nan Ferrari

Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials

The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the ‘raw patient data’ of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24 089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h postdose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provide the highest likelihood of consistent success. Sumatriptan features the longest clinical experience and the widest range of formulations. All triptans are contra-indicated in the presence of cardiovascular disease.

Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation: The population-based MRI CAMERA study

Previous studies have suggested that migraine is a risk factor for brain lesions, but methodological issues hampered drawing definite conclusions. Therefore, we initiated the magnetic resonance imaging (MRI) ‘CAMERA’ (Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis) study. We summarize our previously published results. A total of 295 migraineurs and 140 controls were randomly selected from a previously diagnosed population-based sample (n = 6039), who underwent an interview, physical examination and a brain MRI scan. Migraineurs, notably those with aura, had higher prevalence of subclinical infarcts in the posterior circulation [odds ratio (OR) 13.7; 95% confidence interval (CI) 1.7, 112]. Female migraineurs were at independent increased risk of white matter lesions (WMLs; OR 2.1; 95% CI 1.0, 4.1), and migraineurs had a higher prevalence of brainstem hyperintense lesions (4.4% vs. 0.7%, P = 0.04). We observed a higher lifetime prevalence of (frequent) syncope and orthostatic insufficiency in migraineurs; future research needs to clarify whether autonomic nervous system dysfunction could explain (part of) the increased risk of WMLs in female migraineurs. Finally, in migraineurs aged < 50 years, compared with controls, we found evidence of increased iron concentrations in putamen (P = 0.02), globus pallidus (P = 0.03) and red nucleus (P = 0.03). Higher risks in those with higher attack frequency or longer disease duration were found consistent with a causal relationship between migraine and lesions. This summary of our population-based data illustrates that migraine is associated with a significantly increased risk of brain lesions. Longitudinal studies are needed to assess whether these lesions are progressive and have relevant (long-term) functional correlates.

Towards a definition of intractable headache for use in clinical practice and trials

Headache is the most common problem for which patients seek care from a neurologist, and primary headaches, such as migraine and cluster headache, are the most common disorders whose biology underpins such presentations. Migraine is common in the community (1, 2), highly disabling (3) and the most expensive neurological disorder in the European Community, with costs estimated to be more than €27 billion per year (4). The 1990s saw the introduction of new acute antimigraine treatments, notably serotonin and 5-HT1B/1D receptor agonists (triptans) (5), which are effective (6), well-tolerated medicines (7). Preventive approaches were enhanced by the recognition that some anticonvulsants, such as topiramate (8–10) and valproate (11–13), are effective in reducing attack frequency. However, some patients, who have been called intractable, do not respond to regulatory-approved and other conventional preventive therapies. We explored the definition of intractability to provide some standard against which to test new treatments for these patients.

Iron accumulation in deep brain nuclei in migraine: a population-based magnetic resonance imaging study

A small magnetic resonance imaging (MRI) study showed increased iron depositions in the periaqueductal grey matter in migraineurs, suggestive of a disturbed central antinociceptive neuronal network. With 1.5–T MRI, we assessed iron concentrations in seven deep brain nuclei in a large population-based cohort. We compared T2 values between migraineurs (n = 138) and controls (n = 75), with multivariate regression analysis. Analyses were conducted in age strata (< 50, n = 112; ≥ 50) because iron measures are increasingly influenced by non-iron-related factors in the older group. Overall, migraineurs and controls did not differ, nor did migraineurs with vs. without aura. In the younger migraineurs compared with controls, T2 values were lower in the putamen (P = 0.02), globus pallidus (P = 0.03) and red nucleus (P = 0.03). Similarly, in these younger migraineurs, controlling for age, those with longer migraine history had lower T2 values in the putamen (P = 0.01), caudate (P = 0.04) and red nucleus (P = 0.001). Repeated migraine attacks are associated with increased iron concentration/accumulation in multiple deep nuclei that are involved in central pain processing and migraine pathophysiology. It remains unclear whether iron accumulation in the antinociceptive network has a causative role in the development of (chronic) migraine headache.

The prevalence of premonitory symptoms in migraine: a questionnaire study in 461 patients

Migraine attacks are often preceded by premonitory symptoms. Prevalence rates of migraine patients reporting one or more premonitory symptoms show considerable variability and rates range between 12% and 79%. Sources of variability might be differences in study population or research design. Using a questionnaire, we retrospectively studied the prevalence of 12 predefined premonitory symptoms in a clinic-based population. Of 461 migraine patients, 374 (81%) responded. At least one premonitory symptom was reported by 86.9% and 71.1% reported two or more. The most frequently reported premonitory symptoms were fatigue (46.5%), phonophobia (36.4%) and yawning (35.8%). The mean number of premonitory symptoms per person was 3.2 (± 2.5). Women reported 3.3 premonitory symptoms compared with 2.5 symptoms in men (P = 0.01). Age, education, migraine subtype (with or without aura) and mean attack frequency had no effect on the mean number of symptoms per individual. In conclusion, premonitory symptoms are frequently reported by migraine patients. Sensitivity and specificity of premonitory symptoms for migraine need to be assessed using prospective methods.

Risk Factors for Headache Recurrence After Sumatriptan: A Study in 366 Migraine Patients:

Headache recurrence (HR) is the major limitation of sumatriptan in the acute treatment of migraine attacks. The risk of HR is mainly patient dependent. We analyzed, in 366 migraine patients, clinical differences between patients who always have HR and patients who never have HR. We found remarkably few differences. HR more frequently occurred in patients with more severe attacks and longer untreated attack duration; in patients who experienced a sensation of a subclinically ongoing attack, despite headache relief after sumatriptan; and in females, mainly with menstruation-related migraine, most probably due to the more severe and longer lasting attacks these patients suffer, rather than due to hormonal factors. The incidence of HR was, among other factors, not related to the (other) clinical effects of sumatriptan, the timing of administration within the attack, the duration of use of sumatriptan, pharmacokinetic factors, or whether patients were experiencing HR after use of ergot alkaloids.

Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis.

Tonabersat is a novel putative migraine prophylactic agent with an unique stereospecific binding site in the brain. Tonabersat has been shown, in animal models, to inhibit experimentally induced cortical spreading depression, the likely underlying mechanism for migraine aura, and cerebrovascular responses to trigeminal nerve stimulation. The aim was to study the potential for tonabersat as a migraine preventive. A randomized, double-blind, placebo-controlled, multicentre, parallel group study recruited patients with migraine with and without aura experiencing between two and six migraine attacks per month. After a 1-month baseline they received tonabersat 20 mg daily for 2 weeks and 40 mg daily for a further 10 weeks. The primary end-point was the change in mean number of migraine headache days between the third month and the baseline period in the intention-to-treat population comparing the placebo (n = 65) and tonabersat (n = 58) groups. At the primary end-point there was a 1.0-day (95% confidence interval −0.33, 2.39; P = 0.14) difference in reduction in migraine days between tonabersat and placebo. There were 10 secondary efficacy end-points, of which two were statistically significant. In month 3 of treatment, the responder rate, defined as a 50% reduction in migraine attacks, was 62% for tonabersat and 45% for placebo (P < 0.05), and the rescue medication use was reduced in the tonabersat group compared with placebo by 1.8 days (P = 0.02). Placebo responses were particularly high for all end-points. At least one treatment-emergent adverse event was reported in the tonabersat group in 61% of patients compared with 51% in the placebo group; none was worrisome. Placebo responses were unexpectedly high in this trial, complicating straightforward interpretation of the study results. The good tolerability and promising efficacy results support further exploration of higher doses of tonabersat in larger controlled trials.

Double‐blind, placebo‐controlled, dose‐finding study of rizatriptan (MK‐462) in the acute treatment of migraine

Rizatriptan (MK-462) is a potent 5HTID receptor agonist. This multicenter, double-blind, placebo-controlled, outpatient study investigated the clinical elficacy, safety, and tolerability of rizatriptan (2.5, 5, and 10 mg) as a function of dose for acute migraine. Fatients with moderate or severe migraine (n=417) were treated with placebo (n=67), rizatriptan 2.5 mg (n=75), 5 mg (n=130), or rizatriptan 10 mg (n=145). Headache severity, functional disability, and migraine symptoms were measured immediately before dosing (0) and at 0.5, 1, 1.5, 2, 3, and 4 h post-dose. Patients were permitted to take a second dose of test drug at 2 h if their headache pain was moderate or severe (i.e placebo initiallyrizatriptan 10 mg as optional second dose; rizatriptan 2.5 mg, 5 mg, or 10 mg initiallyplacebo as optional second dose). An upward dose-response relationship was observed among placebo rizatriptan 2.5 mg, 5 mg, and 10 mg in the primary efficacy measure of proportion of patients reporting pain relief, i.e., a change in headache severity to “no pain or mild pain” at 2 h post-dose. The relationship was evident even at the first recorded timepoint, 30 min, and was statistically significant at 1.5 h and beyond. At the primary timepoint of 2 h after the initial dose, the proportion of patients reporting pain relief was 47.6% for rizatriptan 10 mg; 45.4% for rizatriptan 5 mg; 21.3% for rizatriptan 2.5 mg; and 17.9% for pacebo. Seventy percent of patients on rizatriptan 10 mg reported pain relief at 4 h. Patients who took rizatriptan 5 mg and 10 mg were significantly less functionally disabled than those who took placebo at 1.5 and 2n post-dose. Rizatriptan 10 mg was consistently more effective than 5 mg, although the differences were not statistically significant. The most frequent clinical adverse events were dizziness, somnolence, and asthenia/fatigue. No patients were discontinued for any adverse experiences and there were no serious adverse experiences.

First Mutation in the Voltage-Gated Nav1.1 Subunit Gene SCN1A with Co-Occurring Familial Hemiplegic Migraine and Epilepsy

Almost all mutations in the SCN1A gene, encoding the α1 subunit of neuronal voltage-gated Nav1.1 sodium channels, are associated with severe childhood epilepsy. Recently, two mutations were identified in patients with pure familial hemiplegic migraine (FHM). Here, we identified a novel SCN1A L263V mutation in a Portuguese family with partly co-segregating hemiplegic migraine and epilepsy. The L263V mutation segregated in five FHM patients, three of whom also had epileptic attacks, occurring independently from their hemiplegic migraine attacks. L263V is the first SCN1A mutation associated with FHM and co-occurring epilepsy in multiple mutation carriers, and is the clearest molecular link between migraine and epilepsy thus far. The results extend the clinical spectrum associated with SCN1A mutations and further strengthen the molecular evidence that FHM and epilepsy share, at least in part, similar molecular pathways.

Migraine and genetic and acquired vasculopathies

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty (HIHRATL). The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. Common genetic susceptibility, increased susceptibility to cortical spreading depression (CSD) and vascular endothelial dysfunction are among the possible explanations. The relation between migraine and acquired vasculopathies such as ischaemic stroke and coronary heart disease has long been established, further supporting a role of the (cerebral) blood vessels in migraine. This review focuses on genetic and acquired vasculopathies associated with migraine. We speculate how genetic and acquired vascular mechanisms might be involved in migraine.