Efficacy and safety of tonabersat, a gap-junction modulator, in the acute treatment of migraine: a double-blind, parallel-group, randomized study.

The ability of tonabersat to relieve the symptoms of migraine attacks with or without aura was evaluated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients received 20 or 40 mg of tonabersat, or 50 mg of sumatriptan (positive control), or placebo at the onset of a moderate or severe attack. Headache intensity, relief and recurrence were recorded for 24 h after dosing. On the basis of primary or secondary efficacy measures, tonabersat did not provide a clinically or statistically significant advantage over placebo. Tonabersat generally was well tolerated and had no effect on vital signs, electrocardiogram recordings or laboratory values. The lack of efficacy may be a function of the slow absorption of tonabersat. As a consequence of slow absorption, daily administration of tonabersat as prophylaxis for migraine attacks is under investigation in ongoing studies.

Evaluation and registration of adverse events in clinical drug trials in migraine.

Tolerability of a drug should be regarded as important as its efficacy. In all four phases of drug development evaluation of adverse events is important. Recommendations for assessment of adverse events in acute and prophylactic clinical drug trials in migraine are given. Tolerability may be indirectly assessed using measures of general well-being and eight such tools are presented. Finally, recommendations for reporting of adverse events are given.

Almotriptan and zolmitriptan in the acute treatment of migraine.

OBJECTIVE: To compare almotriptan and zolmitriptan in the treatment of acute migraine. METHODS: This multicentre, double-blind trial randomized adult migraineurs to almotriptan 12.5 mg (n = 532) or zolmitriptan 2.5 mg (n = 530) for the treatment of a single migraine attack. The primary end point was sustained pain free plus no adverse events (SNAE); other end points included pain relief and pain free at several time points, sustained pain free, headache recurrence, use of rescue medication, functional impairment, time lost because of migraine, treatment acceptability, and overall treatment satisfaction. RESULTS: No significant difference was seen in SNAE (almotriptan 29.2% vs zolmitriptan 31.8%) or the other efficacy end points measured. The incidence of triptan-associated AEs and triptan-associated central nervous system AEs was significantly lower for patients receiving almotriptan compared to zolmitriptan. CONCLUSIONS: Almotriptan and zolmitriptan were associated with similar efficacy and overall tolerability in the treatment of acute migraine. Almotriptan was associated with a significantly lower rate of triptan-associated AEs.

The natural course of migraine attacks. A prospective analysis of untreated attacks compared with attacks treated with a triptan.

This study was designed to document prospectively and explore scientifically the natural course of untreated migraine attacks in detail. A new, integrated, time-intensity method for self-assessment of the intensity of symptoms was tested on 18 adult International Headache Society migraineurs who volunteered to refrain from treatment during one attack. The area under the curves (AUC) during 72 h of untreated attacks was compared with attacks treated with a triptan. Migraine attacks are heterogeneous both inter- and intra-individually. In untreated attacks, the pain can stabilize and fluctuate around a plateau with a wavelength of hours. In general, the symptoms of each separate migraine attack follow a similar temporal course, with only moderate deviations. In some cases photo- and/or phonophobia (hyperexcitability) were not experienced at all, despite severe pain and nausea. Moreover, there was sometimes no nausea despite severe pain and hyperexcitability. Vomiting does not always correlate to the intensity of nausea and is not always followed by decreased headache intensity. Treatment with a triptan usually only temporarily distorts the basic pattern of attacks. Hyperexcitability can respond before pain to treatment. These genuine findings of the classic symptoms of migraine attacks support the notion of a mutual underlying pathophysiological mechanism.

Efficacy, speed of action and tolerability of almotriptan in the acute treatment of migraine: pooled individual patient data from four randomized, double-blind, placebo-controlled clinical trials.

A meta-analysis of pooled individual patient data from four randomized, placebo-controlled, double-blind trials comparing several doses of almotriptan (n = 1,908) with placebo (n = 386) was used to investigate the efficacy, speed of onset and tolerability of almotriptan in the acute treatment of migraine. As early as 30 min after dosing, almotriptan 12.5 mg was significantly more effective than placebo for pain relief (14.9% vs. 8.2%; P < 0.05) and pain free (2.5% vs. 0.7%; P < 0.05). At 2 h, pain-relief rates were 56.0%, 63.7% and 66.0% for almotriptan 6.25, 12.5 and 25 mg, respectively, compared with 35% for placebo; 2-h pain-free rates were 26.7%, 36.4% and 43.4% compared with 13.9% for placebo. All almotriptan dosages were significantly more effective than placebo in eliminating migraine-associated symptoms (P < 0.05) and in achieving sustained pain relief up to 24 h (P < 0.05). The incidence of adverse events after almotriptan 6.25 mg and 12.5 mg was not significantly different from that of placebo. This meta-analysis confirms the findings of individual clinical trials, while demonstrating for the first time, significant pain-free efficacy at 30 min compared with placebo.

Infrequent or non-response to oral sumatriptan does not predict response to other triptans--review of four trials.

A migraineur can claim to be an infrequent responder ('non-responder') to an oral triptan independent of which triptan he or she is presently using. Four trials of an alternative triptan (zolmitriptan/rizatriptan; eletriptan; naratriptan; almotriptan) in patients with a history of infrequent response to oral sumatriptan were compared and contrasted in terms of study design, patient characteristics, and efficacy and tolerability of the triptan under investigation. Unfortunately, none of the reported studies used an appropriate parallel design, which would have had the non-responding triptan (oral sumatriptan) in one arm and without encapsulation. While the four trials differed in terms of study design (open-label vs. placebo-controlled), definition of sumatriptan 'non-responder' (retrospective vs. prospective) and pain intensity at baseline (30% severe to 70% severe), all four demonstrated that lack of response to sumatriptan did not predict lack of response to an alternative triptan. Changing triptans resulted in 2-h pain-relief rates of 25-81% in patients with a history of poor response to sumatriptan. It can be concluded that migraine patients who respond infrequently to sumatriptan should be switched to a different triptan, as lack of response to one triptan does not predict likelihood of responsiveness to another. A review of the available evidence suggests that almotriptan may be one of the most appropriate choices for an alternative triptan.

Subcutaneous sumatriptan provides symptomatic relief at any pain intensity or time during the migraine attack.

Over the years the paradigm of treating early during the migraine attack has become well established in clinical practice. It is also recommended that the 5-HT(1B/1D) agonists be administered early during the migraine attack for efficacy. This is because it has been proposed that most migraineurs are less responsive to delayed treatment, owing to the development of central sensitization of the pain transmission. The main objective of this prospective, cross-over study at a specialist clinic was to evaluate if these recommendations should also apply to the subcutaneous formulation of sumatriptan. Results are based on 20 adult International Headache Society migraineurs. Two attacks (n=40) were treated with 6 mg subcutaneous sumatriptan as early as possible after the onset of migraine headache and two attacks (n=40) as late as the patients could bear. The median intra-individual difference between the two strategies in time from first occurrence of pain to injection was 5.7 h and the median intra-individual difference in pain intensity at the time of injection was 29 visual analogue units. No significant differences were found in time to freedom from pain, pain severity at 1 and 2 h, area under the curves from injection to pain free or in headache recurrence after injection. At the end of the study, most of the patients claimed that their medication was as effective when given early as when given late in the course of the attack. The discrepancy between our present findings and retrospective analyses of trials on oral triptans probably has more to do with the less disturbed pharmacokinetics early during the migraine attack than with central sensitization. Consequently, we recommend nonoral formulations of triptans, which do not necessarily have to be administered early during the migraine attack to provide efficacy. In conclusion, it is reassuring for migraineurs that it is worthwhile taking their medication in an appropriate formulation even if they have not been able to do so early in the course of the attack.

Focus on trial endpoints of clinical relevance and the use of almotriptan for the acute treatment of migraine.

Almotriptan is a 5-HT(1B/1D) receptor agonist, or triptan, indicated for the acute treatment of migraine. It has been shown to be effective and well tolerated for the treatment of acute migraine in approximately 5000 patients enrolled in short-term placebo- and active-controlled trials and long-term open-label trials. A recent meta-analysis reported that almotriptan has the highest sustained pain-free (SPF) rate and lowest adverse-event (AE) rate of all oral triptans. Sustained pain free is a composite endpoint of pain freedom at 2 h, no recurrence of moderate-to-severe headache and no use of rescue medication from 2 to 24 h after dosing. Patient surveys have indicated that migraine sufferers consider complete pain relief, no recurrence, rapid onset and no side-effects to be the most important attributes of their acute treatment. Composite endpoints such as SPF and SPF with no AEs (SNAE) contain the attributes that migraine sufferers express as being the most important elements of an acute migraine therapy, and their use in future clinical trials should aid in the selection of agents that can offer patients the highest likelihood of consistent treatment success.

[Is migraine a progressive cerebral disease?]. / La migraña es una enfermedad cerebral progresiva?

Migraine is a primary neurovascular headache which affects approximately 12% of the adult population. Migraine particularly affects women of working age and is associated with significant disability and reduced quality of life. During migraine attacks, the capacity to engage in daily activities such as child care, work, and social activities is reduced, and relationships with family members and friends become strained. In this respect, migraine places a heavy economic burden on both the individual and society. It is also known migraine is a risk factor for ischemic stroke in young women with migraine with aura. Recently, it was reported that some individuals that experience migraine with and without aura may be at an increased risk for subclinical lesions in certain areas of the brain. Cerebral white matter lesions (WMLs) are a common finding on cerebral MRI scans. Although, it appears that cerebral WMLs are more common in migraineurs than in the general population, the nature, association and the clinical significance of cerebral WMLs in migraineurs are not yet conclusive. Furthermore, there is no good evidence to support the notion that cerebral WMLs in migraineurs can predict subclinical or clinical stroke in these individuals. Needless to say, the need for more longitudinal and prospective migraine research is immense. The aim of the future migraine research should be to obtain more information about the natural course of migraine as well as evaluate the association between migraine and cerebral WMLs and their consequences. In addition, continuing genetic identification of key proteins involved in migraine will improve our understanding of this common and sometimes most debilitating disorder, which can strike during the most productive years of a person's life.

¿La migraña es una enfermedad cerebral progresiva? / Is migraine a progressive cerebral disease?

La migraña es una cefalea de origen neurovascular sufrida por aproximadamente el 12 % de la población adulta. La migraña afecta particularmente a mujeres en edad laboral y condiciona una considerable carga económica tanto para el individuo que la padece como para la sociedad. El sufrimiento psicosocial y humano, tanto del individuo afectado como de su familia, como consecuencia de la migraña, es de una gran dimensión. Se ha demostrado que la migraña es un factor de riesgo para la isquemia cerebral en mujeres jóvenes y recientemente se ha establecido que aquellos individuos que sufren migraña con y sin aura tienen un mayor riesgo de presentar lesiones subclínicas en ciertas áreas del cerebro. Sin embargo, la asociación, naturaleza y la trascendencia clínica de las lesiones de la sustancia blanca (LSB) en enfermos de migraña no son todavía concluyentes y no hay pruebas definitivas que respalden la noción de que las LSB cerebrales en enfermos de migraña puedan pronosticar isquemia cerebral subclínica o clínica en estos individuos. Por tanto, es absolutamente necesaria una investigación longitudinal y prospectiva en la migraña. Esta futura investigación debe hacer un esfuerzo especial por obtener más información sobre el curso natural de la enfermedad y evaluar la asociación entre la migraña y LSB cerebrales y sus consecuencias. Además, la futura identificación genética de proteínas clave involucradas en la migraña mejorará nuestro conocimiento sobre esta enfermedad tan común y debilitante

Migraine is a primary neurovascular headache which affects approximately 12% of the adult population. Migraine particularly affects women of working age and is associated with significant disability and reduced quality of life. During migraine attacks, the capacity to engage in daily activities such as child care, work, and social activities is reduced, and relationships with family members and friends become strained. In this respect, migraine places a heavy economic burden on both the individual and society. It is also known migraine is a risk factor for ischemic stroke in young women with migraine with aura. Recently, it was reported that some individuals that experience migraine with and without aura may be at an increased risk for subclinical lesions in certain areas of the brain. Cerebral white matter lesions (WMLs) are a common finding on cerebral MRI scans. Although, it appears that cerebral WMLs are more common in migraineurs than in the general population, the nature, association and the clinical significance of cerebral WMLs in migraineurs are not yet conclusive. Furthermore, there is no good evidence to support the notion that cerebral WMLs in migraineurs can predict subclinical or clinical stroke in these individuals. Needless to say, the need for more longitudinal and prospective migraine research is immense. The aim of the future migraine research should be to obtain more information about the natural course of migraine as well as evaluate the association between migraine and cerebral WMLs and their consequences. In addition, continuing genetic identification of key proteins involved in migraine will improve our understanding of this common and sometimes most debilitating disorder, which can strike during the most productive years of a person's life

Role of the needling per se in acupuncture as prophylaxis for menstrually related migraine: a randomized placebo-controlled study.

The objectives were to introduce a new method for controlled trials of acupuncture in the field of headache research and to examine the role of needling per se. Women with menstrually related migraine were randomized to three months of treatment with verum or placebo needles. Three standard size casts were moulded to secure the placebo needles in the head. No significant differences were found between the verum group (n=15) and the placebo group (n=13) during treatment or follow up three and six months later, either in the attack frequency or in the number of days per month with migraine, headache intensity or drug-use. The casts held the needles exactly in place despite movements of the head, and are validated as practical, hygienic and extremely durable. This method is satisfactory for controlled studies of acupuncture in headache. It is possible that the positive results in earlier clinical trials on acupuncture in migraine are attributable to other mechanisms than needling of subcutaneous tissue.

Sumatriptan (5-HT1B/1D-agonist) causes a transient allodynia.

Unpleasant sensory symptoms are commonly reported in association with the use of 5-HT1B/1D-agonists, i.e. triptans. In particular, pain/pressure symptoms from the chest and neck have restricted the use of triptans in the acute treatment of migraine. The cause of these triptan induced side-effects is still unidentified. We have now tested the hypothesis that sumatriptan influences the perception of tactile and thermal stimuli in humans in a randomized, double-blind, placebo-controlled cross-over study. Two groups were tested; one consisted of 12 (mean age 41.2 years, 10 women) subjects with migraine and a history of cutaneous allodynia in association with sumatriptan treatment. Twelve healthy subjects (mean age 38.7 years, 10 women) without migraine served as control group. During pain- and medication-free intervals tactile directional sensibility, perception of dynamic touch (brush) and thermal sensory and pain thresholds were studied on the dorsal side of the left hand. Measurements were performed before, 20, and 40 min after injection of 6 mg sumatriptan or saline. Twenty minutes after injection, sumatriptan caused a significant placebo-subtracted increase in brush-evoked feeling of unpleasantness in both groups (P < 0.01), an increase in brush-evoked pain in migraineurs only (P = 0.021), a reduction of heat pain threshold in all participants pooled (P = 0.031), and a reduction of cold pain threshold in controls only (P = 0.013). At 40 min after injection, no differences remained significant. There were no changes in ratings of brush intensity, tactile directional sensibility or cold or warm sensation thresholds. Thus, sumatriptan may cause a short-lasting allodynia in response to light dynamic touch and a reduction of heat and cold pain thresholds. This could explain at least some of the temporary sensory side-effects of triptans and warrants consideration in the interpretation of studies on migraine-induced allodynia.

Attitudes and burden of disease among self-considered migraineurs--a nation-wide population-based survey in Sweden.

The authors have earlier reported a 1-year prevalence of 13.2 +/- 1.9% for migraine in Sweden. This is a subsequent extensive postal survey of the burden of disease and attitudes among migraineurs in a sample (n = 423, 23% men and 77% women, aged 18-74 years) randomly recruited from all main regions of the country, representative of adults in the general Swedish population with self-considered migraine. Results are presented only from participants who after analysis of symptoms were found to fulfil the International Headache Society's migraine criteria. In order to assess headache duration open-mindedly, the strict time criterion 4-72 h was deliberately disregarded as an inclusion criterion. Individuals who did not consider themselves to have migraine were excluded. Less than half of the group (45%) had received a diagnosis of migraine from a physician. Accordingly, a large number of individuals that would not have come to attention in a clinic-based study have been included. The mean attack frequency was 1.3 per month, and the number of attacks per year in Swedish adults is approximately 10 million. A minority (27%) of sufferers have a majority (68%) of all attacks. The mean attack duration was 19 h. A considerable number of individuals reported attacks < 4 h (15.8%) or > 72 h (6.4%). Less than half of the individuals recovered completely between the attacks. Despite this, only every fourth (27%) participant was currently consulting a physician (6% regularly; 21% occasionally). Most of the migraineurs reported absence from school or work, a negative influence of migraine on the most important aspects of life, and an interest in testing other treatments for migraine during the last year. Of those (n = 231) migraineurs who had consulted a physician, about 60% were satisfied with information given or treatment offered. This implies, however, that there is still room for improvement in the management of migraine in Sweden.

A six-item short-form survey for measuring headache impact: the HIT-6.

BACKGROUND: Migraine and other severe headaches can cause suffering and reduce functioning and productivity. Patients are the best source of information about such impact. OBJECTIVE: To develop a new short form (HIT-6) for assessing the impact of headaches that has broad content coverage but is brief as well as reliable and valid enough to use in screening and monitoring patients in clinical research and practice. METHODS: HIT-6 items were selected from an existing item pool of 54 items and from 35 items suggested by clinicians. Items were selected and modified based on content validity, item response theory (IRT) information functions, item internal consistency, distributions of scores, clinical validity, and linguistic analyses. The HIT-6 was evaluated in an Internet-based survey of headache sufferers (n = 1103) who were members of America Online (AOL). After 14 days, 540 participated in a follow-up survey. RESULTS: HIT-6 covers six content categories represented in widely used surveys of headache impact. Internal consistency, alternate forms, and test-retest reliability estimates of HIT-6 were 0.89, 0.90, and 0.80, respectively. Individual patient score confidence intervals (95%) of app. +/-5 were observed for 88% of all respondents. In tests of validity in discriminating across diagnostic and headache severity groups, relative validity (RV) coefficients of 0.82 and 1.00 were observed for HIT-6, in comparison with the Total Score. Patient-level classifications based in HIT-6 were accurate 88.7% of the time at the recommended cut-off score for a probability of migraine diagnosis. HIT-6 was responsive to self-reported changes in headache impact. CONCLUSIONS: The IRT model estimated for a 'pool' of items from widely used measures of headache impact was useful in constructing an efficient, reliable, and valid 'static' short form (HIT-6) for use in screening and monitoring patient outcomes.

Ethical aspects of placebo in migraine research.

Randomized placebo-controlled clinical trials have been the 'golden standard' during the last decades in the development of new drug therapies. This scientifically valid approach has recently been questioned in the fifth revised version of the Declaration of Helsinki, which states that the use of placebo-controlled clinical trials is only acceptable when no proven treatment exists for the studied disease. The World Medical Association further claims that no national ethical, legal or regulatory requirements should be allowed to reduce or eliminate any of the statements in the declaration. In spite of this, the document is not generally accepted as the world ethical standard, as demonstrated by its lack of adoption by many professional associations. In the evaluation process for a drug to be approved in many countries today, clinical investigators at the hospitals and researchers at the pharmaceutical companies are obliged to use study protocols that would be rejected if the new declaration were to be fully adopted. Adherence to the clinical trial guidelines of the International Headache Society could also mean violation of the new Helsinki declaration of ethics. Some ethics committees have already adopted the new declaration, which has caused concern among clinical investigators, who find this document to be vastly out of the line with common practice. At the moment, the situation is unclear and debated with increasing polarity concerning the scientific and ethical issues regarding the use of placebo in clinical trials.

Eletriptan for the treatment of migraine in patients with previous poor response or tolerance to oral sumatriptan.

To determine the tolerability and efficacy of eletriptan in patients who had discontinued oral sumatriptan due to lack of efficacy or intolerable adverse events (AEs) during previous clinical treatment (not a controlled trial). Eletriptan is a potent, selective 5-HT1B/1D receptor agonist with beneficial pharmacokinetic properties compared with sumatriptan. In a double-blind, parallel group, placebo-controlled multicentre study, patients with and without aura (n = 446) were randomized to 40 mg eletriptan (E40, n = 188), 80 mg eletriptan (E80, n = 171) or placebo (n = 87) for treatment of up to three migraine attacks. Two-hour headache response, based on first-dose, first-attack data, was 59% for eletriptan 40 mg, 70% for eletriptan 80 mg, and 30% for placebo (P < 0.0001 for both doses of eletriptan vs. PBO; P < 0.05 for E80 vs. E40). Onset of action was rapid, with 1-h headache response rates significantly superior for E40 and E80 vs. placebo (40%, 48%, 15%; P < 0.0005). Both E40 and E80 were significantly superior to placebo, based on first-dose, first-attack data, for 2-h pain-free response (35%, 42%, and 7%; P < 0.0001). Both E40 and E80 demonstrated significant consistency of response, with headache relief rates at 2 h on at least two of three attacks in 66% and 72% vs. 15% on placebo (P < 0.001). AEs were mild to moderate in severity and dose related. The most commonly reported AEs included nausea, vomiting, asthenia, and chest symptoms. E40 and E80 produce an effective response in patients who had previously discontinued treatment with sumatriptan due to lack of efficacy or side-effects.

Efficacy, safety and tolerability of oral eletriptan in the acute treatment of migraine: results of a phase III, multicentre, placebo-controlled study across three attacks.

The efficacy, safety and tolerability of the 5-HT1B/D receptor agonist eletriptan (40 mg and 80 mg) in acute treatment of migraine was evaluated in a multinational, randomized, double-blind, parallel-group, placebo-controlled, three-attack study treating 1153 patients. In the initial attack, significantly more eletriptan patients reported headache relief and complete pain relief at 2 h vs. placebo (40 mg 62% and 32%, 80 mg 65% and 34%, placebo 19% and 3%; P < 0.0001). Headache relief occurred faster after eletriptan, with more patients at both doses reporting relief 30 min (P < 0.01) and 1 h (P < 0.0001) after treatment than after placebo. There was a significantly lower recurrence rate with eletriptan 80 mg compared with placebo (P < 0.01). Adverse events for all treatments were generally mild or moderate and self-limiting. Eletriptan 40 mg and eletriptan 80 mg both appear to be effective and well-tolerated acute migraine treatments.

Dose finding, placebo-controlled study of oral almotriptan in the acute treatment of migraine.

OBJECTIVE: To assess the efficacy and tolerability of oral almotriptan, a selective serotonin receptor (5-HT1B/1D) agonist, when used at different doses in the treatment of acute migraine. METHODS: This was a placebo controlled, double-blind, parallel-group, dose-finding study. Patients satisfying International Headache Society criteria for acute migraine were randomized to a single dose of placebo or oral almotriptan 2, 6.25, 12.5, or 25 mg at the onset of moderate or severe pain. Patients graded pain intensity on a 4-point verbal scale from 0 (no pain) to 3 (severe pain) and recorded adverse events. The primary efficacy variable was headache response at 2 hours. Data were analyzed on an intent-to-treat basis. RESULTS: Nine hundred and three patients were randomized, and 742 were included in the evaluation of the efficacy and tolerability. Headache response at 2 hours was 32.5% with placebo, and 30%, 56.3%, 58.5%, and 66.5% with almotriptan 2, 6.25, 12.5, and 25 mg doses (p < 0.05 for 6.25, 12.5, and 25 mg vs placebo). A dose-dependent decrease in the incidence of migraine-associated symptoms and the need for escape medication was observed. The incidence of adverse events with the almotriptan 2-mg, 6.25-mg, and 12.5-mg groups was comparable to that with the placebo group. CONCLUSION: Almotriptan 12.5 mg demonstrated the most favorable ratio between efficacy and tolerability, offering equivalent efficacy and better tolerability compared with the 25 mg dose. The minimum effective dose of almotriptan was 6.25 mg.