Patterns of migraine medication use in Norway: A nationwide registry-based observational study.

OBJECTIVE: The objective of this study was to describe and discuss patterns of migraine medication use in the entire Norwegian population. METHODS: In this nationwide, observational study, all individuals with a migraine-related prescription between 2010 and 2020 were identified using the Norwegian Prescription Database. The outcomes of interest were the incidence and 1-year prevalence of migraine medication users, as well as individuals with triptan overuse. Patterns of medication use were statistically compared between women and men adjusted for age, year of treatment start, comorbidities and county of residence calculating adjusted odds ratios (aOR) with 95% confidence intervals (CI). RESULTS: We identified 327,904 migraine medication users. The incidence ranged from 0.39% to 0.46%, and the 1-year prevalence increased from 1.99% to 2.99%. Preventive use increased >50% during the study period. Preventives were significantly more often prescribed to women than to men (39.72% vs. 33.75%; aOR 1.41, 95% CI 1.38 to 1.44). Triptan overuse was significantly more common among women, but women with overuse were more often using preventives, as compared to men (56.64% vs 52.69%; aOR = 1.43, 95% CI 1.37 to 1.49). CONCLUSION: The prevalence of medically treated migraine is low. Overuse of triptans is frequent, especially among women. Clinicians should be encouraged to try out different triptans, recognize triptan overuse, and prescribe preventives when indicated.

Onabotulinum toxin A block of the sphenopalatine ganglion in patients with persistent idiopathic facial pain: a randomized, triple-blind, placebo-controlled, exploratory, cross-over study.

OBJECTIVE: To investigate the efficacy and safety of injecting onabotulinum toxin A (BTA) towards the sphenopalatine ganglion (SPG) using the MultiGuide® in patients with persistent idiopathic facial pain (PIFP). METHODS: This cross-over, exploratory study compared the injection of 25 units BTA versus placebo in patients who met modified ICDH-3 criteria for PIFP. Daily pain diaries were registered for a 4-week baseline, a 12-week follow-up after each injection, and an 8-week conceptual washout period in between. The primary efficacy endpoint was the change from baseline to weeks 5-8 in average pain intensity using a numeric rating scale. Adverse events were recorded. RESULTS: Of 30 patients who were randomized to treatment, 29 were evaluable. In weeks 5-8, there was no statistically significant difference in average pain intensity between BTA versus placebo (0.00; 95% CI = -0.57 to 0.57) (P = 0.996). Following both BTA and placebo injections, five participants reported at least a 30% reduction in average pain during weeks 5-8 (P = 1.000). No serious adverse events were reported. Post-hoc analyses indicated a possible carry-over effect. CONCLUSIONS: Injection of BTA toward the SPG with the MultiGuide® did not appear to provide a reduction in pain reduction at 5-8 weeks, although this finding may be influenced by a carry-over effect. The injection appears to otherwise be safe and well-tolerated in patients with PIFP.Trial Registration: The study protocol is registered in ClinicalTrial.gov (NCT03462290) and EUDRACT (number: 2017-002518-30).

The HARDSHIP databases: a forthcoming free good from the Global Campaign against Headache.

In order to pursue its purpose of reducing the global burden of headache, the Global Campaign against Headache has gathered data on headache-attributed burden from countries worldwide. These data, from the individual participants in adult population-based studies and child and adolescent schools-based studies, are being collated in two databases, which will be powerful resources for research and teaching and rich information sources for health policy.Here we briefly describe the structure and content of these databases, and announce the intention to make them available in due course as a free good.

Insufficient sleep may alter cortical excitability near the migraine attack: A blinded TMS crossover study.

BACKGROUND: Migraine is a brain disorder with a multifaceted and unexplained association to sleep. Brain excitability likely changes periodically throughout the migraine cycle. In this study we examine the effect of insufficient sleep on neuronal excitability during the course of the migraine cycle. METHODS: We examined 54 migraine patients after two nights of eight-hour habitual sleep and two nights of four-hour restricted sleep in a randomised, blinded crossover study. We performed transcranial magnetic stimulation and measured cortical silent period, short- and long-interval intracortical inhibition, intracortical facilitation and short-latency afferent inhibition. We analysed how responses changed before and after attacks with linear mixed models. RESULTS: Short- interval intracortical inhibition was more reduced after sleep restriction compared to habitual sleep the shorter the time that had elapsed since the attack (p = 0.041), and specifically in the postictal phase (p = 0.013). Long-interval intracortical inhibition was more increased after sleep restriction with time closer before the attack (p = 0.006), and specifically in the preictal phase (p = 0.034). Short-latency afferent inhibition was more decreased after sleep restriction with time closer to the start of the attack (p = 0.026). CONCLUSION: Insufficient sleep in the period leading up to a migraine attack may cause dysfunction in cortical GABAergic inhibition. The results also suggest that migraine patients may have increased need for sufficient sleep during a migraine attack to maintain normal neurological function after the attack.

Continuous positive airway pressure in cluster headache: A randomized, placebo-controlled, triple-blind, crossover study.

BACKGROUND: Oxygen inhalation aborts cluster headache attacks, and case reports show the effect of continuous positive airway pressure. The aim of this study was to investigate the prophylactic effect of continuous positive airway pressure in chronic cluster headache. METHODS: This was a randomized placebo-controlled triple-blind crossover study using active and sham continuous positive airway pressure treatment for chronic cluster headache. Patients entered a one month's baseline period before randomly being assigned to two months' active continuous positive airway pressure treatment followed by a four weeks' washout period and two months' sham continuous positive airway pressure or vice versa. Primary outcome measure was number of cluster headache attacks/week. RESULTS: Of the 30 included participants (12 males, median age 49.5 years, min-max 20-66 years), 25 completed both treatment/sham cycles (two discontinued, three lost to follow-up). The median number of cluster headache attacks per week was reduced from 8.25 (0.75-89.75) attacks to 6.25 (0-56.00) attacks for active continuous positive airway pressure and to 7.50 (0.50-43.75) attacks for sham continuous positive airway pressure, but there was no difference in active versus sham (p = 0.904). One patient had a serious adverse event during active treatment, none occurred during sham treatment. CONCLUSIONS: Continuous positive airway pressure treatment did not reduce the number of cluster headache attacks compared to sham treatment in chronic cluster headache patients. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03397563.

Global epidemiology of migraine and its implications for public health and health policy.

Migraine is one of more than 200 headache disorders but stands out among these as a major cause of population ill health. In migraine epidemiology, the key variable is prevalence, but, from the perspective of public health, prevalence is uninformative without burden estimates. Here, we discuss how migraine epidemiology, from a quite recent start, has evolved into the respectable though imperfect science of today, but with the legacy that much of the large corpus of older literature is of questionable reliability. Newer studies have benefited from a universally accepted definition of migraine, while methodological developments have broadened the scope of migraine caseness, and published guidelines address important methodological issues. In the light of these developments, we question the apparent increase in migraine prevalence over time, offering explanations as to why this may be illusory. We suggest that the current best estimates are that global migraine prevalence is 14-15%, and that migraine accounts for 4.9% of global population ill health quantified in years lived with disability (YLDs). These evaluations are probably under-quantified rather than over-quantified, and YLDs are not a comprehensive measure of migraine-attributed burden. Despite these uncertainties, such high estimates of population ill health have clear implications for health policy.

The Global Campaign turns 18: a brief review of its activities and achievements.

The Global Campaign against Headache, as a collaborative activity with the World Health Organization (WHO), was formally launched in Copenhagen in March 2004. In the month it turns 18, we review its activities and achievements, from initial determination of its strategic objectives, through partnerships and project management, knowledge acquisition and awareness generation, to evidence-based proposals for change justified by cost-effectiveness analysis.

The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates.

BACKGROUND: According to the Global Burden of Disease (GBD) study, headache disorders are among the most prevalent and disabling conditions worldwide. GBD builds on epidemiological studies (published and unpublished) which are notable for wide variations in both their methodologies and their prevalence estimates. Our first aim was to update the documentation of headache epidemiological studies, summarizing global prevalence estimates for all headache, migraine, tension-type headache (TTH) and headache on ≥15 days/month (H15+), comparing these with GBD estimates and exploring time trends and geographical variations. Our second aim was to analyse how methodological factors influenced prevalence estimates. METHODS: In a narrative review, all prevalence studies published until 2020, excluding those of clinic populations, were identified through a literature search. Prevalence data were extracted, along with those related to methodology, world region and publication year. Bivariate analyses (correlations or comparisons of means) and multiple linear regression (MLR) analyses were performed. RESULTS: From 357 publications, the vast majority from high-income countries, the estimated global prevalence of active headache disorder was 52.0% (95%CI 48.9-55.4), of migraine 14.0% (12.9-15.2), of TTH 26.0% (22.7-29.5) and of H15+ 4.6% (3.9-5.5). These estimates were comparable with those of migraine and TTH in GBD2019, the most recent iteration, but higher for headache overall. Each day, 15.8% of the world's population had headache. MLR analyses explained less than 30% of the variation. Methodological factors contributing to variation, were publication year, sample size, inclusion of probable diagnoses, sub-population sampling (e.g., of health-care personnel), sampling method (random or not), screening question (neutral, or qualified in severity or presumed cause) and scope of enquiry (headache disorders only or multiple other conditions). With these taken into account, migraine prevalence estimates increased over the years, while estimates for all headache types varied between world regions. CONCLUSION: The review confirms GBD in finding that headache disorders remain highly prevalent worldwide, and it identifies methodological factors explaining some of the large variation between study findings. These variations render uncertain both the increase in migraine prevalence estimates over time, and the geographical differences. More and better studies are needed in low- and middle-income countries.

FollowTheSutures: Piloting a new way to administer onabotulinumtoxinA for chronic migraine.

BACKGROUND: Anatomical and experimental data indicate that onabotulinimtoxin A could be more efficient and cost-effective for treating chronic migraine with injections targeting the cranial sutures, where collaterals from the meninges penetrate the skull. METHODS: A new injection paradigm (FollowTheSutures) was tested for safety, tolerability and feasibility in a Phase II, open-label, non-controlled, single-center pilot study. Ninety units of onabotulinimtoxin A (Botox®), were injected in 18 sites over the area of the cranial sutures. Adverse events and potential beneficial effects were recorded in a headache diary at least 4 weeks before, and for 12 weeks after the injections. A higher dilution than normal of onabotulinimtoxin A was used to get better diffusion. RESULTS: Nineteen (of 20 included) women with chronic migraine received the injections and were evaluable. There was only one treatment-related adverse event (reduced power of chewing for some weeks). Otherwise, the procedure was overall well tolerated. Patients improved on most efficacy parameters after the injections. There was little or no effect on glabellar or forehead lines. CONCLUSIONS: The protocol was safe and well tolerated. Lower risk of unblinding due to the absence of cosmetic effects should make the injection procedure well suited for a large, randomized, placebo-controlled study. If efficacy is confirmed, it will be markedly less costly than the standard procedure.Trial registration: EUDRACT (2017-002516-13), ClinicalTrials.gov (NCT03543254).

Pain thresholds and suprathreshold pain after sleep restriction in migraine - A blinded crossover study.

OBJECTIVE: There is an unexplained association between disturbed sleep and migraine. In this blinded crossover study, we investigate if experimental sleep restriction has a different effect on pain thresholds and suprathreshold pain in interictal migraineurs and controls. METHODS: Forearm heat pain thresholds and tolerance thresholds, and trapezius pressure pain thresholds and suprathreshold pain were measured in 39 interictal migraineurs and 31 healthy controls after two consecutive nights of partial sleep restriction and after habitual sleep. RESULTS: The effect of sleep restriction was not significantly different between interictal migraineurs and controls in the primary analyses. Pressure pain thresholds tended to be lower (i.e., increased pain sensitivity) after sleep restriction in interictal migraineurs compared to controls with a 48-hour preictal-interictal cut-off (p = 0.061). We found decreased pain thresholds after sleep restriction in two of seven migraine subgroup comparisons: heat pain thresholds decreased in migraineurs with lower pain intensity during attacks (p = 0.005) and pressure pain thresholds decreased in migraineurs with higher severity of photophobia during attacks (p = 0.031). Heat pain thresholds tended to decrease after sleep restriction in sleep-related migraine (p = 0.060). Sleep restriction did not affect suprathreshold pain measurements in either group. CONCLUSION: This study could not provide strong evidence for an increased effect of sleep restriction on pain sensitivity in migraineurs compared to healthy controls. There might be a slightly increased effect of sleep restriction in migraineurs, detectable using large samples or more pronounced in certain migraine subgroups.

OnabotulinumtoxinA injection towards the SPG for treating symptoms of refractory chronic rhinosinusitis with nasal polyposis: a pilot study.

BACKGROUND AND OBJECTIVE: The main objective of this prospective, open, uncontrolled pilot study was to investigate the safety of administering onabotulinumtoxinA (BTA) towards the sphenopalatine ganglion (SPG) in 10 patients with refractory chronic rhinosinusitis with nasal polyposis (CRSwNP) using a novel injection tool, the MultiGuide®. MATERIAL AND METHODS: A one-month baseline period was followed by bilateral injections of 25 U BTA in the SPG and a follow-up of 12 weeks. The primary outcome was adverse events (AE), and the main efficacy outcome was a 50% reduction in visual analogue scale (VAS) symptoms for nasal obstruction and rhinorrhea in months 2 and 3 post-treatment compared to baseline. RESULTS: We registered 13 AEs, none of which were serious, however, one patient experienced diplopia which moderately affected his daily activities. The symptoms slowly improved and resolved 4 weeks after injection. Five patients were treatment responders with at least 50% median reduction in the nasal obstruction, and four were treatment responders concerning rhinorrhea. CONCLUSIONS: Injection of BTA toward the SPG using the MultiGuide® in patients with CRSwNP appears to be safe but with a potential for moderately disabling side effects. The study indicates a beneficial effect on nasal obstruction.

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

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

High sensitivity C-reactive protein and risk of migraine in a 11-year follow-up with data from the Nord-Trøndelag health surveys 2006-2008 and 2017-2019.

BACKGROUND: Several previous studies have reported a cross-sectional association between elevated high sensitivity C-reactive protein (hs-CRP) and migraine. The aim of this population-based follow-up study was to investigate the influence of hs-CRP at baseline on the risk of developing migraine 11 years later. METHODS: Data from the Nord-Trøndelag Health Study performed in 2006-2008 (baseline) and 2017-2019 were used. A total of 19,574 participants without migraine at baseline were divided into three groups based on hs-CRP levels (< 3 mg/L, 3-9.99 mg/L and 10.00-20 mg/L). Poisson regression was used to evaluate the associations between hs-CRP levels and risk ratios (RRs) of migraine, and precision of the estimates was assessed by 95% confidence interval (CIs). RESULTS: In the multi-adjusted model, increased risk of migraine (RR 1.46, 95% CI 1.05-2.04) was found in the highest hs-CRP levels group compared to the lowest group. In the group with the highest hs-CRP levels, a nearly three times higher risk of chronic migraine (RR 2.81, 95% CI 1.12-7.06) was found, whereas no evident relationship was found between high hs-CRP level and risk of developing episodic migraine. CONCLUSIONS: The main finding in this 11-year follow-up was that hs-CRP levels between 10.00-20.00 mg/L at baseline was associated with increased risk of chronic migraine.

Time trends of major headache diagnoses and predictive factors. Data from three Nord-Trøndelag health surveys.

AIMS: The primary aim of this study was to investigate time trends of major headache diagnoses using cross-sectional data from two population-based health surveys. In addition, we aimed to perform a longitudinal assessment of baseline characteristics and subsequent risk for having headache at 22-years' follow-up among those participating in three health surveys. METHODS: Data from the Nord-Trøndelag Health Study (HUNT) performed in 1995-1997 (HUNT2), 2006-2008 (HUNT3) and 2017-2019 (HUNT4) were used. The 1-year prevalence time trends of major headache diagnoses were estimated among 41,460 participants in HUNT4 and among 39,697 participants in HUNT3, two surveys with identical headache questions. 16,118 persons participated in all three surveys, and among these, a Poisson regression was used to evaluate health-related baseline information in HUNT2 and the risk ratios (RRs) with 95% confidence interval (CIs) of consistently reporting headache during follow-up. RESULTS: Compared with the 1-year prevalence in HUNT3, a higher proportion of participants in HUNT4 had tension-type headache (20.7% vs. 15.9%, p < 0.001), whereas a lower 1-year prevalence was found for migraine (11.1% vs. 12.0%, p < 0.001) and medication overuse headache (MOH) (0.3% vs. 1.0%, p < 0.001). Participants in the age group 20-39 years at baseline nearly three times increased risk (RR = 2.8, 95% CI 2.5-3.1) of reporting headache in HUNT2, HUNT3 and HUNT4 than persons aged 50 years or more. Female sex, occurrence of chronic musculoskeletal complaints and high score of depression or anxiety at baseline doubled the risk of having headache in all three surveys. CONCLUSIONS: The 1-year prevalence of migraine and MOH was lower in HUNT4 than in HUNT3. Young age, female sex, and occurrence of musculoskeletal complaints and high score of anxiety and/or depression were all associated with substantially increased risk of reporting headache in all three surveys.

The crossover design for migraine preventives: an analyses of four randomized placebo-controlled trials.

AIMS: To evaluate the crossover design in migraine preventive treatment trials by assessing dropout rate, and potential period and carryover effect in four placebo-controlled randomized controlled trials (RCTs). METHODS: In order to increase statistical power, the study combined data from four different RCTs performed from 1998 to 2015 at St. Olavs Hospital, Norway. Among 264 randomized patients, 120 received placebo treatment before and 144 after active treatment. RESULTS: Only 26 (10%) dropped out during the follow-up period of 30-48 weeks, the majority (n = 19) in the first 12 weeks. No period effect was found, since the treatment sequence did not influence the responder rate after placebo treatment, being respectively for migraine 30.5% vs. 27.4% (p = 0.59) and for headache 25.0% vs. 24.8% (p = 0.97, Chi-square test) when placebo occurred early or late. Furthermore, no carryover effect was identified, since the treatment sequence did not influence the treatment effect (difference between placebo and active treatment). There was no significant difference between those who received active treatment first and those who received placebo first with respect to change in number of days per 4 week of headache (- 0.9 vs. -1.3, p = 0.46) and migraine (- 1.2 vs. -0.9, p = 0.35, Student's t-test). CONCLUSIONS: Summary data from four crossover trials evaluating preventive treatment in adult migraine showed that few dropped out after the first period. No period or carryover effect was found. RCT studies with crossover design can be recommended as an efficient and cost-saving way to evaluate potential new preventive medicines for migraine in adults.

The impact of C-reactive protein levels on headache frequency in the HUNT study 2006-2008.

BACKGROUND: Increased high sensitivity C- reactive protein (hs-CRP) levels have been found in many earlier studies on migraine, and recently also in persons with migraine and insomnia. The aim of this study was to see whether these findings could be reproduced in a large-scale population-based study. METHODS: A total of 50,807 (54%) out of 94,194 invited aged ≥20 years or older participated in the third wave of the Nord-Trøndelag Health Study study performed in 2006-2008. Among these, 38,807 (41%) had valid measures of hs-CRP and answered questions on headache and insomnia. Elevated hs-CRP was defined as > 3.0 mg/L. The cross-sectional association with headache was estimated by multivariate analyses using multiple logistic regression. The precision of the odds ratio (OR) was assessed with 95% confidence interval (CI). RESULTS: In the fully adjusted model, elevated hs-CRP was associated with migraine (OR 1.14, 95% CI 1.04-1.25) and migraine with aura (OR 1.15, 95% CI 1.03-1.29). The association was strongest among individuals with headache ≥15 days/month for any headache (OR 1.26, 95% CI 1.08-1.48), migraine (OR 1.62, 95% CI 1.21-2.17), and migraine with aura (OR 1.84, 95% CI 1.27-2.67). No clear relationship was found between elevated hs-CRP and headache less than 7 days/month or with insomnia. CONCLUSIONS: Cross-sectional data from this large-scale population-based study showed that elevated hs-CRP was associated with headache ≥7 days/month, especially evident for migraine with aura.

Diffusion tensor imaging in middle-aged headache sufferers in the general population: a cross-sectional population-based imaging study in the Nord-Trøndelag health study (HUNT-MRI).

BACKGROUND: Several studies have investigated white matter with diffusion tensor imaging (DTI) in those suffering from headache, but so far only in clinic based samples and with conflicting results. METHODS: In the present study, 1006 individuals (50-66 years) from the general population (Nord-Trøndelag Health Study) participated in an imaging study of the head at 1.5 T (HUNT-MRI). Hundred and ninety-six individuals were excluded because of errors in the data acquisition or brain pathology. Two hundred and forty-six of the remaining participants reported suffering from headache (69 from migraine and 76 from tension-type headache) the year prior to the scanning. DTI data were analysed with Tract-Based Spatial Statistics and automated tractography. Type of headache, frequency of attacks and evolution of headache were investigated for an association with white matter fractional anisotropy (FA), mean diffusivity (MD), axonal diffusivity (AD), radial diffusivity (RD) and tract volume. Correction for various demographical and clinical variables were performed. RESULTS: Headache sufferers had widespread higher white matter MD, AD and RD compared to headache free individuals (n = 277). The effect sizes were mostly small with the largest seen in those with middle-age onset headache, who also had lower white matter FA. There were no associations between white matter microstructure and attack frequency or type of headache. CONCLUSION: Middle-age onset headache may be related to a widespread process in the white matter leading to altered microstructure.

The burden of headache disorders in the Eastern Mediterranean Region, 1990-2016: findings from the Global Burden of Disease study 2016.

OBJECTIVES: Using the findings of the Global Burden of Disease Study (GBD), we report the burden of primary headache disorders in the Eastern Mediterranean Region (EMR) from 1990 to 2016. METHODS: We modelled headache disorders using DisMod-MR 2.1 Bayesian meta-regression tool to ensure consistency between prevalence, incidence, and remission. Years lived with disability (YLDs) were calculated by multiplying prevalence and disability weight (DW) of migraine and tension-type headache (TTH). We assumed primary headache disorders as non-fatal, so their YLD is equal to disability-adjusted life years (DALYs). RESULTS: Migraine and TTH were the second and twentieth leading causes of YLDs in EMR. Between 1990 and 2016, the absolute YLD numbers of migraine and TTH increased from 2.3 million (95% uncertainty interval (UI): 1.5-3.2) to 4.7 million (95%UI: 3-6.5) and from 383 thousand (95%UI: 240-562) to 816 thousand (95%UI: 516-1221), respectively. During the same period, age-standardised YLD rates of migraine and TTH in EMR increased by 0.7% and 2.5%, respectively, in comparison to a small decrease in the global rates (0.2% decrease in migraine and TTH). The bulk of burden due to headache occurred in the 30-49 year age group, with a peak at ages 35-44 years. The age-standardised YLD rates of both headache disorders were higher in women with female to male ratio of 1.69 for migraine and 1.38 for TTH. All countries of the EMR except for Somalia and Djibouti had higher age-standardised YLD rates for migraine and TTH in compare to the global rates. Libya and Saudi Arabia had the highest increase in age-standardised YLD rates of migraine and TTH, respectively. CONCLUSION: The findings of this study show that primary headache disorders are a major and a growing cause of disability in EMR. Since 1990, burden of primary headache disorders has constantly been higher in EMR compared to rest of the world, which indicates that health systems in EMR must focus further on developing and implementing preventive and management strategies to control headache.