Migraine: integrated approaches to clinical management and emerging treatments.

Migraine is a highly disabling neurological disorder that directly affects more than 1 billion individuals worldwide. Available treatment options differ between countries and include acute, preventive, and non-pharmacological therapies. Because of major progress in the understanding of migraine pathogenesis, novel mechanism-based medications have emerged and expanded the armamentarium of treatments. We provide a comprehensive overview of the current standard of care that will enable informed clinical management. First, we discuss the efficacy, tolerability, and safety profile of various pharmacological therapies for acute and preventive treatment of migraine. Second, we review the current knowledge on non-pharmacological therapies, such as neuromodulation and biobehavioural approaches, which can be used for a multidisciplinary approach to clinical management. Third, we emphasise that any effective treatment strategy starts with building a therapeutic plan tailored to individual clinical characteristics, preferences, and needs. Finally, we explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management of migraine.

Contralesional Cathodal Transcranial Direct Current Stimulation Does Not Enhance Upper Limb Function in Subacute Stroke: A Pilot Randomized Clinical Trial.

Transcranial direct current stimulation (tDCS) has the potential to improve upper limb motor outcomes after stroke. According to the assumption of interhemispheric inhibition, excessive inhibition from the motor cortex of the unaffected hemisphere to the motor cortex of the affected hemisphere may worsen upper limb motor recovery after stroke. We evaluated the effects of active cathodal tDCS of the primary motor cortex of the unaffected hemisphere (ctDCSM1UH) compared to sham, in subjects within 72 hours to 6 weeks post ischemic stroke. Cathodal tDCS was intended to inhibit the motor cortex of the unaffected hemisphere and hence decrease the inhibition from the unaffected to the affected hemisphere and enhance motor recovery. We hypothesized that motor recovery would be greater in the active than in the sham group. In addition, greater motor recovery in the active group might be associated with bigger improvements in measures in activity and participation in the active than in the sham group. We also explored, for the first time, changes in cognition and sleep after ctDCSM1UH. Thirty subjects were randomized to six sessions of either active or sham ctDCSM1UH as add-on interventions to rehabilitation. The NIH Stroke Scale (NIHSS), Fugl-Meyer Assessment of Motor Recovery after Stroke (FMA), Barthel Index (BI), Stroke Impact Scale (SIS), and Montreal Cognitive Assessment (MoCA) were assessed before, after treatment, and three months later. In the intent-to-treat (ITT) analysis, there were significant GROUP∗TIME interactions reflecting stronger gains in the sham group for scores in NIHSS, FMA, BI, MoCA, and four SIS domains. At three months post intervention, the sham group improved significantly compared to posttreatment in FMA, NIHSS, BI, and three SIS domains while no significant changes occurred in the active group. Also at three months, NIHSS improved significantly in the sham group and worsened significantly in the active group. FMA scores at baseline were higher in the active than in the sham group. After adjustment of analysis according to baseline scores, the between-group differences in FMA changes were no longer statistically significant. Finally, none of the between-group differences in changes in outcomes after treatment were considered clinically relevant. In conclusion, active CtDCSM1UH did not have beneficial effects, compared to sham. These results were consistent with other studies that applied comparable tDCS intensities/current densities or treated subjects with severe upper limb motor impairments during the first weeks post stroke. Dose-finding studies early after stroke are necessary before planning larger clinical trials.

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.

Patterns of religiosity and spirituality of psychiatrists in Brazil and the implications for clinical practice: a latent profile analysis.

BACKGROUND: Although there is consensus, in psychiatry, over the inclusion of religious and spiritual aspects when evaluating and treating the patient, investigation of these dimensions is rare. There is evidence as to the relationship between psychiatrists' religious/spiritual beliefs and their willingness to discuss a patient's religion and spirituality (R/S). Due to the lack of information about how psychiatrists in Brazil deal with R/S in patient care, the aim of the present study is to analyze the religious/spiritual profile of these professionals and to ascertain its influence on attitudes and behavior in clinical practice. METHODS: Five hundred and ninety-two psychiatrists from Brazil answered a questionnaire about R/S in clinical practice. The latent profile analysis was used to search for differences of religious/spiritual profiles. The ANOVA and Pearson's chi-square tests were employed to identify any correlation between clinical opinion and behaviors according to the different profiles. RESULTS: Two religious/spiritual profiles were identified (entropy value > 0,96): the so called "less religious" group (n = 245), comprised predominantly by men, professionally more experienced, with a higher level of academic education (Master or PhD degrees) and were the ones who least enquired about their patients' R/S; and the "more religious" psychiatrists (n = 347) those who had higher consideration for R/S on health, and who more often addressed R/S with their patients and therefore usually ascribed importance to include R/S in their professional training. CONCLUSION: The latent profile analysis produced two distinct classes between the Brazilian psychiatrists according to their R/S views: the more religious professionals, who investigate the patient's R/S in a more detailed manner, and the less religious, who tend to disregard this aspect.

Optimism, Pessimism, and Migraine: A Cross-Sectional, Population-Based Study.

BACKGROUND: Optimism and pessimism are related to several mental health and brain disorders, are significant predictors of physical and psychological health outcomes, and implicated as psychosocial determinants of the pain experience. Despite this promising evidence, limited information is available on optimism and pessimism in headache disorders. OBJECTIVE: To evaluate the influence of optimism and pessimism in meeting criteria for migraine and related disability in a population-based sample. METHODS: This is an observational, cross-sectional study. The sample population was selected through a stratified, multi-stage area probability sample of households, as used by the last Brazilian Census. A validated questionnaire eliciting data on demographics, headache features, migraine-related disability, depression (PHQ-9), anxiety (GAD-7), optimism, and pessimism (life orientation test - revised) was administered to people with migraine and headache-free control participants from the general population in São Paulo, Brazil via trained interviewers. Six hundred individuals were contacted. The odds for having migraine/no headache diagnosis were calculated by binary logistic regression, and ordinal regression was performed to check associations between migraine-related disability and optimism. RESULTS: A total of 302 individuals (mean ± SD age: 39.7 ± 12.7; BMI: 26.5 ± 5.9) met inclusion criteria and were included, 140 controls (with no history of headache disorders) and 162 people meeting criteria for migraine (29 with chronic migraine, that is, 15 or more headache days/month). People with migraine were less optimistic and more pessimistic than controls, and endorsed higher levels of anxious and depressive symptoms. Pessimism (OR 95% CI = 1.16 [1.05-1.28], P = .005) and anxiety (OR 95% CI = 1.19 [1.10-1.29], P < .001) were predictors of meeting criteria for migraine, while optimism (ß 95% CI = -0.915 [-1.643, -0.188], P = .01) was inversely associated with migraine-related disability. CONCLUSIONS: Optimism and pessimism are associated with migraine and migraine-related disability. These concepts should be further explored in people with migraine with regard to their potential influences on clinical research outcomes and treatments.

Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache.

Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management.

The role of vitamin D in pathophysiology and treatment of fibromyalgia.

Recent studies showed that most cells have receptors and enzymes responsible for metabolism of vitamin D. Several diseases have been linked to vitamin D deficiency, such as hypertension, diabetes, depression, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and chronic pain syndromes such as fibromyalgia. The association between fibromyalgia and vitamin D deficiency is very controversial in the literature with conflicting studies and methodological problems, which leads to more questions than answers. The purpose of this article is to raise questions about the association of hypovitaminosis D with fibromyalgia considering causal relationships, treatment, and pathophysiological explanations.

Generalized anxiety disorder, subthreshold anxiety and anxiety symptoms in primary headache.

AIMS: The aim of the present study was to evaluate the association between generalized anxiety disorder, subthreshold anxiety (SubAnx) and anxiety symptoms in the prevalence of primary headache. METHODS: This cross-sectional study evaluated 383 people from a Brazilian low-income community. One-year prevalence rates of migraine, chronic migraine and tension-type headache were calculated. Anxiety symptoms were then separated into the following groups (based on DSM-IV criteria): no anxiety criteria; one anxiety criterion; two anxiety criteria; and generalized anxiety disorder (GAD). The control group (no headaches) was compared with headache sufferers for each anxiety group using an adjusted model controlled for confounding factors. RESULTS: GAD was present in 37.0% of participants and SubAnx in 16.6%. Those with SubAnx had a 2.28-fold increased chance of having migraine; 3.83-fold increased chance of having chronic migraine, a 5.94-fold increased chance of having tension-type headache and a 3.27-fold increased chance of having overall headache. Some anxiety criteria (irritability, difficulty with sleep, concentration problems, muscle tension and fatigue) had similar prevalence to International Classification of Headache Disorders (ICHD-II) headache criteria such as unilateral pain and nausea for migraine and chronic migraine. CONCLUSION: Headache sufferers seem to have a high prevalence of anxiety symptoms and SubAnx. In addition, the presence of two or more anxiety criteria (not necessarily fulfilling all the criteria for GAD) was associated with having a headache disorder.

Social anxiety score is high in adolescents with chronic migraine.

BACKGROUND: Social anxiety disorder, also known as social phobia, is a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. It usually begins in mid-adolescence and has a chronic course and interferes in academic, social, family and personal functioning. Recent studies have shown that social anxiety disorder is more prevalent in adults with migraine. Little evidence on this subject is available for the adolescent population. METHODS: This study was performed between August 2009 and August 2010; all patients were recruited in schools, pediatric or neuropediatric facilities, and were submitted to a detailed headache questionnaire, which consisted of demographic and clinical data. To evaluate social anxiety, the Social Phobia Inventory was used. RESULTS: A total of 151 subjects were evaluated: 50 had chronic migraine, 50 had episodic migraine and 51 were control subjects. In the chronic migraine group, the mean score in the Social Phobia Inventory was 18.5 ± 12.4, which was significantly higher than in the episodic migraine group (12.1 ± 8.1) and in the control group (13.8 ± 10.8; F(2131) = 4.8, P= 0.010). The mean score, however, was not significantly different between the control and episodic migraine groups. CONCLUSIONS: Chronic migraine is strongly associated with high social anxiety score, regardless of demographic data and pain intensity. The total burden of migraine may be increased with social anxiety disorder comorbidity.

Religiosity and tobacco and alcohol use in a Brazilian shantytown.

This article analyzes the role of religious involvement and religious beliefs in the prevalence and frequency of smoking and alcohol consumption. This was a cross-sectional, population-based study. In 2005, we conducted door-to-door interviews with 383 people, aged 18 years or more, randomly selected from the "Paraisopolis" shantytown in São Paulo, Brazil. Four regression models were created to explain the relationships among religious involvement, tobacco and alcohol use, controlling for demographic, social, and psychobehavioral factors. High religious attendance was associated with less alcohol use, alcohol abuse, tobacco use, and combined alcohol/tobacco use, as well as less days consuming alcoholic beverages per week, controlling for confounding factors. Additionally, high nonorganizational religious behavior was associated with less tobacco and combined alcohol/tobacco use. Religiosity plays an important role in the control of alcohol and tobacco use in a shantytown setting; further management initiatives in the area should consider this issue. The study's limitations are noted.

Increased variability of motor cortical excitability to transcranial magnetic stimulation in migraine: a new clue to an old enigma.

Increased, decreased or normal excitability to transcranial magnetic stimulation (TMS) has been reported in the motor (M1) and visual cortices of patients with migraine. Light deprivation (LD) has been reported to modulate M1 excitability in control subjects (CS). Still, effects of LD on M1 excitability compared to exposure to environmental light exposure (EL) had not been previously described in patients with migraine (MP). To further our knowledge about differences between CS and MP, regarding M1 excitability and effects of LD on M1 excitability, we opted for a novel approach by extending measurement conditions. We measured motor thresholds (MTs) to TMS, short-interval intracortical inhibition, and ratios between motor-evoked potential amplitudes and supramaximal M responses in MP and CS on two different days, before and after LD or EL. Motor thresholds significantly increased in MP in LD and EL sessions, and remained stable in CS. There were no significant between-group differences in other measures of TMS. Short-term variation of MTs was greater in MP compared to CS. Fluctuation in excitability over hours or days in MP is an issue that, until now, has been relatively neglected. The results presented here will help to reconcile conflicting observations.

New daily persistent headache and panic disorder.

BACKGROUND: New daily persistent headache (NDPH) is a primary chronic daily headache that is generally considered to be difficult to treat. Migraine has been linked to comorbid psychiatric conditions, mainly mood and anxiety disorders, but NDPH has never been linked to psychiatric conditions, and never studied extensively for such an association. CASE: We report nine cases (six women and three men) of patients diagnosed with NDPH and panic disorder who were treated for both conditions. Six of them (66%) had good or excellent responses. CONCLUSION: The spectrum of anxiety disorders, particularly panic disorder, should be considered in NDPH patients. Simultaneous treatment of both disorders may lead to good outcomes.

The prevalence of migraine and probable migraine in a Brazilian favela: results of a community survey.

OBJECTIVES: The objectives of the present study were to estimate the 1-year prevalence of primary headaches and the role of select socio-demographic aspects in a representative sample of adults living in a Brazilian shanty town. BACKGROUND: Some socio-demographic factors, such as marital status, income, education, and job status have been described in studies with contentious results. Nevertheless, few studies have assessed the prevalence of headache and the role of socio-demographic aspects in very low-income communities. METHODS: A cross-sectional, population-based study was undertaken. Door-to-door interviews with 383 people were conducted. Individuals were aged greater than 18 years, randomly selected from the "Paraisopolis" shanty town in São Paulo, Brazil. The degree of the association was calculated through prevalence ratios and adjusted with backward logistic regression by gender, age, and some socio-demographic factors, including living conditions. RESULTS: The estimated 1-year prevalence of headache, migraine, chronic migraine, and tension-type headache were 47% (CI 95%: 39.5-52.6%), 20.4% (CI 95%: 16.6-24.9%), 8.4% (CI 95%: 6.1-12.0%), and 6.2% (CI 95%: 3.3-9.8%), respectively. Migraine was more prevalent in women and among employed people. No other relationship was found. The overall prevalence of migraine and chronic migraine in this very low-income community were high and migraine was associated with gender and job status. CONCLUSION: The overall prevalence of migraine and chronic migraine in this very low-income community were high and tension-type headache was low. A paradox was noted in the employment status and income association, one would expect higher levels of migraine in a low-income population, but higher numbers were found in those employed vs unemployed. These findings will need to be replicated in other population samples.

Primary headaches in patients with generalized anxiety disorder.

Although anxiety disorders and headaches are comorbid conditions, there have been no studies evaluating the prevalence of primary headaches in patients with generalized anxiety disorder (GAD). The aim of this study was to analyze the lifetime prevalence of primary headaches in individuals with and without GAD. A total of 60 individuals were evaluated: 30 GAD patients and 30 controls without mental disorders. Psychiatric assessments and primary headache diagnoses were made using structured interviews. Among the GAD patients, the most common diagnosis was migraine, which was significantly more prevalent among the GAD patients than among the controls, as were episodic migraine, chronic daily headache and aura. Tension-type headache was equally common in both groups. Primary headaches in general were significantly more common and more severe in GAD patients than in controls. In anxiety disorder patients, particularly those with GAD, accurate diagnosis of primary headache can improve patient management and clinical outcomes.

Religious Affiliations Influence Health-Related and General Decision Making: A Brazilian Nationwide Survey.

Approximately 90% of the world's population is involved in some spiritual/religious practice, and this dimension has a relevant role in life. Many studies demonstrate the associations between spirituality/religiosity (S/R), and physical, mental, and social health. Systematic reviews have indicated positive associations; however, the mechanisms behind religious coping are not fully understood. The present study aimed to examine the role of religious affiliation in general (ordinary) and health-related decisions. A nationwide, population-based, cross-sectional study was conducted in Brazil using a self-administered online survey. How much religious affiliation influences decision making was investigated. A total of 1133 participants were included, who were classified as Catholics (43.9%), Evangelicals (18.7%), spiritualists (12.8%), non-religious (11.9%), and others (12.7%). Most participants (66.5%) believed that their religious affiliations had moderate to high influences on their decisions. Participants rated the influence as high in marriage (62.7%), in donations (60.1%), in volunteering (55%), in friendships (53.9%), and in work (50.5%). Concerning health-related decisions, the influence was rated as high in drug use (45.2%), in accepting medical recommendations (45%), and in smoking (43.2%). The influence of religious affiliation on general decision making was significantly correlated for dietary restrictions (r = 0.462), alcohol consumption (r = 0.458), drug use (r = 0.441), tobacco consumption (r = 0.456), and refusal of medical recommendations (r = 0.314). Improving the understanding of how a patient's beliefs, practices, and experiences affect their health may help healthcare practitioners to take into account religious considerations, not only regarding influences on habits but also regarding adherence to medical treatment advice.

Lasmiditan efficacy in migraine attacks with mild vs. moderate or severe pain.

OBJECTIVE: To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity. METHODS: Pooled data from two single-attack, placebo-controlled studies (SAMURAI [NCT02439320] and SPARTAN [NCT02605174]), and a prospective, randomized, open-label study (GLADIATOR [NCT02565186]) were assessed. Efficacy measures included the proportion of attacks with 2-h pain freedom (PF), 2-h most bothersome symptom (MBS) freedom, and 24-h sustained pain freedom (SPF). Fisher's exact test was used to compare the proportion of PF, SPF, or MBS freedom outcomes among attacks treated at mild, moderate, or severe pain. RESULTS: In SAMURAI and SPARTAN, most treated attacks were of moderate (N = 2768) or severe (N = 1147) intensity, compared to mild (N = 65). Numerically greater 2-h PF and 24-h SPF response rates were observed in attacks treated at mild compared to moderate or severe pain. Analysis of GLADIATOR data included 273 (1.5%), 11,644 (65.1%), and 5948 (33.3%) attacks treated when pain was mild, moderate, and severe, respectively. In general, a significantly greater proportion of attacks treated at mild pain achieved 2-h PF and MBS freedom, as well as 24-h SPF. The incidence of treatment-emergent adverse events in LTN treatment groups were similar regardless of baseline head pain intensity. CONCLUSIONS: Data from two placebo-controlled, single-attack trials, and an open-label study including treatment of multiple attacks, suggested a tendency to relatively better efficacy outcomes when LTN treatment was initiated at mild vs. moderate to severe pain. Further research is needed to better understand the relationship of lasmiditan outcomes to the time of administration in the course of a migraine attack.

Effect of a change in lasmiditan dose on efficacy and safety in patients with migraine.

Background: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg.Objective: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses.Methods: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study. Eight patient groups were created based on the initial dose received in SAMURAI or SPARTAN and the subsequent dose in GLADIATOR: placebo-100, placebo-200, 50-100, 50-200, 100-100, 100-200, 200-100, 200-200. Migraine pain freedom, migraine-related functional disability freedom, most bothersome symptom (MBS) freedom, and pain relief were evaluated at 2-h post-dose. The occurrence of most common treatment-emergent adverse events (MC-TEAE) was evaluated. Shift analyses were performed for pain freedom and ≥1 MC-TEAE. The incidence of patients with a specific outcome from the first and subsequent doses were compared within each dose change group using McNemar's test.Results: Small, but consistent, increases in incidences of pain freedom, migraine-related functional disability freedom, MBS freedom, and pain relief occurred when the second lasmiditan dose was higher than the initial dose. For patients starting on 50 mg, increasing to 100 or 200 mg provided a positive efficacy-TEAE balance, despite an increase in incidence of ≥1 MC-TEAE. For patients starting on 100 mg, increasing to 200 mg provided a positive efficacy-TEAE balance. If the initial dose was 100 or 200 mg, the incidence of patients experiencing ≥1 MC-TEAE decreased or stayed the same with their subsequent dose, regardless of dose. Decreasing from 200 to 100 mg led to a decrease in patients with pain freedom and ≥1 MC-TEAE, resulting in a neutral efficacy-TEAE balance. Shift analyses supported these findings.Conclusion: A positive efficacy-TEAE balance exists for patients increasing their lasmiditan dose for treatment of a subsequent migraine attack. These results could be important for optimizing dosing for individual patients.Clinicaltrials.gov: SAMURAI (NCT02439320); SPARTAN (NCT02605174); GLADIATOR (NCT02565186).

Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities.

OBJECTIVE: To assess urinary 6-sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls. BACKGROUND: Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and headache disorders. METHODS: Urine samples were collected into a single plastic container over a 12-hour period from 8:00 pm to 8:00 am of the next day, and 6-sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State-Trait Anxiety Inventory, and the Beck Depression Inventory. RESULTS: A total of 220 subjects were evaluated - 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6-sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6-sulphatoxymelatonin levels and depression, anxiety, and fatigue. CONCLUSIONS: To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.