Cephalalgia

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Online ISSN: 1468-2982
Publications
Characteristics of the study population by headache subtype. 
Association between stress increase on VAS and headache frequency. 
Article
We studied the association between stress intensity and headache frequency for tension-type headache (TTH), migraine and migraine with coexisting TTH (MigTTH). We studied a population-based sample of 5159 participants (21-71 years) who were asked quarterly between March 2010 and April 2012 about headache and stress. Log-linear regression in the framework of generalized estimating equations was used to estimate regression coefficients presented as percent changes to describe the association between stress intensity (modified visual analog scale (VAS) from 0 to 100) and headache frequency (days/month) stratified by headache subtypes and age groups and adjusted for sex, age, frequent intake of acute pain drugs, drinking, smoking, BMI and education. TTH was reported in 31% participants (48.1 ± 12.5years, 51.5% women, 2.2 ± 3.9 mean headache days/month, 52.3 ± 26.7 mean stress), migraine in 14% (44.8 ± 11.3years, 73.3%, 4.5 ± 5.2 days/month, 62.4 ± 23.3), MigTTH in 10.6% (43.5 ± 11.5 years, 61.0%, 3.6 ± 4.8 days/month, 58.6 ± 24.1), 23.6% were unclassifiable, and 20.8% had no headache. In participants with TTH an increase of 10 points on VAS was associated with an increase of headaches days/month of 6.0% (adjusted). Higher effects were observed in younger age groups (21-30/31-40/41-50/51-60/61-71 years: 9.8/10.2/7.0/6.5/3.5%). Slightly lower effects were observed for migraine (4.3%, 8.1/5.1/3.4/6.3/0.3%) and MigTTH (4.2%, 5.5/6.8/6.9/5.8/-0.7%). Our study provides evidence for an association between stress intensity and headache frequency. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
 
Article
Cluster headache (CH) is a debilitating disorder characterized by unilateral, severe pain attacks with accompanying autonomic symptoms, often waking the patient from sleep. As it exhibits strong chronobiological traits and genetic studies have suggested a link with the hypocretin (HCRT) system, the objective of this study was to investigate HCRT-1 in CH patients. Cerebrospinal fluid HCRT-1 concentration was measured in 12 chronic and 14 episodic CH patients during an active bout, and in 27 healthy controls. The patients were well characterized and clinical features compared to the HCRT concentration. We found significantly lower HCRT levels both in chronic (p = 0.0221) and episodic CH (p = 0.0005) patients compared with controls. No significant relationship was found with other clinical features. This is the first report of significantly reduced HCRT concentrations in CH patients. We speculate that decreased HCRT may reflect insufficient antinociceptive activity of the hypothalamus. The mechanism of the antinociceptive effect of HCRT is not known and requires further investigation. This study supports the hypothesis of a connection between arousal regulation and CH. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
 
Article
Rizatriptan is a potent, highly selective 5HT1B/1D agonist with rapid onset of action for acute treatment of migraine. Rizatriptan wafer is a novel, freeze-dried dosage formulation of rizatriptan which rapidly disintegrates on the tongue, is swallowed with saliva, and may be taken without liquids. The efficacy and tolerability of rizatriptan wafer were examined in a placebo-controlled, double-blind, outpatient study in 555 migraineurs. The primary efficacy endpoint was pain relief at 2 h. From 30 min onwards, significantly more patients experienced pain relief and became pain-free after rizatriptan 10-mg wafer compared to placebo. At 2 h, the percentage of patients with pain relief was significantly higher after rizatriptan 10-mg wafer (74%), 5-mg wafer (59%) compared with placebo (28%). Rizatriptan 10-mg wafer was superior to rizatriptan 5-mg wafer on pain relief at 1.5 and 2 h (p < 0.05). Significantly more patients were pain-free at 2 h after rizatriptan 10-mg wafer (42%), 5-mg wafer (35%) compared with placebo (10%). Both doses of rizatriptan wafer were well tolerated. Rizatriptan wafer is a convenient, highly effective new formulation for acute treatment of migraine.
 
Article
The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period. A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose timepoints over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times. The mean difference in time-weighted (0-2.5 h) MAP (90% confidence interval) was 1.2 mmHg (-0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6h and Cmax of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels. Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.
 
Article
The International Headache Society (IHS) diagnostic criteria for headache improved the accuracy of primary headache diagnoses, including migraine. However, many migraineurs receive an 'atypical migraine' diagnosis according to the IHS nosology (IHS 1.7), indicating that they approximate but do not fully meet all IHS criteria. This study characterized and sub-classified patients with atypical migraine. Within a clinical sample of 382 headache sufferers, 83 patients met IHS criteria for 'atypical migraine'. Patients receiving the IHS 1.7 designation did not converge to form a homogeneous group. Rather, distinct and clinically relevant subgroups were empirically derived (e.g. migraine with atypical pain parameters, brief migraine, chronic migraine). The results call for revisions of the IHS diagnostic criteria for migraine that would minimize the number of patients receiving an atypical diagnosis. Revisions would include decreasing the minimum headache duration criteria from 4 h to 2 h, and developing a classification for 'chronic migraine' for migraine greater than 15 days per month. The proposed revision provides a means of diagnosing the daily and near-daily headache commonly observed in clinical populations.
 
Article
Therapies in current use for episodic tension-type headache (ETTH) are often unsatisfactory. Few trials have been conducted to demonstrate efficacy of any of them. This multicenter placebo-controlled randomized parallel-groups study compared the analgesic efficacy of single oral doses of ketoprofen 25 mg and acetaminophen 1000 mg as outpatient treatment of 1 attack of ETTH. Efficacy was assessed by patients as pain relief on a diary-entered 7-point categorical scale. A total of 457 patients treated 348 attacks, 330 of which were evaluable. There were no serious adverse events (AEs); gastrointestinal AEs were most common on all treatments. Total relief from pain after 2 h was recorded by 16% of patients on placebo, 28% on ketoprofen, and 22% on acetaminophen. Worthwhile effect or total relief (all other responses were regarded as treatment failures) were recorded by 36% on placebo, 70% on ketoprofen (p < 0.001), 61% on acetaminophen (p < 0.001). The difference between ketoprofen and acetaminophen was not significant (p = 0.24). Various secondary efficacy measures confirmed superiority of both active treatments over placebo, with some trends for slightly better outcome on ketoprofen that on acetaminophen. This study demonstrates that ketoprofen is an effective alternative to standard therapy in ETTH.
 
Article
The purpose of this study was to compare the efficacy and tolerance of a single dose of the acetaminophen 400 mg-codeine 25 mg combination (ACC) aspirin 1000 mg (A) and a placebo (P) for the treatment of acute migraine attack. The study design was randomized, multicentre, double-blind and double dummy with cross-over on three periods. Of the 198 patients who had three attacks 29.8%, 52.3% and 49.7% had recorded the complete or almost complete disappearance of the pain at 2 h after P, A and ACC respectively. When compared with the placebo, the difference was significant for the A and ACC. When complete disappearance of pain at 2 h was used as a criterion, no significant difference was observed. These results enabled the sensitivity of the evaluation criteria suggested for clinical trials of migraine attack to be discussed.
 
Article
In this multicentre, randomized, double-blind, single-dose study a total of 374 patients generally suffering from migraine attacks suitable for treatment with non-prescription drugs, received either oral acetylsalicylic acid effervescent 1000 mg (ASAE) or effervescent placebo for the treatment of an acute migraine attack. Of the 343 patients fulfilling the criteria for efficacy analysis 169 patients took acetylsalicylic acid and 174 placebo. Response rates (reduction of headache severity from severe or moderate to mild or no pain at 2 h after administration) were 55.0% for acetylsalicylic acid and 36.8% for placebo (P < 0.001). Twenty-nine percent of patients in the active treatment group were pain-free after 2 h compared with 16.7% in the placebo group (P = 0.007). No headache recurred within 24 h post-dose in 84.6% of patients in the active group and in 85.1% of patients in the placebo group. Effervescent placebo reduced nausea and vomiting to the same degree as the active drug. Adverse events of acetylsalicylic acid (8.3%) were generally mild or moderate and comparable to those of placebo (2.9%). This study shows that oral ASAE is safe and effective for the treatment of acute migraine attacks.
 
Plasma concentration of LBR-101 after a single intravenous administration as a function of dose and time after dose. 
Systolic and diastolic blood pressure in individuals receiving LBR-101 or placebo. The upper figure displays systolic blood pressure. The lower figure displays diastolic blood pressure. Only selected time-points are presented for clarity. Data are presented as mean and 95% confidence intervals. 
Baseline-subtracted (single-delta) QTcF in individuals receiving LBR-101 or placebo. QTcF: QT interval after Fridericia's correction. 
Article
The vascular effects of acute calcitonin gene-related peptide (CGRP) inhibition are well described, but the effects of sustained inhibition warrant further exploration in humans. The objective of this article is to assess the effects of sustained CGRP inhibition on blood pressure, heart rate, and ECGs in healthy women ≥40 years of age. In this double-blind, placebo-controlled study, 31 women (mean age = 56) were randomized to receive placebo or an anti-CGRP monoclonal antibody at doses up to 2000 mg. Participants were confined for seven days and followed for 168 days. Cardiac telemetry was conducted for eight hours after infusion completion. Hemodynamic assessments and ECGs were conducted six times during Day 1 and periodically for three months. No clinically relevant changes in systolic or diastolic blood pressure, heart rate, or ECG parameters (RR, PR, QRS, or QTcF) were observed when comparing baseline vs. post-dose time-points or in-between groups. No significant changes were seen for adjusted QTcF (baseline subtracted and placebo and baseline subtracted). No significant differences or relevant abnormalities were seen when comparing parameters obtained at Tmax vs. any other time-point. Sustained CGRP inhibition was not associated with hemodynamic or ECG changes in a population at an increased age risk for cardiovascular events.
 
Summary of clinical studies of LBR-101. 
Article
LBR-101 is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide. The objective of this article is to characterize the safety and tolerability of LBR-101 when administered intravenously to healthy volunteers, by presenting the pooled results of the Phase 1 program. LBR-101 was administered to 94 subjects, while 45 received placebo. Doses ranged from 0.2 mg to 2000 mg given once (Day 1), as a single IV infusion, or up to 300 mg given twice (Day 1 and Day 14). Subjects receiving placebo reported an average of 1.3 treatment-emerging adverse events vs 1.4 per subject among those receiving any dose of LBR-101, and 1.6 in those receiving 1000 mg or higher. Treatment-related adverse events occurred in 21.2% of subjects receiving LBR-101, compared to 17.7% in those receiving placebo. LBR-101 was not associated with any clinically relevant patterns of change in vital signs, ECG parameters, or laboratory findings. The only serious adverse event consisted of "thoracic aortic aneurysm" in a participant later found to have an unreported history of Ehlers-Danlos syndrome. Single IV doses of LBR-101 ranging from 0.2 mg up to 2000 mg and multiple IV doses up to 300 mg were well tolerated. Overt safety concerns have not emerged. A maximally tolerated dose has not been identified.
 
Article
The prevalence and characterization of premonitory symptoms have not been rigorously studied in children and adolescents. Using a questionnaire, we retrospectively studied the prevalence of 15 predefined premonitory symptoms in a clinic-based population. In 103 children and adolescents fulfilling the International Classification of Headache Disorders, 2nd edn criteria for paediatric migraine, at least one premonitory symptom was reported by 69 (67%). The most frequently reported premonitory symptoms were face changes, fatigue and irritability. The mean number of premonitory symptoms reported per subject was 1.8 (median 2.2). Age, migraine subtype (with or without aura) and mean attack frequency per month had no effect on the mean number of premonitory symptoms reported per subject. In conclusion, premonitory symptoms are frequently reported by children and adolescents with migraine. Face changes seem to be a premonitory symptom peculiar to paediatric migraine.
 
Article
As migraine is associated with an increased risk for ischaemic stroke and peripheral vasospastic disorders, it was hypothesized that interictal vascular changes may be present in migraine patients. Using ultrasound and applanation tonometry, the cardiovascular properties of migraine patients were compared with those of matched control subjects. Vascular parameters of the carotid arteries, cardiac output and systemic vascular resistance did not differ between both groups. Right temporal artery diameter was larger in migraine patients (mean difference 101 micro m; 95% confidence interval (CI) 9/194 micro m; P = 0.033). At the brachial artery, migraine patients displayed a smaller distension (difference -24 micro m; 95% CI -45/-4 micro m; P = 0.021) and a decreased compliance (difference -0.025 mm2/kPa; 95% CI -0.047/-0.003 mm2/kPa; P = 0.024). Thus, migraine patients display an increased peripheral arterial stiffness. The presence of these interictal vascular changes suggests that migraine might be part of a more generalized vascular disorder.
 
Article
It has been disputed whether or not large intracranial arteries are dilated during migraine attacks. In order to answer this question the present transcranial Doppler study focused on side-to-side differences of middle cerebral artery blood velocity during unilateral attacks of migraine without aura in 25 patients. Blood velocity in the middle cerebral artery was lower on the headache side (59 cm/s) than on the non-headache side (65 cm/s) during the migraine attack. No such difference was found outside of attack (65 cm/s both sides). The difference (headache side minus non-headache side) was on average -6.1 cm/s during attack compared to -0.4 cm/s outside of attack (p = 0.01). Assuming that rCBF is unchanged during attacks of migraine without aura, our results suggest a 9% increase in middle cerebral artery lumen (cross-sectional area) on the affected side during unilateral attacks of migraine without aura. The findings, however, do not necessarily mean that arterial dilatation is the only or even the most significant cause of pain.
 
Article
AimTo investigate the occupancy at brain 5-hydroxytryptamine (5-HT) 1B receptors in human subjects after administration of the antimigraine drug zolmitriptan.Methods Positron emission tomography (PET) studies were undertaken using the radioligand [(11)C]AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets. The subjects were examined after two consecutive administrations of 10 mg zolmitriptan, approximately 1 week apart. Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan. One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment.ResultsAfter administration of 10 mg zolmitriptan, mean receptor occupancy was 4-5%. No consistent changes in 5-HT(1B) receptor binding were observed for subjects who received 5 mg zolmitriptan. There was a statistically significant negative relationship between binding potential (BP(ND)) and plasma concentration of zolmitriptan and the active metabolite 183C91, respectively. All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP(ND) post drug administration compared with baseline.Conclusion This is the first demonstration of CNS 5-HT(1B) receptor occupancy of a triptan. The findings are consistent with the low receptor occupancy previously reported in PET studies with agonists at other G protein coupled receptors.
 
Article
In 2013 the International Headache Society published the third International Classification of Headache Disorders beta-version, ICHD-3 beta. Its structure is identical to that of the present proposed version of the International Classification of Diseases (ICD-11), although slightly abbreviated to fulfill the needs of ICD-11. In the following, only ICHD-3 beta is mentioned, but findings regarding the validity of ICHD-3 beta categories are equally relevant to the forthcoming ICD-11. Here we field-tested the criteria for 1.2 migraine with aura (MA), 1.2.1 migraine with typical aura (MTA), 1.2.3 hemiplegic migraine, 1.2.2 migraine with brainstem aura, and the alternative criteria A1.2 MA and A1.2.1 MTA. Clinical characteristics were systematically and prospectively collected from patients with 1.2.1 MTA, 1.2.4 familial hemiplegic migraine (FHM), 1.2.5 sporadic hemiplegic migraine (SHM) and 1.2.6 basilar-type migraine according to ICHD-2 in a cross-sectional study design. A database of 2464 patients with 1.1 migraine without aura and 1.2 migraine with non-hemiplegic aura and a database of 252 hemiplegic migraine patients (1.2.4 FHM or 1.2.5 SHM) was collected. We used SPSS 20 for Windows 8.0 for the statistical analysis. All ICHD-2 patients fulfilled ICHD-3 beta criteria for 1.2 MA. The ICHD-3 beta criteria for 1.2.1 MTA were more sensitive than ICHD-2 and ICHD-3 beta alternative criteria; they resulted in fewer probable MA diagnoses. Too many patients fulfilled ICHD-2 and ICHD-3 beta criteria for 1.2.2 migraine with brainstem aura. ICHD-3 beta criteria for 1.2.4 FHM and 1.2.5 SHM both comply with ICHD-2. The new criteria in ICHD-3 beta/proposed ICD-11 for 1.2 MA, 1.2.1 MTA, 1.2.3.1 FHM and 1.2.3.2 SHM have more desirable properties than ICHD-2 and the ICHD-3 beta alternative criteria. The criteria for 1.2.2 migraine with brainstem aura should be more restrictive. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
 
Article
Status migrainosus (SM) and migraine aura status (MAS) are two migraine complications. Few data exist in literature. This 11-year retrospective study in one French center describes patients' characteristics, modifications of the migraine before complication, evolution after the episode and management in patients who had SM or MAS according to International Classification of Headache Disorders, second edition (ICHD-II) criteria. Among 8821 patients, 24 had SM, three had MAS and one had both forms. Mean duration of SM was 4.8 weeks and four weeks for MAS. Stress and menstruation were the main precipitating factors for SM (68.8% and 31.3%, respectively). No precipitating factor was found for MAS. For a majority of patients, the frequency of migraine attack was the same before and after SM or MAS. SM and MAS occurred more frequently in patients with initial low-frequency migraine attacks. Eight patients had a relapse of SM and three of MAS. Fifteen were hospitalized for amitriptyline intravenous treatment. SM and MAS are rare. Our results highlight a high rate of relapse and a similar frequency of migraine attacks before and after SM.
 
Article
Mitochondrial dysfunction has been reported in patients with migraine. We investigated leukocyte mitochondrial DNA 11084 A to G polymorphism in 166 Japanese migraineurs and 483 Japanese controls. The migraine group consisted of 43 patients suffering from migraine with aura (MWA) and 123 from migraine without aura (MOA). The frequency of the transition was 7.2% (12/166) in the migraine group and 7.3% (35/483) in the controls. The frequency of the transition was 4.7% in MWA and 8.1% in MOA. There was no significant difference among the groups (chi-square test). The mitochondrial DNA 11084 A to G transition was more common in Japanese subjects than reported in Caucasians; however, this polymorphism is not a genetic risk factor for migraine in Japanese patients.
 
Article
In a female population of Turkey (1146 adult females), some epidemiological and clinical characteristics of migraine and tension type headache and their subtypes were investigated. The relation of the headache severity to clinical characteristics were inquired. Migraine prevalence was found to be statistically higher in the 35–44 years age group (P < 0.01) and those who were university graduates (P < 0.001), married (P < 0.01) and living in urban areas (P < 0.01). Tension type headache was found to be higher in the 45–64 years age group (P < 0.05). Chronic tension type headache patients were found to be older than episodic type (P < 0.01) and frequently were in the lowest education level (P < 0.05). Presence of impact on daily activities because of the severity of headache was found to be related to aggravation by physical activities (P = 0.001) in tension type headache, with no clinical characteristics in migraine headache and on consideration of all headache patients with throbbing nature (P < 0.05), aggravation on physical activities (P = 0.001), nausea (P < 0.01), vomiting (P < 0.05) and phonophobia (P < 0.05).
 
Images constructed from PET average K* values ( m l/g/minute) comparing baseline K* values before and after administration of eletriptan in control subjects on the left side of the panel and in migraine subjects on the right side of the panel. The color bars on the side of the panel correlate with the K* values. PET: positron-emission tomography; MRI: magnetic resonance imaging; NC: normal control; Pt: patient. 
Demographic data.
Article
Alteration in central serotonin biology has been implicated in migraine, and serotonin (5-HT) agonists have been available for more than a decade in the treatment of that condition. To test this hypothesis, we studied in vivo using positron-emission tomography (PET) and α-[(11)C] methyl-L-tryptophan (α-[(11)C]MTrp) as a surrogate marker of cerebral 5-HT synthetic rate before and after administration of eletriptan in migraine and control subjects. Six nonmenopausal female migraine subjects with migraine without aura (MoA) and six nonmenopausal age-matched female control subjects were scanned at baseline and after oral administration of 40 mg of eletriptan. Migraine subjects at the time of PET had to have been headache free for a minimum of three days. Images of (α-[(11)C]MTrp) brain trapping were colocalized with individual MRI images in three dimensions and analyzed. There was no difference in baseline cerebral global 5-HT synthesis between migraine and control subjects. After administration of eletriptan, there was a striking global reduction in cerebral 5-HT synthesis (K*) in the migraine group and in 22 regions of interest (ROIs). In control subjects, no significant changes were found in global cerebral 5-HT synthesis (K*) or in any of the ROIs. These findings suggest in migraine an interictal alteration in the regulation mechanisms of cerebral 5-HT synthesis.
 
Article
Nine healthy volunteers aged 18-28 years were recruited into this open, single-centre, two-phase trial. In phase 1, two volunteers received a single dose of 11C-zolmitriptan 2.5 mg administered as a nasal spray and then underwent positron emission tomography (PET) scanning to determine the most appropriate times for scanning in phase 2. In phase 2, six volunteers received two doses and an additional volunteer one dose of 11C-zolmitriptan 2.5 mg intranasally. Volunteers underwent PET scanning over sectors covering one of the nasopharynx, lungs or abdomen, for up to 1.5 h postdose. The brain was also scanned and plasma zolmitriptan levels were measured. Almost 100% of the administered dose was detected in the nasopharynx immediately after dosing. This declined thereafter to about 50% at 20 min and to 35% at 80 min after dosing. Radioactivity appeared slowly in the upper abdomen, with 25% of given radioactivity detected at 20 min and persisting until 80 min after dosing. Minimal radioactivity was detected in the lungs. Radioactivity was detectable within brain tissue suggesting central penetration of zolmitriptan. Zolmitriptan in plasma had approached its maximum concentration by 15 min postdose. The data indicate initial absorption across the nasal mucosa contributing to an early systemic availability. 11C-Zolmitriptan administered intranasally was well tolerated.
 
Percentage of patients pain-free at 2 hours, SPF and SNAE
Patient disposition during the
                            study.
Percentage of patients pain-free at each time
                                point after drug intake (modified intent-to-treat
                                [mITT] population).
Article
Menstrually related migraine (MRM) affects more than half of female migraineurs. Because such migraines are often predictable, they provide a suitable target for treatment in the mild pain phase. The present study was designed to provide prospective data on the efficacy of almotriptan for treatment of MRM. Premenopausal women with MRM were randomized to almotriptan (N = 74) or placebo (N = 73), taken at onset of the first perimenstrual migraine. Patients crossed over to the other treatment for the first perimenstrual migraine of their second cycle, followed by a two-month open-label almotriptan treatment period. Significantly more patients were pain-free at two hours (risk ratio [RR] = 1.81; p = .0008), pain-free from 2-24 hours with no rescue medication (RR = 1.99; p = .0022), and pain-free from 2-24 hours with no rescue medication or adverse events (RR = 1.94; p = .0061) with almotriptan versus placebo. Nausea (p = .0007) and photophobia (p = .0083) at two hours were significantly less frequent with almotriptan. Almotriptan efficacy was consistent between three attacks, with 56.2% of patients pain-free at two hours at least twice. Adverse events were similar with almotriptan and placebo. Almotriptan was significantly more effective than placebo in women with MRM attacks, with consistent efficacy in longer-term follow-up.
 
Article
This study was a multinational, multicentre, double-blind, active controlled phase III trial designed to investigate efficacy and safety of 300 mg acetylsalicyclic acid (ASA) (n = 135) vs. 200 mg metoprolol (n = 135) in the prophylaxis of migraine. In total 270 (51 male and 219 female) patients, aged 18-65 years, suffering between two and six migraine attacks per month were recruited. The main objective was to show equivalence with respect to efficacy, defined as a 50% reduction in the rate of migraine attacks. A run-in phase was carried out with placebo for 4 weeks, followed by a 16-week drug phase. In both treatment groups the median frequency of migraine attacks improved during the study period, from three to two in the ASA group and from three to one in the metoprolol group; 45.2% of all metoprolol patients were responders compared with 29.6% with ASA. Medication-related adverse events were less frequent in the ASA group (37) than in the metoprolol group (73). The findings from this trial show that metoprolol is superior to ASA for migraine prophylaxis but has more side-effects. Acetylsalicylic acid is better tolerated than metoprolol. Using a strict responder criterion ASA showed a responder rate comparable with the placebo rate in the literature.
 
Article
Infiltration of the greater occipital nerve (GON) with local anaesthetics and corticosteroids is a treatment option for cluster headache. We retrospectively analysed the efficacy and safety of 121 GON injections in 60 patients with episodic or chronic cluster headache over a period of 4 years. Almost 80% of the infiltrations were at least partially effective (reduction of attack frequency, duration or severity) and 45% resulted in a complete response (no further attacks). The effect was maintained for 3.5 weeks on average in chronic cluster headache. In episodic cluster headache, the effect lasted for most of the bout. In 18 infiltrations, transient side effects were reported, such as local pain, steroid effects (facial oedema, sleeping disorders, acne), bradycardia or syncope. Our data show that GON infiltration is a valuable and safe option in the clinical setting to treat patients suffering from cluster headache, especially for the episodic form of the disorder.
 
Article
This study evaluates osmophobia and taste abnormalities in relationship to sensitivity and specificity in the classification of migraine. Consecutive International Headache Society (IHS) classified patients (n = 1237) were evaluated. Symptoms were graded from 0 to 3. Osmophobia and taste abnormalities were tested for sensitivity and specificity in migraine diagnosis. The patients were 85.4% female and their mean age was 38.1 years. Of 673 patients 24.7% complained of osmophobia, and 24.6% of 505 complained of taste abnormalities. In the absence of nausea and vomiting the combinations of two symptoms gave the following sensitivity and specificity percentages, respectively: photophobia and phonophobia, 10.6 and 84.9; photophobia and osmophobia, 1.1 and 99.0; phonophobia and osmophobia, 1.1 and 98.6; photophobia and taste abnormality, 9.6 and 99.0; phonophobia and taste abnormality, 9.6 and 98.8; and osmophobia and taste abnormality, 4.2 and 99.4. Osmophobia and taste abnormalities were demonstrated to be very specific in diagnosing migraine IHS 1.1-1.6, but very insensitive.
 
Article
Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand 123I-3-iodo-6-methoxybenzamide (123I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of 123I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities.
 
Article
Studies in experimental animals have suggested that the hypocretin/orexin system may be involved in migraine pathophysiology. Using a case-control design study, we genotyped 246 migraine patients and 239 healthy controls for the 1246G-->A polymorphism of the hypocretin receptor 2 (HCRTR2) gene. Genotypic and allelic frequencies of the examined polymorphism were similarly distributed between cases and controls (chi2 = 2.22, P = 0.14 and chi2 = 2.45, P = 0.29, respectively). When different migraine subgroups were compared (migraine with aura vs. migraine without aura and episodic vs. chronic migraine) no significant difference was found. Comparison of the clinical features of the disease with the 1246G-->A genotypes showed no significant difference. Our data suggest that the HCRTR2 gene is not a genetic risk factor in migraine.
 
Article
To test the existence of inherited liability to migraine, formal segregation analysis of family data collected from 128 patients has been performed. Patients were subdivided into three groups in accordance with the presence or absence of migraine in their parents. The results obtained in each group were then compared with those expected on the basis of two different modes of simple Mendelian inheritance, namely autosomal dominant and autosomal recessive transmission. Our data show that neither of the two hypotheses can be accepted, thus suggesting the existence of a possible genetic heterogeneity of liability to migraine.
 
Article
The most frequently reported abnormal MRI finding in migraine is the presence of high signal white matter foci (WMF) on long TR images. Recently, WMF have been distinguished in periventricular WMF (PVF), when contiguous to ventricles, and deep WMF (DF), when far from these. DF, but not PVF, appear positively correlated with cerebrovascular risk factors and are called leukoaraiosis. In this study the MRI examination was performed in 129 consecutive migraine patients (83 of them had migraine without aura and 46 migraine with aura). In 19.3% of the migraineurs studied we observed WMF on T2 weighted images strictly localized in the deep white matter (DF). No PVF were observed. These findings were independent of the type of migraine and did not correlate with age, sex, disease duration, or frequency of attacks. The presence in a subgroup of migraineurs of leukoaraiosis (DF), for which a vascular genesis has been hypothesized, suggests that migraine could represent, a cerebrovascular risk factor in these patients.
 
Article
To estimate the lifetime migraine prevalence in school adolescents aged 13-15 in Taiwan, we conducted a self-administered questionnaire survey in four sampled public junior high schools. Migraine was diagnosed according to the diagnostic criteria of the International Headache Society. A total of 4064 students (1983 boys, 2081 girls) completed the questionnaire (response rate 91.6%). The lifetime prevalence of migraine was 6.8%. It was significantly higher in girls than boys (7.8% vs. 5.7%) and increased with age in both sexes. Students with migraine were more likely to be absent from school because of their headaches than those with non-migraine headaches (30% vs. 14%, odds ratio (OR) 2.7). They were also more likely to use painkillers for their headaches than their non-migraine headache peers (72% vs. 40%, OR 4.0). These results suggest that migraine is a common disorder of adolescents in Taiwan and its impact on the quality of life can not be ignored.
 
Article
In this work we have developed and characterized primary cultures of neonatal rat trigeminal ganglia neurones; calcitonin-gene-related-peptide (CGRP) released from cells was taken as a marker of neuronal function. A significant and consistent increase in CGRP secretion was elicited by non-specific (56 mm KCl or veratridine) or specific (capsaicin) depolarizing stimuli. This paradigm was subsequently used to investigate the effects of nociceptin, an opioid-like peptide involved in central and peripheral control of nociception. We found that the nociceptin analogue nociceptin (1-13)NH2 (NOC) did not affect baseline CGRP release, but it reduced in a concentration-dependent manner CGRP release induced by all tested stimuli. NOC-induced reduction was statistically significant from 0.01 nm onward and achieved maximal effects at 10 nm. Such effects of NOC were seemingly mediated by the activation of specific ORL1 receptors, as a well-known nociceptin antagonist, N(Phe1)nociceptin (1-13)NH2, was able to completely revert NOC inhibition of capsaicin-stimulated CGRP release.
 
Article
Studies of twins, spouses and familial aggregation strongly suggest that migraine without aura (MO) and migraine with aura (MA) are genetically determined. The mode of inheritance is most likely multifactorial in both MO and MA. However, autosomal dominant inheritance with reduced penetrance cannot be excluded in either MO or MA. At present the only evidence for genetic heterogeneity of MA is familial hemiplegic migraine with slowly progressive ataxia. This phenomenon can also be explained by linkage of different genes. All existing studies have been characterized by one or more of the following methodologic shortcomings: selection of probands from clinic populations, information obtained by questionnaire, family history obtained through probands, insufficient description of the attacks, lack of distinction between MO and MA. Useful strategies for future studies of migraine genetics are discussed.
 
Article
Introduction: Supraorbital neuralgia (SON) is an uncommon disorder characterized by pain in the area supplied by the supraorbital nerve, which covers the medial aspect of the forehead, together with tenderness over the supraorbital notch or along the course of the nerve. Few hospital-based series of non-trauma SON have been published. Methods and results: We prospectively analyzed 13 patients (11 females, two males) diagnosed with SON in a headache outpatient clinic over a four-year period. Background pain was mostly dull and of moderate intensity. In addition, nine patients reported sharp, burning or stabbing exacerbations of severe intensity. Eight cases were treated with an anesthetic blockade and achieved complete relief lasting from two to six months. Three patients also received gabapentin, with no or only slight improvement. Conclusion: Non-traumatic SON is an uncommon disorder in our headache clinic. Female preponderance and clinical features are comparable to the data collected in previous studies. A spontaneously remitting pattern is not uncommon, and anesthetic blockades are not always required.
 
Article
We established a cohort of 60 subjects with chronic daily headache (CDH) out of 1533 community-based elderly in 1993 and finished two short-term follow-ups in 1995 and 1997. All of the 26 survivors without dementia (4 M/22 F, mean age 82.7 +/- 3.4 years) finished the follow-up in 2006. The mean headache frequency was 8.4 +/- 11.8 days per month in the past year, and seven (27%) had persistent CDH. Based on the International Classification of Headache Disorders, 2nd edn, the CDH subtypes diagnoses were chronic migraine in three subjects, chronic tension-type headache in three, and one with medication-overuse headache. All these seven subjects had CDH during the 1995 and 1997 follow-ups. The diagnosis of CDH with migrainous features increased from 25 to 71% in those with CDH from 1993 to 2006. Migraine was the most common headache type in those with CDH resolution. Aggressive treatment should be applied especially for those with persistent CDH at short-term follow-ups.
 
Article
Whether the prevalence of migraine is increasing is controversial. We conducted annual surveys in 1999-2001 to investigate migraine prevalence among a nationwide sample of 13 426 adolescents aged 13-15 years. Participants from five junior high schools around different regions of Taiwan completed self-administered questionnaires. The diagnosis of migraine was based on the classification criteria proposed by the International Headache Society, 1988. Data for 23 433 person-years were collected and analysed for trends in prevalence and incidence. The 1-year prevalence of migraine increased 42% during 1999-2001 (from 5.2 to 7.4%, P < 0.001). This increasing trend was demonstrated in both sexes, all ages, and all but one studied regions of Taiwan. Of note was the biggest increment of prevalence (79%) among 7th graders (students aged 13 years) through these 3 years. Annual incidence rates did not differ between 1999 and 2000 and 2000 and 2001 (6.1% vs. 5.7%; P = 0.4). One-year persistence rates of migraine diagnosis, surrogates of migraine duration, did not differ between 1999 and 2000 and 2000 and 2001 (34.2% vs. 41.2%; P = 0.1). Our study found that the prevalence of migraine was increasing in our sampled adolescents, which results from an increment starting at age 13 or younger. The prevalence of migraine in Asians might be increasing, although previous studies showed lower prevalence in this region. Children or adolescents may be more vulnerable to the environmental or societal change.
 
Article
Three editions of International Classification of Headache Disorders (ICHD) diagnostic criteria for Tolosa-Hunt syndrome (THS) have been published in 1998, 2004 and 2013; in ICHD-3 beta, there have been considerable changes. The validity of these new diagnostic criteria remains to be established. We retrospectively identified 77 patients with non-traumatic painful ophthalmoplegia (PO) admitted between 2003 and 2013. We reviewed patients' age at onset and gender, time courses between onset of pain and development of cranial nerve palsy, the cranial nerves involved, imaging findings, therapeutic efficacy of steroid treatment and recurrence of attacks. THS was the most frequent type of PO (46/77). In THS patients, the third cranial nerve was most commonly involved (76.3%). The median time interval between pain and cranial nerve palsy was two days, although in five patients (10.9%) the interval ranged from 16 to 30 days. Definitely abnormal MRI findings were found in 24 patients (52.2%). It is essential to rule out other causes of PO in diagnosing THS, with MRI playing a crucial role in differential diagnosis. It may be helpful to understand and master the entity of THS for researchers and clinicians to adjust the gradation and ranking of the diagnostic criteria.
 
Characteristics of patients. 
Comparison of cannabis users to nonusers among CH patients. 
Article
Aims: A case report suggested the efficacy of cannabis to treat cluster headache (CH) attacks. Our aims were to study the frequency of cannabis use in CH patients, and the reported effects on attacks. Methods: A total of 139 patients with CH attending two French headache centers filled out questionnaires. Results: Sixty-three of the 139 patients (45.3%) had a history of cannabis use. As compared to nonusers, cannabis users were more likely to be younger (p < 0.001), male (p = 0.002) and tobacco smokers (p < 0.001). Among the 27 patients (19.4% of the total cohort) who had tried cannabis to treat CH attacks, 25.9% reported some efficacy, 51.8% variable or uncertain effects, and 22.3% negative effects. Conclusions: Cannabis use is very frequent in CH patients, but its efficacy for the treatment of the attacks is limited. Less than one third of self-reported users mention a relief of their attacks following inhalation. Cannabis should not be recommended for CH unless controlled trials with synthetic selective cannabinoids show a more convincing therapeutic benefit.
 
Article
The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.
 
Article
In this randomized, double-blind, placebo-controlled, parallel-group study, patients received a single 50-mg oral dose of a 5-HT(1D) agonist, PNU-142633 (n = 34), or matching placebo (n = 35) during an acute migraine attack. No statistically significant treatment effects were observed at 1 and 2 h after dosing, even after stratifying by baseline headache intensity. At 1 and 2 h post-dose, 8.8% and 29.4% of the PNU-142633 group, respectively, and 8.6% and 40.0% of the placebo group, respectively, experienced headache relief; 2.9% and 8.8% of the PNU-142633 group and 0% and 5.7% of the placebo group were free of headache pain. Adverse events associated with PNU-142633 treatment included chest pain (two patients) and QTc prolongation (three patients). Results from this study suggest that anti-migraine efficacy is not mediated solely through the 5-HT(1D) receptor subtype, although this receptor may contribute, at least in part, to the adverse cardiovascular effects observed with 5-HT agonist medications.
 
Article
Vasoactive metabolites deriving from arachidonic acid (AA) have been considered as putative mediators in the pathogenesis of various types of headache. In the present study we therefore compare the ability to synthesize AA containing precursor phospholipids in polymorphonuclear cells (PMNs) from healthy controls and cluster headache patients. 3.7% +/- 1.4 (mean +/- SD) of the (1-14C)AA incorporated into total PMN glycerophospholipids (GPLs) was recovered in the phosphatidylserine (PS) in a group of cluster headache patients (n = 12). This was almost twice the value of 1.9% +/- 0.8% found in a corresponding group of 24 healthy controls (p less than 0.001). A significant decrease in the incorporation of (1-14C)AA into phosphatidylcholine (PC) (p less than 0.01) and an increase in the incorporation of (1-14C)AA into phosphatidyletanolamine (PE) (p less than 0.05) were also found in cluster headache patients when compared to the control group. The increased incorporation of (1-14C)AA into PS in PMNs from this group of patients is interesting because PS plays an important role in the activation of protein kinase C, an enzyme involved in transmembrane signalling. The clinical implications of the present findings in cluster headache, if any, cannot yet be defined.
 
Article
As recently demonstrated by our group, polymorphonuclear cells (PMNs) from cluster headache patients have an increased ability to incorporate arachidonic acid (AA) and L-serine into phosphatidylserine (PS). To evaluate whether there is an increased incorporation into PS also from fatty acids not involved in eicosanoid metabolism, PMNs from controls (n = 14) and cluster headache patients (n = 12) were incubated with (1-14C)oleic acid. After 1 h 2.7% +/- 1.1 (mean value +/- SD) of the glycerophospholipid radioactivity was found in PS in controls, whereas 4.2% +/- 1.2 was found in cluster headache patients (p less than 0.005). For phosphatidylcholine (PC) the corresponding figures were 74.2 +/- 5.4 in controls and 66.7 +/- 7.6 in cluster headache patients (p less than 0.01). The results suggest that the de novo biosynthesis of PS is increased and the biosynthesis of PC is decreased in cluster headache. The results may have an effect on the role of PS as an obligate protein kinase C activator.
 
Article
It has recently been demonstrated by our group that polymorphonuclear cells (PMNs) from cluster headache patients incorporate more arachidonic acid (AA) into phosphatidylserine (PS) than PMNs from controls. In the present report, the incorporation of L-(U-14C)serine into PS in PMNs from 14 healthy volunteers and 12 cluster headache patients was studied. PMNs from controls incorporated 1194 +/- 578 (mean +/- SD) cpm of L-(U-14C)serine into PS, 268 +/- 292 cpm into phosphatidylethanolamine, and 57 +/- 71 cpm into sphingomyeline. The corresponding figures in cluster headache patients were 2365 +/- 841 cpm, 291 +/- 207 cpm, and 88 +/- 66 cpm, respectively. Incorporation of L-(U-14C)serine into PS was significantly increased (p less than 0.0004) in PMNs from cluster headache patients, whereas no significant difference was seen in other lipids. The results confirm that patients with cluster headache have an increased incorporation of precursors into PS in isolated PMNs, and they indicate that this is due to an increased de novo synthesis of PS.
 
Article
Red wine-induced release of [14C]5-hydroxytryptamine (5HT) from platelets of red wine-sensitive migraine patients, migraine patients not sensitive to red wine and controls, was determined in vitro. No significant differences in platelet [14C]5HT release were found between any of the groups investigated.
 
Article
Sphenopalatine ganglion percutaneous radiofrequency thermocoagulation treatment can improve the symptoms of cluster headaches to some extent. However, as an ablation treatment, radiofrequency thermocoagulation treatment also has side effects. To preliminarily evaluate the efficacy and safety of a non-ablative computerized tomography-guided pulsed radiofrequency treatment of sphenopalatine ganglion in patients with refractory cluster headaches. We included and analysed 16 consecutive cluster headache patients who failed to respond to conservative therapy from the Pain Management Center at the Beijing Tiantan Hospital between April 2012 and September 2013 treated with pulsed radiofrequency treatment of sphenopalatine ganglion. Eleven of 13 episodic cluster headaches patients and one of three chronic cluster headaches patient were completely relieved of the headache within an average of 6.3 ± 6.0 days following the treatment. Two episodic cluster headache patients and two chronic cluster headache patients showed no pain relief following the treatment. The mean follow-up time was 17.0 ± 5.5 months. All patients enrolled in this study showed no treatment-related side effects or complications. Our data show that patients with refractory episodic cluster headaches were quickly, effectively and safely relieved from the cluster period after computerized tomography-guided pulsed radiofrequency treatment of sphenopalatine ganglion, suggesting that it may be a therapeutic option if conservative treatments fail. © International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
 
Article
This was a phase-IV double-blind equivalence trial designed to assess the efficacy and tolerability of two doses of flunarizine (10 mg o.d.=FLU 10 mg and 5 mg o.d.=FLU 5 mg) in the prophylaxis of migraine, in comparison with slow-release propranolol (160 mg o.d.). A total of 808 subjects were treated in a treatment period of 16 weeks. 142 subjects discontinued the trial prematurely, mainly because of adverse events (n=58). The mean attack frequency in the double-blind period was 2.0 for the FLU 5 mg group, 1.9 for the FLU 10 mg group, and 1.9 for the propranolol group. The mean attack frequency in the last 28 days of the double-blind period was 1.8 for FLU 5 mg, 1.6 for FLU 10 mg, and 1.7 for propranolol. Both flunarizine groups were at least as effective as propranolol (P<0.001 in one-sided test). The percentage of responders (defined as subjects for whom attack frequency decreased by at least 50% compared to run-in) in the last 28 days of the double-blind period was 46% (118/259) for FLU 5 mg, 53% (141/264) for FLU 10 mg, and 48% (125/258) for propranolol. Statistical analysis showed that FLU 10 mg is at least as effective as propranolol (P<0.001) and showed a trend for noninferiority of FLU5 and propranolol (P=0.053). No statistically significant differences between the treatment groups were found for any of the secondary parameters. Overall, 190 subjects reported one or more adverse events during the run-in phase: 54 (20.5%) in the FLU 5 mg group, 76 (27.7%) in the FLU 10 mg group and 60 (22.3%) in the propranolol group. The results of this equivalence trial show that 10 mg flunarizine daily with a drug-free weekend is at least as effective as 160 mg propranolol in the prophylaxis of migraine for all evaluated parameters (one-sided equivalence tests) after 16 weeks of treatment. In addition, 5 mg flunarizine proves to be at least as effective as 160 mg propranolol when looking at the mean attack frequency for both the whole double-blind period and the last 28 days of treatment. However, in the analysis of responders, 160 mg propranolol seems to be slightly better than 5 mg flunarizine. In addition, no significant differences between the three treatments were found with regard to safety: all three treatments were generally well-tolerated and safe.
 
Article
Thirty patients with severe classical and common migraine participated in a double-blind placebo-controlled cross-over study of migraine prophylaxis with propranolol LA (long-acting) 80 mg once daily, or propranolol LA 160 mg once daily or placebo. Each treatment was given for two months. There were no significant differences between the three treatment periods in headache frequency, headache severity, nausea frequency or severity. There was a non-significant trend for reduced duration of headache with the two doses of propranolol. The possible reasons for this negative effect are discussed. The safety of propranolol and its lack of serious side effects were demonstrated.
 
Top-cited authors
Richard Lipton
  • Albert Einstein College of Medicine
Stephen D Silberstein
  • Thomas Jefferson University
Jes Olesen
  • Rigshospitalet
Catherine Turkel
  • Novus Therapeutics Inc.
Messoud Ashina
  • Region Hovedstaden