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1.

Purpose of Review

This review evaluates and explains our current understanding of a rare subtype of migraine, typical aura without headache, also known as migraine aura without headache or acephalgic migraine.

Recent Findings

Typical aura without headache is a known entity within the spectrum of migraine. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. No clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura. Bilateral greater occipital nerve blocks may be helpful in aborting migraine with prolonged aura. Transcranial magnetic stimulation has shown efficacy in aborting attacks of migraine with aura but has not been specifically tested in isolated aura.

Summary

Typical aura without headache occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura. Typical aura without headache commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment.
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2.

Purpose

Migraine is associated with vascular disorders, but the underlying mechanism is unknown. Nitric oxide (NO) sensitivity is believed to play a major role in migraine pathophysiology. We investigated flow-mediated vasodilatation (FMD) and nitroglycerin-mediated vasodilatation (NMD) of the brachial artery by means of a key molecular mediator, NO, in patients with migraine without aura in the interictal period whether the abnormality is found.

Methods

A total of 12 patients with migraine without aura and 12 matched healthy controls were enrolled in this study. FMD and NMD were measured in all patients and controls using brachial artery ultrasonography.

Results

There was no significant difference in brachial artery diameter between migraineurs and nonmigraineurs (3.39?±?0.68 vs 3.89?±?0.67 mm, respectively; p?=?0.083). A significant difference in FMD was not found between migraineurs and nonmigraineurs (6.94?±?5.72 vs 6.08?±?2.98%, respectively; p?=?0.651). However, NMD in migraineurs was significant higher than that in nonmigraineurs (21.56?±?7.36 vs 14.23?±?7.41%, respectively; p?=?0.024).

Conclusion

We think that patients with migraine without aura in the interictal period have selective sensitivity in dilator response to nitroglycerin and may have systemic NO sensitivity.
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3.

Purpose of Review

Vasoactive peptides play a key role in the attack-initiating cascade of migraine. Recent studies have highlighted a potentially important role for endothelin-1, a potent vasoconstrictor peptide, in migraine pathophysiology. Here, we review the current data on endothelin’s involvement in migraine.

Recent Findings

We identified 23 articles. Nine studies reported on endothelin-1 plasma concentrations in patients with migraine, eight studies investigated relevant genetic associations, five studies investigated endothelin-1 and spreading depression in animals, and one randomized controlled clinical trial tested the efficacy of an endothelin antagonist in the acute treatment of migraine in patients both with and without aura. Elevated endothelin-1 plasma levels have been reported in the early phase of migraine attacks. Genetic abnormalities related to the endothelin type A receptor have been reported in migraineurs. Endothelin-1 potently induces spreading depression in animals, which may explain the connection between endothelial irritation and migraine aura.

Summary

Endothelin-1 could be a primary factor in the attack-triggering cascade of migraine attacks with and without aura. Additional studies in humans and animal models are needed to further elucidate the role of endothelin-1 in migraine.
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4.

Purpose of Review

It is sometimes assumed that children and adolescents with migraine have a psychiatric or behavioral comorbidity, a belief that can be stigmatizing. This review will examine the recent literature addressing this area to determine if pediatric and adolescent migraineurs are at increased risk for psychiatric comorbidity and to discuss management strategies.

Recent Findings

A large systematic review of pediatric and adolescent studies concluded anxiety and depression were not associated with onset of recurrent headaches. Children with increasing migraine frequency have reduced school attendance. Pediatric migraineurs have mildly lower quality of life (QOL) scores than healthy peers but not abnormally low. Finally, children with higher migraine frequency as well as migraineurs with aura were more likely to report suicidal ideation.

Summary

Migraine is a primary neurologic disorder. Migraine and psychiatric disorders may be comorbid; however, at this time, it can be difficult to clearly delineate some migraine features from psychiatric diagnoses with the current screening tools available. The majority of pediatric migraineurs do not have behavioral comorbidities; however, when such comorbidities occur, they should be addressed and appropriately managed. We need more accurate ways of delineating psychiatric and behavioral comorbidities from the migraine phenotype.
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5.

Background

Resting state magnetic resonance imaging allows studying functionally interconnected brain networks. Here we were aimed to verify functional connectivity between brain networks at rest and its relationship with thalamic microstructure in migraine without aura (MO) patients between attacks.

Methods

Eighteen patients with untreated MO underwent 3 T MRI scans and were compared to a group of 19 healthy volunteers (HV). We used MRI to collect resting state data among two selected resting state networks, identified using group independent component (IC) analysis. Fractional anisotropy (FA) and mean diffusivity (MD) values of bilateral thalami were retrieved from a previous diffusion tensor imaging study on the same subjects and correlated with resting state ICs Z-scores.

Results

In comparison to HV, in MO we found significant reduced functional connectivity between the default mode network and the visuo-spatial system. Both HV and migraine patients selected ICs Z-scores correlated negatively with FA values of the thalamus bilaterally.

Conclusions

The present results are the first evidence supporting the hypothesis that an abnormal resting within networks connectivity associated with significant differences in baseline thalamic microstructure could contribute to interictal migraine pathophysiology.
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6.

Purpose of Review

Symptoms of autonomic dysfunction are common in patients with migraine, both during and between migraine attacks. Studies evaluating objective autonomic testing in patients have found significant, though somewhat conflicting results. The purposes of this review are to summarize and interpret the key findings of these studies, including those evaluating heart rate variability, autonomic reflex testing, and functional imaging in patients with migraine. The neuroanatomy of the central autonomic network as it relates to migraine is also reviewed.

Recent Findings

Several studies have evaluated autonomic balance in migraineurs, with conflicting results on the magnitude of sympathetic versus parasympathetic dysfunction. Most studies demonstrate sympathetic impairment, with a lesser degree of parasympathetic impairment.

Summary

Three trends have emerged: (1) migraine with aura tends to produce more significant autonomic dysfunction than migraine without aura, (2) sympathetic impairment is more common than parasympathetic impairment, and (3) sympathetic impairment is common in the interictal period, with increased sympathetic responsiveness during the ictal period, suggesting adrenoreceptor hypersensitivity.
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7.

Purpose of review

The goal of this review is to provide an actualized overview on vestibular migraine in childhood and adolescence, with focus on the epidemiology and clinical presentation as well as its treatment.

Recent findings

Vertigo spells in childhood can evolve into other periodic syndromes and/or migraine types and persist even into adulthood.

Summary

Vestibular migraine (VM) and benign paroxysmal vertigo are the most common causes of vertigo in children and adolescents. The diagnostic criteria for VM are dizziness and vertigo, headache, phonophobia and photophobia, and visual aura. The prevention of attacks is the treatment for children and adolescents with VM, as is recommended for migraine with or without aura. Thus, non-pharmacological measures are the first-line option; when these measures fail or daily activities are notably affected, drugs are administrated. Psychological assessment and cognitive behavioral therapy are also important therapeutic measures in this patient group. There is still insufficient research on VM in children and adolescents; future studies on clinical presentation, evolvement, and specific treatment are necessary.
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8.

Background

Migraine is characterized by a series of phases (inter-ictal, pre-ictal, ictal, and post-ictal). It is of great interest whether resting-state electroencephalography (EEG) is differentiable between these phases.

Methods

We compared resting-state EEG energy intensity and effective connectivity in different migraine phases using EEG power and coherence analyses in patients with migraine without aura as compared with healthy controls (HCs). EEG power and isolated effective coherence of delta (1–3.5 Hz), theta (4–7.5 Hz), alpha (8–12.5 Hz), and beta (13–30 Hz) bands were calculated in the frontal, central, temporal, parietal, and occipital regions.

Results

Fifty patients with episodic migraine (1–5 headache days/month) and 20 HCs completed the study. Patients were classified into inter-ictal, pre-ictal, ictal, and post-ictal phases (n?=?22, 12, 8, 8, respectively), using 36-h criteria. Compared to HCs, inter-ictal and ictal patients, but not pre- or post-ictal patients, had lower EEG power and coherence, except for a higher effective connectivity in fronto-occipital network in inter-ictal patients (p?<?.05). Compared to data obtained from the inter-ictal group, EEG power and coherence were increased in the pre-ictal group, with the exception of a lower effective connectivity in fronto-occipital network (p?<?.05). Inter-ictal and ictal patients had decreased EEG power and coherence relative to HCs, which were “normalized” in the pre-ictal or post-ictal groups.

Conclusion

Resting-state EEG power density and effective connectivity differ between migraine phases and provide an insight into the complex neurophysiology of migraine.
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9.

Background

Migraine is a neurological disorder resulting in large socioeconomic burden. This network meta-analysis (NMA) is designed to compare the relative efficacy and tolerability of non-steroidal anti-inflammatory agents (NSAIDs) and triptans.

Methods

We conducted systematic searches in database PubMed and Embase. Treatment effectiveness was compared by synthesizing direct and indirect evidences using NMA. The surface under curve ranking area (SUCRA) was created to rank those interventions.

Results

Eletriptan and rizatriptan are superior to sumatriptan, zolmitriptan, almotriptan, ibuprofen and aspirin with respect to pain-relief. When analyzing 2 h-nausea-absence, rizatriptan has a better efficacy than sumatriptan, while other treatments indicate no distinctive difference compared with placebo. Furthermore, sumatriptan demonstrates a higher incidence of all-adverse-event compared with diclofenac-potassium, ibuprofen and almotriptan.

Conclusion

This study suggests that eletriptan may be the most suitable therapy for migraine from a comprehensive point of view. In the meantime ibuprofen may also be a good choice for its excellent tolerability. Multi-component medication also attracts attention and may be a promising avenue for the next generation of migraine treatment.
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10.

Purpose of Review

Migraine is a disabling and prevalent neurological disease, commonly affecting women during their reproductive years. It is crucial for providers to be able to adequately counsel women who are pregnant, planning pregnancy, or nursing, regarding preventive and abortive treatment options for episodic migraine. This review will discuss (1) the expected course of migraine during pregnancy and the post-partum period, (2) recommended preventive therapies for migraine during pregnancy and lactation, and (3) recommended abortive medications for migraine during pregnancy and lactation.

Recent Findings

Recent research has indicated safety for triptan use during pregnancy and ibuprofen use during the first trimester of pregnancy. Considerations for use of emerging migraine-preventive treatment, such as non-invasive neurostimulators, are discussed.

Summary

For clinical decision-making and patient counseling, it is important to understand both the limitations in determining teratogenic effects in humans and the principles affecting medication transmission from mother to breast milk.
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11.

Purpose of Review

In contrast to well-established relationships between headache and affective disorders, the role of alcohol use in primary headache disorders is less clear. This paper provides a narrative overview of research on alcohol use disorders (AUDs) in primary headache and presents a meta-analysis of the role of alcohol as a trigger (precipitant) of headache.

Recent Findings

The majority of studies on AUDs in headache have failed to find evidence that migraine or tension-type headache (TTH) is associated with increased risk for AUDs or problematic alcohol use. The meta-analysis indicated that 22% (95% CI: 17–29%) of individuals with primary headache endorsed alcohol as a trigger. No differences were found between individuals with migraine (with or without aura) or TTH. Odds of endorsing red wine as a trigger were over 3 times greater than odds of endorsing beer.

Summary

An absence of increased risk for AUDs among those with primary headache may be attributable to alcohol’s role in precipitating headache attacks for some susceptible individuals. Roughly one fifth of headache sufferers believe alcohol precipitates at least some of their attacks. Considerable study heterogeneity limits fine-grained comparisons across studies and suggests needs for more standardized methods for studying alcohol-headache relationships and rigorous experimental designs.
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12.

Purpose of Review

Migraine is a common and highly disabling condition that is particularly prevalent among women and especially women of reproductive age. The tremendous rise in adiposity in the Western world has led to an epidemic of obesity in women. The particular effects of obesity on women with migraine of various ages are the focus of this review.

Recent Findings

Conflicting findings from various studies with different approaches and populations have made challenging definitive conclusions about associations between migraine and obesity. While the association between obesity and migraine frequency has been consistently demonstrated and obesity is considered a risk factor for progression from episodic to chronic migraine, the association between obesity and migraine prevalence is still somewhat debated and appears to be dependent on gender and age, with the most consistent effects observed in women younger than 55 years of age.

Summary

Association between migraine and obesity is most commonly observed in women of reproductive age. The multimodal changes associated with age and hormonal change in women likely play a role in this relationship, as obesity does not appear to be related to migraine in women over 55 years of age. Future studies focusing on the migraine-obesity relationship in women should examine the effects of age, endogenous hormonal state, and exogenous hormones on migraine and obesity.
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13.

Background

The precuneus/posterior cingulate cortex, which has been associated with pain sensitivity, plays a pivotal role in the default mode network. However, information regarding migraine-related alterations in resting-state brain functional connectivity in the default mode network and in local regional spontaneous neuronal activity is not adequate.

Methods

This study used functional magnetic resonance imaging to acquire resting-state scans in 22 migraineurs without aura and in 22 healthy matched controls. Independent component analysis, a data-driven method, was used to calculate the resting-state functional connectivity of the default mode network in the patient and healthy control groups. Regional homogeneity (ReHo) was used to analyse the local features of spontaneous resting-state brain activity in the migraineurs without aura.

Results

Compared with the healthy controls, migraineurs without aura showed increased functional connectivity in the left precuneus/posterior cingulate cortex within the default mode network and significant increase in ReHo values in the bilateral precuneus/posterior cingulate cortex, left pons and trigeminal nerve entry zone. In addition, functional connectivity was decreased between the areas with abnormal ReHo (using the peaks in the precuneus/posterior cingulate cortex) and other brain areas.

Conclusions

The abnormalities in the precuneus/posterior cingulate cortex suggest that migraineurs without aura may exhibit information transfer and multimodal integration dysfunction and that pain sensitivity and pian processing may also be affected.
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14.

Background

Although the comorbidity of migraine and restless legs syndrome (RLS) has been well-documented, the association between RLS and migraine frequency has yet to be elucidated. The present study aims to evaluate the prevalence of RLS among individuals who experience low-frequency, high-frequency, or chronic migraine presenting with and without aura.

Methods

We conducted a cross-sectional, case-controlled study involving 505 participants receiving outpatient headache treatment. Standardized questionnaires were administered to collect information on experiences of migraine, RLS, sleep quality, anxiety, depression, and demographics. Participants were categorized into low-frequency (1–8/month), high-frequency (9–14/month), and chronic (≥15/month) headache groups. RLS was diagnosed according to the criteria outlined by the International RLS Study Group (IRLSSG). The Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) were used to assess sleep quality and identify symptoms of anxiety and depression. Associations between migraine frequency and RLS prevalence were investigated using multivariate linear and logistic regression.

Results

Univariate analysis revealed an effect of migraine frequency on RLS prevalence (p?=?0.026), though this effect did not persist following adjustment for baseline characteristics (p?=?0.256). The trend was robust in patients whose migraines presented with auras (p univariate?=?0.002; p multivariate?=?0.043) but not in those without auras (p univariate and p multivariate?>?0.05). Higher anxiety [odds ratio (OR)?=?1.18, p?=?0.019] and sleep disturbance (OR?=?1.17, p?=?0.023) scores were associated with higher RLS prevalence.

Conclusions

Higher migraine frequency correlates with a higher prevalence of RLS, particularly among patients with auras.
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15.

Purpose of Review

The biological and pathophysiological interaction between sleep and chronic migraine (CM) remains to be fully elucidated. In this article, we provide a narrative review of the literature on sleep disturbance and CM, highlighting recent advances in sleep research and insights into mechanisms that could mediate a role of sleep disturbances in migraine chronification. We discuss the potential for cognitive-behavioral insomnia therapy (CBTi) as an intervention for CM with comorbid insomnia. Finally, we propose a model of the mechanisms underlying the interactions among sleep physiology, maladaptive migraine-coping behaviors, and coexisting factors which contribute to sleep disturbances in CM based on conceptual models used in sleep research.

Recent Findings

Insomnia is the most common sleep complaint among patients with CM. CM patients experience more frequent and severe insomnia symptoms than patients with episodic migraine (EM). It has been suggested that sleep disturbances may predispose individuals to migraine attacks, which may affect the pain-processing trigeminovascular system and thus play a role in migraine progression. Encouraging but limited evidence suggests that management of insomnia via behavioral sleep therapy may reverse CM to EM and possibly prevent migraine chronification.

Summary

Migraine has a complex relationship with sleep. The use of objective sleep study such as polysomnographic microstructural sleep analysis and actigraphy could help connect sleep disturbances and processes related to CM. Future longitudinal studies should examine whether effective behavioral treatments such as CBTi can reverse migraine chronification.
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16.

Purpose of Review

This review is intended to examine how the diagnostic criteria for migraine have evolved over the past 45 years and to evaluate the strengths and weaknesses of the current diagnostic criteria promulgated by the International Classification of Headache Disorders (ICHD).

Recent Findings

The ICHD is a comprehensive and systematic classification system for headache disorders. As the pathophysiology of migraine is more fully elucidated and more sophisticated diagnostic technologies are developed (e.g., the identification of biomarkers), the current diagnostic criteria for migraine will likely be further refined. The ICHD has allowed for more precise research study design in the field of headache medicine.

Summary

The current diagnostic criteria for migraine outlined in the 3rd version of the ICHD are far more sensitive and specific than the clinical criteria proposed in 1962. In future iterations, dividing episodic and chronic migraine into subtypes based on frequency (i.e., low frequency vs high frequency; near-daily vs daily) potentially could assist in guiding clinical management. In addition, a better understanding of aura, vestibular migraine, migrainous infarction, and hemiplegic migraine likely will lead to more refined diagnostic criteria for those entities.
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17.

Purpose of Review

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an important disease to consider in the differential diagnosis of migraine with aura. This review examines current literature regarding migraine in CADASIL, as well as diagnostic and treatment modalities.

Recent Findings

Recent studies have shown that smoking is a modifiable risk factor for progression of CADASIL (Chabriat et al. in Stroke 47:4–11, 2015). Specific imaging changes and findings on clinical exam can predict disease progression. However, migraine symptoms often precede MRI changes (Guey et al. in Cephalalgia 36:1038–47, 2015). A recent paper on migraine treatment in CADASIL reevaluates the prevailing belief that vasoconstrictive abortive medications are contraindicated in these patients (Tan and Markus in PLoS ONE 11:e0157613, 2016).

Summary

CADASIL is an autosomal dominantly inherited vasculopathy causing ischemic pathology in younger individuals due to a mutation in the NOTCH3 gene. The mutation results in impaired arterial contractility due to accumulation of granular osmiophilic extracellular material (GOM) in vascular smooth muscle cells (VSMCs). Clinical manifestations include migraine with and without aura, cognitive decline, ischemic events, and mood disorders. The presenting symptom is often migraine with aura. Characteristic MRI changes are often present. Genetic screening is available to confirm NOTCH3 mutation and pathognomic changes are often seen in skin biopsy. Treatment of migraine is similar to the general population, but with some notable and specific differences. Further studies in CADASIL, other small vessel arteriopathies, and migraine may help us understand more about the pathophysiology of these conditions and help with treatment development.
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18.

Purpose of the Review

The goals of this review are to evaluate recent studies regarding comorbidity between migraine and different metabolic and endocrine disorders and to discuss the role of insulin resistance as a common pathogenetic mechanism of these diseases.

Recent Findings

Recently, several studies showed that migraine is associated with insulin resistance, a condition in which a normal amount of insulin induces a suboptimal physiological response. All the clinical studies that used the oral glucose tolerance test to examine insulin sensitivity found that, after glucose load, there is in migraine patients a significant increase of both plasmatic insulin and glucose concentrations in comparison with controls. On the contrary, no association was found between migraine and type 2 diabetes, while type 1 diabetes seems to have a protective effect in the disease. Obesity and hypertension were shown to be risk factors for both episodic and chronic migraine. Metabolic syndrome has been recently associated mainly with migraine with aura and is now considered a risk factor also for medication overuse headache. Finally, a bidirectional association between migraine and hypothyroidism has been recently demonstrated, suggesting that common genetic or autoimmune mechanisms underlie both diseases.

Summary

Recent studies showed that insulin receptor signaling and the related physiological responses are altered in migraine and may have a relevant pathogenic role in the disease. Further studies are warranted in order to better elucidate mechanisms underlying insulin resistance in migraine in order to develop new therapeutic strategies for this debilitating disease.
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19.

Purpose of Review

Episodic migraine is common. Everyday behavioral patterns are associated with migraine attacks and disability. This paper reviews health behaviors that can be targeted in people with episodic migraine to enhance migraine-related outcomes.

Recent Findings

Stressful events and perceived stress have demonstrated associations with migraine attack onset among people with episodic migraine. Consistency in daily patterns (eating, sleeping, exercise, and hydration status) is also associated with migraine activity. Sleep deprivation, fatigue, and poor quality sleep have demonstrated relationships with migraine attack onset, as well as headache frequency and headache-related disability in people with episodic migraine.

Summary

The health behaviors implicated in episodic migraine are part of everyday patterns and can be targeted routinely in clinical practice to improve migraine management. Behavior change is challenging and should ideally be supported by a multidisciplinary team. Future research should focus on evaluating specific behavior change interventions and the relative impact of behavior on migraine outcomes in high- and low-frequency episodic migraine.
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20.

Introduction

Large postmarketing surveillance (PMS) studies have demonstrated the efficacy and tolerability of frovatriptan for treatment of acute migraine in patients attending general practitioners (GPs). The aim of the ALADIN (Allegro® Anwendung durch interessierte Neurologen [Allegro® application by interested neurologists]) PMS study was to evaluate frovatriptan in patients attending neurologists or pain therapists.

Methods

Patients fulfilling International Headache Society criteria for migraine, with or without aura, were enrolled. Patients completed an attack diary, including details of the attack, time to onset of action of frovatriptan, and recurrence of headache. Physicians completed a case report form detailing prior and actual migraine treatment. Frovatriptan 2.5 mg was administered for up to three consecutive attacks.

Results

In total, 2160 patients were enrolled and data were obtained for 5831 attacks. Patients attending neurologists had more frequent attacks and longer history of migraine compared with those attending GPs. Median time to frovatriptan onset of action was 40 min and time to freedom from headache 70 min. An average of 1.2 frovatriptan tablets was required per attack, and mean additional analgesic use was 0.13. Recurrent headache occurred in 13.6%–15.5% of patients. Physicians as well as patients judged frovatriptan onset and duration of action as at least “good” in approximately 80% of attacks. A similar number judged the efficacy of frovatriptan against headache as “better” than previous treatment. The study drug was generally well tolerated. The frequency of adverse events was 0.6%.

Conclusion

Frovatriptan, with fast onset of action and low rate of headache recurrence, was efficacious and well accepted by migraineurs attending neurologists or pain therapists. Approximately 80% of patients wished to continue migraine treatment with frovatriptan.
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