 0.01), unspecific headache (aOR 2.04 [95% CI: 1.08-3.93]; P = 0.03), and using preventive treatment (aOR 2.75 [95% CI: 1.68-4.57]; P < 0.001). CONCLUSION: This study provides insights to how GPs manage patients with long-lasting headache. Focus should be on reducing opioids, increasing preventive treatment, and keeping more patients in primary care.

Treatment of medication overuse headache: Effect and predictors after 1 year-A randomized controlled trial.

BACKGROUND: Combined withdrawal and early preventive medication was the most effective treatment for medication overuse headache (MOH) within the first 6 months in a previous study, but results from a longer follow-up period are lacking. OBJECTIVE: (1) To measure the efficacy at 1 year of three different treatment approaches to MOH; (2) to compare withdrawal and early preventives (W+P), preventives with potential withdrawal therapy after 6 months (P+pW), and withdrawal with delayed potential preventives (W+pP); and (3) to identify predictors of chronic headache after 1 year. METHODS: Patients with MOH and migraine and/or tension-type headache were randomly assigned to one of the three outpatient treatments. Headache calendar and questionnaires were filled out. Primary outcome was a reduction in headache days/month after 1 year. RESULTS: Of 120 patients, 96 completed 1-year follow-up, and all were included in our analyses. Overall headache days/month were reduced from 24.6 (23.4-25.8) to 15.0 (13.0-17.0) (p < 0.0001), and only 11/96 patients (11%) relapsed. Reduction in monthly headache days was 10.3 days (95% CI: 6.7-13.9) in the W+P group, 10.8 days (95% CI: 7.6-14) in the P+pW group, and 7.9 days (95% CI: 5.1-10.7) in the W+pP group. No significant differences in treatment effect were seen between the three groups (p = 0.377). After 1 year, 39/96 (41%) had chronic headache. Predictors of chronic headache after 1 year were higher headache frequency (aOR 1.19; 1.09-1.31), more days with acute medication (aOR 1.11; 1.03-1.19), higher pain intensity (aOR 1.04; 1.01-1.08), and depression (aOR 4.7; 1.38-18.95), whereas higher self-rated health (aOR 0.61; 0.36-0.97) and high caffeine consumption (aOR 0.40; 0.16-0.96) were predictors of a lower risk of chronic headache. No adverse events were reported. CONCLUSIONS: All treatment strategies proved effective in treating MOH with a low relapse rate. The W+P strategy leads to the fastest effect, confirming earlier treatment recommendations. Identification of predictors for chronic headache may help identify more complex patients.

Manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education for patients with tension-type headache. A systematic review and meta-analysis.

BACKGROUND: Tension-type headache (TTH) has been ranked the second most prevalent health condition worldwide. Non-pharmacological treatments for TTH are widely used as a supplement or an alternative to medical treatment. However, the evidence for their effects are limited. Therefore, the aim of this study was to review the evidence for manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education as treatments for TTH on the effect of headache frequency and quality of life. METHODS: A systematic literature search was conducted from February to July 2020 for clinical guidelines, systematic reviews, and individual randomised controlled trials (RCT). The primary outcomes measured were days with headache and quality of life at the end of treatment along with a number of secondary outcomes. Meta-analyses were performed on eligible RCTs and pooled estimates of effects were calculated using the random-effect model. The overall certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach (GRADE). In addition, patient preferences were included in the evaluation. RESULTS: In all, 13 RCTs were included. Acupuncture might have positive effects on both primary outcomes. Supervised physical activity might have a positive effect on pain intensity at the end of treatment and headache frequency at follow-up. Manual joint mobilisation techniques might have a positive effect on headache frequency and quality of life at follow-up. Psychological treatment might have a positive effect on stress symptoms at the end of treatment. No relevant RCTs were identified for patient education. The overall certainty of evidence was downgraded to low and very low. No serious adverse events were reported. A consensus recommendation was made for patient education and weak recommendations for the other interventions. CONCLUSION: Based on identified benefits, certainty of evidence, and patient preferences, manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture, and patient education can be considered as non-pharmacological treatment approaches for TTH. Some positive effects were shown on headache frequency, quality of life, pain intensity and stress symptoms. Few studies and low sample sizes posed a challenge in drawing solid conclusions. Therefore, high-quality RCTs are warranted.

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

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.

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

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).

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

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).

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

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).

National awareness campaign to prevent medication-overuse headache in Denmark.

Background Medication-overuse headache is prevalent, but in principle preventable. Objective To describe the Danish national awareness campaign for medication-overuse headache. Methods The Danish Headache Center, the Association of Danish Pharmacies, and headache patient organizations implemented a four-month medication-overuse headache awareness campaign in 2016. Target groups were the general public, general practitioners, and pharmacists. Key messages were: Overuse of pain-medication can worsen headaches; pain-medication should be used rationally; and medication-overuse headache is treatable. A range of communication technologies was used. A survey on the public's awareness of medication-overuse headache was conducted. Results The Danish adult population is 4.2 million. Online videos were viewed 297,000 times in three weeks. All 400 pharmacies received campaign materials. Over 28,000 leaflets were distributed. Two radio interviews were conducted. A television broadcast about headache reached an audience of 520,000. Forty articles were published in print media. Information was accessible at 32 reputable websites and five online news agencies. Three scientific papers were published. Information was available at an annual conference of general practitioners, including a headache lecture. The survey showed an increase in percentage of the public who knew about medication-overuse headache (from 31% to 38%). Conclusion A concerted campaign to prevent medication-overuse headache can be implemented through involvement of key stakeholders.

Pericranial Muscle Stiffness, Pain Thresholds, and Tenderness during a Treatment Cycle of OnabotulinumtoxinA for Chronic Migraine Prevention.

BACKGROUND: Treatment with OnabotulinumtoxinA (BoNT-A) is effective as a preventive treatment for chronic migraine (CM). Preclinical studies suggest that the mechanism of action of BoNT-A in migraine is based on blocking unmyelinated C fibers. We aimed to investigate whether the muscle-relaxing effect of BoNT-A is associated with the preventive mechanism in patients with chronic migraine by measuring the stiffness, pain thresholds, and tenderness of the BoNT-A-applied muscles. METHODS: A total of 22 patients with CM who were already in BoNT-A treatment participated in this longitudinal prospective study. Pericranial muscle stiffness was measured using ultrasound shear wave elastography, which measures the speed of shear waves propagating through the muscle. Pressure pain thresholds (PPT) were obtained via algometry, and muscle tenderness was measured via manual palpation. Measurements were made before BoNT-A injections and six weeks after the treatment. The measurements were performed while the muscles were maximally relaxed. The patients also completed daily diaries on headache and neck pain. RESULTS: No change was observed in muscle stiffness (p = 0.737) or pericranial muscle tenderness (p = 0.400). The PPT over the trapezius muscles increased from 250 kPa before treatment to 304 kPa six weeks after treatment (p = 0.027). No change was observed on the temporalis muscles (p = 0.200) nor the non-dominant index finger (p = 0.067). BoNT-A decreased neck pain (p = 0.008) and headache (p = 0.007). CONCLUSIONS: The findings suggest that BoNT-A leads to the desensitization of cutaneous and muscle nociceptors in the head and neck regions, whereas muscle relaxation might not be an important part of the anti-migraine effect.

Validation of a Digital Headache Calendar at a Tertiary Referral Center.

BACKGROUND: Headache calendars are essential tools in monitoring changes in headache frequency and type. They are used in clinical practice for long-term monitoring, but their validation remains limited. The aim of this study was to validate the use of a digital calendar in monitoring single migraine and tension-type headache attacks. METHODS: From July 2022 to February 2023, patients diagnosed with migraine and tension-type headache were enrolled. The validation of the digital calendar involved the comparison of self-reported single headache attacks in the digital calendar with the diagnostic headache diary based on the ICHD-3 criteria for migraine and tension-type headache. Sensitivity and specificity were calculated to assess reliability, and the level of agreement was calculated using kappa statistics. RESULTS: This study included 30 patients (87% women) diagnosed with migraine and tension-type headache. The level of agreement in the classification of a single migraine attack revealed a sensitivity of 82% and a specificity of 78%, representing a substantial level of agreement (κ = 0.60). The classification of a single tension-type headache attack revealed a sensitivity of 84% and a specificity of 72%, with a moderate level of agreement (κ = 0.54). CONCLUSIONS: The digital calendar proves effective in monitoring single headache attacks in patients with migraine and tension-type headache. In clinical practice, we recommend using the digital calendar as a monitoring tool for headache patients, as they can accurately identify true migraine and tension-type headache days.

Adding eptinezumab to brief patient education to treat chronic migraine and medication-overuse headache: Protocol for RESOLUTION-A phase 4, multinational, randomized, double-blind, placebo-controlled study.

Introduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine. Methods and analysis: RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo (n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1-4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1-12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population. Ethics and dissemination: This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results.

[Non-pharmacological treatment of migraine and tension-type headache].

Migraine and tension-type headache are among the most frequent diseases of the world. As pharmacological treatment often is associated with distinct side effects, there is an increasing need for non-pharmacological treatment options. However, there has been a striking lack of evidence with regards to the efficacy of the huge variety of non-pharmacological interventions. In this review, we present the available evidence for the most common non-pharmacological treatment options with focus on the national clinical guideline for non-pharmacological treatment of headache disorders published in 2021.

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

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.

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

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.