Symptoms of classic migraine attacks: Modifications brought about by metoprolol

There is little information available concerning whether, and to what extent, migraine-prophylactic agents interfere with the symptoms of migraine attacks. The present study is a placebo-controlled, double-blind study concerning metoprolol in classic migraine. The data refer to the symptoms of single migraine attacks. During metoprolol treatment more attacks were characterized as mild (p = 0.002), and mean global rating (an integrated estimate of headache intensity and of other discomfort) was lower (4.2 versus 5.2, p = 0.003). The mean headache intensity per attack (1.97 versus 2.15) and the mean duration (5.5 versus 6.8 h) were not significantly different. Consumption of analgesics per attack was lower during metoprolol treatment (0.6 versus 1.1; p = 0.02). Attacks with associated symptoms accompanying the headache were fewer during metoprolol treatment (p = 0.014). Total visual and non-visual aura symptoms occurred with similar frequency, but scintillations and paraesthesia were more frequent during metoprolol treatment, whereas speech disturbances were less frequent. In spite of lower consumption of analgesics, the symptoms appeared milder during metoprolol than during placebo. The pattern of changes indicates that metoprolol exerts its action via the sympathetic nervous system; peripheral vasoconstriction is hardly the underlying mechanism of action.     

Propranolol in the treatment of acute migraine attacks

The efficacy of the beta-adrenoceptor antagonist propranolol in the acute treatment of patients in attacks of either classical (migraine with aura) or common migraine (migraine without aura) headache was assessed in a double-blind placebo-controlled crossover trial with fixed doses. The trial was carried out on 25 patients. The treatment period was set at eight weeks, with the provision of shortening or lengthening it if necessary with a maximum period of seventeen weeks. A minimum of three migraine attacks were treated during each treatment period. Patients were assessed according to: the mean duration and mean severity per treatment period of migraine attacks. The secondary efficacy assessment was made on the basis of the percentage of attacks requiring escape medication per treatment period. The study, based on the t-distribution statistical model with a confidence level of 95%, showed that propranolol had no significant effect in aborting acute attacks of migraine when compared with placebo.     

European Multicenter Trial of Nimodipine in the Prophylaxis of Classic Migraine (Migraine With Aura)

SYNOPSIS
This double-blind, randomized study of the Nimodipine 40 mg t.i.d. vs placebo in the prophylaxis of classic migraine (migraine with aura) included 89 patients. Required migraine frequency was 2–8 migraine days/4 weeks and at least two of the attacks within the last 6 months had to be with aura. The study was carried out at 11 European centers. After a 4 week run-in period, patients were randomly allocated to nimodipine or placebo for 12 weeks (parallel groups). There were 7 dropouts, 3 on Nimodipine, and 4 on placebo. A gradual and verymarked improvement was seen both with Nimodipine and placebo amounting to between 60 and 90 per cent during the last 4 weeks. Statistical analysis on all included patients (intention to treat) revealed no difference between Nimodipine and placebo for migraine days or migraine index. In patients "valid for analysis of efficacy" there were also no significant difference. Due to a very marked placebo effect and use of the parallel groups design, the present trial is relatively weak despite a fairly large sample size. It cannot rule out the possibility of an important effect of Nimodipine in classic migraine with a high degree of certainty.     

Hydroxocobalamin,a nitric oxide scavenger,in the prophylaxis of migraine: an open,pilot study

Drugs which directly counteract nitric oxide (NO), such as endothelial receptor blockers, NO-synthase inhibitors, and NO-scavengers, may be effective in the acute treatment of migraine, but are also likely to be effective in migraine prophylaxis. In the underlying pilot study the prophylactic effect of the NO scavenger hydroxocobalamin after intranasal administration in migraine was evaluated. Twenty patients, with a history of migraine of > 1 year and with two to eight migraine attacks per month, were included in an open trial. A baseline period was followed by an active treatment period of 3 months with 1 mg intranasal hydroxocobalamin daily. Patients were instructed to complete a diary in which details of each attack were described. A reduction in migraine attack frequency of >/ or = 50% was seen in 10 of 19 patients, which corresponds to 53% of the patients (responders). A reduction of > or = 30% was noted in 63% of the patients. The mean attack frequency in the total study population showed a reduction from 4.7 +/- 1.7 attacks per month to 2.7 +/- 1.6 (P < 0.001). For the responders the migraine attack frequency was reduced from 5.2 +/- 1.9 (baseline) to 1.9 +/- 1.3 attacks per month (P < 0.005), while for those who did not respond a non-significant reduction was found: 4.1 +/- 1.4 to 3.7 +/- 1.5 (P > 0.1). A reduction was also observed for the total duration of the migraine attacks per month, the total number of migraine days per month and the number of medication doses for acute treatment used per month. This is the first prospective, open study indicating that intranasal hydroxocobalamin may have a prophylactic effect in migraine. As a percentage of responders in prophylactic trials of > 35-40% is unlikely to be a placebo effect, a double-blind study is warranted.     

The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis--a double-blind,multicentre, randomized placebo-controlled dose-response study

Tanacetum parthenium (feverfew), is a well-known herb for the prophylactic treatment of migraine. The primary objective was to show a dose-response of a new stable extract (MIG-99) reproducibly manufactured with supercritical CO2 from feverfew (T. parthenium). Furthermore, the study should provide data on the safety and tolerability of MIG-99. In a randomized, double-blind, multicentre, controlled trial with an adaptive design, the clinical efficacy and safety of three dosages of MIG-99 (2.08 mg; 6.25 mg; 18.75 mg t.i.d.) were compared with placebo. The patients (n = 147) suffered from migraine with and without aura according to International Headache Society (IHS) criteria and were treated with one of the study medications for 12 weeks after a 4-week baseline period. The primary efficacy parameter was the number of migraine attacks during the last 28 days of the treatment period compared with baseline. Secondary endpoints were total and average duration and intensity of migraine attacks, mean duration of the single attack, number of days with accompanying migraine symptoms, number of days with inability to work due to migraine as well as type and amount of additionally taken medications for the treatment of migraine attacks. The design of the study included a pre-planned adaptive interim analysis for patients with at least four migraine attacks within the baseline period. With respect to the primary and secondary efficacy parameter, a statistically significant difference was not found between the overall and the confirmatory intention-to-treat (ITT) sample in the exploratorily analysed four treatment groups. The frequency of migraine attacks for the predefined confirmatory subgroup of patients (n = 49) with at least four migraine attacks during the baseline period decreased in a dose-dependent manner (P = 0.001). The highest absolute change of migraine attacks was observed under treatment with 6.25 mg t.i.d. (mean +/- SD = -1.8 +/- 1.5 per 28 days) compared with placebo (-0.3 +/- 1.9; P = 0.02). Overall, 52 of 147 (35%) patients reported at least one adverse event (AE). The incidence of AEs in the active treatment groups was similar to that in the placebo group, and no dose-related effect was observed in any safety parameter. MIG-99 failed to show a significant migraine prophylactic effect in general. Accordingly, in the ITT analysis a dose-response relationship could not be observed. MIG-99 was shown to be effective only in a small predefined subgroup of patients with at least four attacks during the 28-day baseline period where the most favourable benefit-risk ratio was observed with a dosage of three capsules of 6.25 mg MIG-99 extract per day. Because of the low number of patients, these findings need to be verified in a larger sample. The incidence of AEs was similar for all treatment groups.     

Migraine postdromes: symptoms after attacks

To determine the nature and duration of symptoms after the headache phase of migraine, 40 migraineurs (11 with and 29 without an aura) were given a questionnaire to complete on the day after a migraine attack. The most common symptoms that remained were physical and mental tiredness, subdued or depressed mood, impaired concentration, reduced physical activities and yawning; weak or clumsy limbs, head tenderness, neck ache or stiffness, impaired sight and altered fluid balance were less frequent. The number of symptoms ranged from 2 to 11 (average 6) per patient lasting for a mean of 18 h, usually the whole of the next day. Symptoms after the main migraine attack can help to diagnose migraine particularly when there is no aura before the onset of headache. Eliciting postdromes aids patient-doctor rapport and confidence. The range of symptoms lends support to the notion that the whole of the brain is involved in the aftermath of migraine attacks.     

Magnesium in the prophylaxis of migraine-a double-blind, placebo-controlled study

The migraine prophylactic effect of 10 mmol magnesium twice-daily has been evaluated in a multicentre, prospective, randomized, double-blind, placebo-controlled study. Patients with two to six migraine attacks per month without aura, and history of migraine of at least 2 years, were included. A 4-week baseline period without medication was followed by 12 weeks of treatment with magnesium or placebo. The primary efficacy end-point was a reduction of at least 50% in intensity or duration of migraine attacks in hours at the end of the 12 weeks of treatment compared to baseline. With a calculated total sample size of 150 patients, an interim analysis was planned after completing treatment of at least 60 patients, which in fact was performed with 69 patients (64F, 5M), aged 18–64 years. Of these, 35 had received magnesium and 34 placebo. The number of responders was 1 in each group (28.6% under magnesium and 29.4% under placebo). As determined in the study protocol, this was a major reason to discontinue the trial. With regard to the number of migraine days or migraine attacks there was no benefit with magnesium compared to placebo. There were no centre-specific differences, and the final assessments of treatment efficacy by the doctor and patient were largely equivocal. With respect to tolerability and safety, 45.7% of patients in the magnesium group reported primarily mild adverse' events like soft stool and diarrhoea in contrast to 23.5% in the placebo group.     

Treatment of Acute Migraine Attack: Ibuprofen and Placebo Compared

The efficacy of ibuprofen in comparison with that of placebo was assessed in the treatment of acute migraine attacks. The material consisted of 40 migraine patients. Each treatment period continued for five migraine attacks. The initial dose of ibuprofen was 800 mg, with additional 400 mg taken if and when needed. The mean duration of migraine attacks treated with ibuprofen was significantly shorter than the duration of migraine attacks treated with placebo. Need for supplementary medication was also significantly lower in the ibuprofen-treated migraine attack group. Ibuprofen was well tolerated and no marked side effects were reported during the trial.     

Relationship of locus of control in women with migraine and healthy volunteers

OBJECTIVE: To investigate potential differences in various aspects of personality in women with migraine with aura, without aura, and in healthy volunteers. METHODS: The following instruments were used to evaluate a sample of 35 women with migraine with aura, 35 women with migraine without aura, and 35 healthy women: Locus of Control and Competence Questionnaire, Health Locus of Control Questionnaire, Trait scale of the State-Trait Anxiety Inventory, and the depression scale by von Zerssen. RESULTS: There were no significant differences in generalized locus of control beliefs among the 3 groups. Migraineurs with aura were found to score very low on the social locus of control scale. Statistically significant differences were found regarding anxiety in migraineurs with aura as opposed to migraineurs without aura and healthy control subjects. As for depression, migraineurs with aura were significantly more likely to indicate feelings of worthlessness and lack of self-confidence. CONCLUSIONS: Our results suggest that migraineurs with aura differ from migraineurs without aura and healthy control subjects in terms of anxiety and depression. With regard to health-related locus of control, there was no correlation among mean number of migraine attacks per year, duration of disease, time of last migraine attack, and number of aura symptoms.     

Pharmacokinetics of rizatriptan tablets during and between migraine attacks

Gastric stasis during migraine attacks results in delayed absorption of several orally administered antimigraine agents. This study, as part of a larger trial, was conducted to examine the pharmacokinetics of rizatriptan tablets during and between migraine attacks. Participating patients met IHS criteria for migraine with or without aura, and suffered between one and eight migraines per month for the previous 6 months. In part 1 of the study, 21 patients were randomized to receive a single 5-mg tablet of rizatriptan or placebo in the migraine-free state. In part 2, the same patients were treated during migraine with rizatriptan 5-mg tablets (n=18) or placebo (n=3). Blood samples were obtained before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after dosing. The plasma concentration profile (ie, AUC_(0-∞), C_max, T_max) of rizatriptan 5-mg tablets administered during and between migraine attacks were comparable. The median T_max for rizatriptan between and during attacks was 1 hour, indicating rapid absorption even during a migraine attack. Rizatriptan 5 mg was well tolerated and 67% of the patients experienced headache relief 2 hours postdose.     

The aura: a tertiary care study of 952 migraine patients

The aim of this study was to document the frequency and types of aura symptoms, to define the relationship between aura symptoms and to define the aura frequency in different migraine types. In 952 migraine patients, aura frequency, duration, time to headache, characteristics and percentage of headaches with aura were analysed. Thirty-eight percent of IHS 1.1-1.5 patients reported aura, 38.1% of females and 33.0% of males. Average percentage of aura occurrence with headache was 19.7% of headaches, average aura duration 27.3 min and aura was followed by headache in 10.4 min on average. Visual disturbances occurred in 92.1% and aura without visual aura was rare. Aura frequency was headache-type dependent. The highest frequency of aura was seen in the more 'full-blown' migraine attack. Visual aura is the overwhelming aura symptom. Even in patients with aura the percentage of aura with migraine attacks is limited.     

Improved description of the migraine aura by a diagnostic aura diary

We present a diagnostic aura diary for prospective recordings of migraine with aura. Three questionnaires are supplemented with sheets for drawings and plottings of visual and sensory auras. Twenty patients recorded 54 attacks of migraine with aura and 2 attacks of migraine aura without headache. The visual and sensory aura were usually gradually progressive, reaching maximum development in 15 and 25 min (median) respectively and had a total duration of 20 and 55 min (median) respectively. Approximately 13% of the attacks had acute onset of visual aura associated with other features more typical of migraine. The visual and sensory auras always preceded typical migraine headache, and headache occurring before aura symptoms was always of the tension type, The migraine headache was milder than in attacks of migraine without aura and often did not have migraine characteristics. In attacks with unilateral head pain, headache and aura symptoms were contralateral in 90% and ipsilateral in 10%.     

Prophylactic botulinum type A toxin complex (Dysport®) for migraine without aura

(Headache 2011;51:52‐63) Objective.— To evaluate the efficacy, safety, and optimum dose of a highly purified Clostridium botulinum type A toxin‐hemagglutinin complex (Dysport) for migraine prophylaxis. Background.— Botulinum toxin type‐A has demonstrated good efficacy in several open‐label studies of patients with migraine, involving either individualized or standardized protocols, although data from placebo‐controlled trials have been conflicting. Methods.— A 12‐week, double‐blind, randomized trial of Dysport (120 or 240 units) vs placebo was conducted in 6 centers in Thailand to evaluate the efficacy, safety, and optimum dose of botulinum toxin type‐A (Dysport) for migraine prophylaxis. A total of 128 patients with migraine without aura were enrolled. The primary end point was the change in the mean number of migraine attacks per 4‐week period from the pre‐treatment period to 8‐12 weeks post injection. Secondary efficacy measures included the change in the mean total intensity score from the pre‐treatment period to 8‐12 weeks, the investigator and patient global assessments of change at each visit compared with pre‐treatment, and Migraine Disability Assessment and Short Form‐36 scores. Results.— Change in number of migraine attacks from pre‐treatment to weeks 8‐12 was not significantly different. There was a greater improvement in total intensity score at weeks 8‐12 with Dysport‐240 (not significant), and interim visit data showed that this was significant at weeks 0‐4 (P = .03 Dysport‐240 vs placebo). The mean duration of headache during weeks 0‐4 was lower with Dysport‐240 (P = .04 vs placebo). Improvements in patient and investigator global assessments of change between weeks 0‐4 and 8‐12 were significant for the Dysport‐240 group (both P < .05 vs placebo). Conclusions.— Limitations in study design and assessment tools employed may have contributed to the inconclusive nature of the primary end point data. Dysport‐240 showed significant benefit over placebo at some end points and further trials with more appropriate outcome measures are required to evaluate effectively this treatment.     

Divalproex sodium in migraine prophylaxis: a dose-controlled study

Objective : To evaluate the efficacy and safety of divalproex sodium (DVPX) when used as prophylactic monotherapy in patients with migraine. Design : Multicenter, double-blind, placebo-controlled, parallel group. Patients were previously untreated or had failed no more than two adequate trials of prophylactic therapy. During the 4-week (single-blind) baseline, patients received placebo and completed a headache diary. Patients with two or more migraine attacks during the baseline were randomized to receive a DVPX daily dose of 500, 1000, or 1500 mg, or to placebo. The experimental phase (EP) lasted 12 weeks, the first 4 weeks for dose escalation to randomized dose, and the remaining 8 weeks for maintenance at that dose. The primary efficacy variable was 4-week migraine attack frequency during the EP. Results : One-hundred-and-seventy-six patients (44 placebo, 132 DVPX) were randomized; 171 provided efficacy data and 137 completed the study. During the EP, after adjustment for differences in baseline migraine attack frequencies, mean reductions in the DVPX groups were 1.7 (500 mg), 2.0 (1000 mg) and 1.7 (1500 mg) migraine attacks per 4 weeks compared to a mean reduction of 0.5 migraine attacks in the placebo group ( p 0.05 vs placebo). Forty-four to 45% of DVPX-treated patients, compared to 21% of patients in the placebo group achieved 50% reduction in their migraine attack frequencies ( p 0.05 vs placebo). The recommended initial dose of DVPX in migraine prophylaxis is 500 mg per day, although some patients may benefit from higher doses. Adverse events were similar in the DVPX and placebo treatment groups except for nausea, dizziness and tremor, in which incidence rates were significantly higher in the DVPX 1500 mg group (nausea was also higher in 500 mg group) than in the placebo group. Conclusion : Divalproex sodium is an effective prophylactic treatment in migraine and is generally well tolerated.     

Double-blind study of naproxen vs placebo in the treatment of acute migraine attacks

Naproxen was compared with placebo in a double-blind, crossover trial in classic and common migraine. The trial was terminated at a fixed date; 37 patients had entered, 5 of whom were excluded. Naproxen was given as 750 mg at the first symptom of the attack, a total of 1250 mg per 24 h was allowed. Patients were followed for six attacks or three months in each phase, whichever came first. The severity of the headache was significantly less with naproxen in the first 2 h of the attack (p = 0.047), whereas there was no difference when the whole attack was considered. Significantly more patients preferred naproxen (p = 0.042). Side effects occurred in five patients, causing withdrawal of one patient while on naproxen.     

Sex differences in migraine attack characteristics: A longitudinal E-diary study

Objective

In this prospective cohort study, characteristics of perimenstrual and non-perimenstrual migraine attacks in women were compared with migraine attacks in men.

Background

Women report longer migraine attacks and more accompanying symptoms than men in cross-sectional questionnaire studies, but this has not been confirmed in longitudinal studies. Supposed differences could result from different characteristics specific to perimenstrual migraine attacks, or of attacks in women in general.

Methods

This cohort study was performed among patients with migraine who were treated at the Leiden Headache Clinic. We assessed differences in migraine attack characteristics between men and women who were prospectively followed by a previously validated electronic headache diary. The primary outcome was “attack” duration. Differences between perimenstrual (Days −2 to +3 of the menstrual cycle) and non-perimenstrual attacks in women versus attacks in men were corrected for age, chronic migraine, and medication overuse headache.

Results

A total of 1347 women and 284 men were included, reflecting the preponderance of women in migraine prevalence. Crude median (first and third quartile [Q1−Q3]) attack duration in men was 32.1 [17.7–53.6] h, compared to 36.7 [21.9–62.4] h for non-perimenstrual migraine attacks and 44.4 [17.9–79.0] h for perimenstrual migraine attacks in women. After correction for confounding, perimenstrual migraine attacks were 1.62 (95% confidence interval [CI] 1.47–1.79; p < 0.001) and non-perimenstrual 1.15 (95% CI 1.05–1.25; p = 0.003) times longer compared to migraine attacks in men. The mean relapse percentage in men was 9.2%, compared to 12.6% for non-perimenstrual migraine attacks, and 15.7% for perimenstrual migraine attacks. Relapse risk was greater for perimenstrual (odds ratio [OR] 2.39, 95% CI 1.93–2.95; p < 0.001), but not for non-perimenstrual (OR 1.18, 95% CI 0.97–1.45; p = 0.060) attacks. Migraine attacks in women were more often accompanied by photophobia, phonophobia, and nausea, but less often aura.

Conclusion

Compared to attacks in men, both perimenstrual and non-perimenstrual migraine attacks are of longer duration and are more often accompanied by associated symptoms. A sex-specific approach to migraine treatment and research is needed.     

Effectiveness of lamotrigine in the prophylaxis of migraine with aura: an open pilot study

We report a small open pilot study to evaluate the efficacy of lamotrigine (100 mg/day) in the prevention of migraine with aura attacks. We studied 24 patients affected by migraine with aura with a high frequency of attacks. Following a 1-month run-in period, the patients took lamotrigine for 3 months. Mean attack number per month was reduced from 6.1 +/- 4.1 during the run-in period to 0.7 +/- 1.3 at the 3rd month of treatment (p < 0.0001). In 13 out of 21 patients who completed the study, the attacks were completely abolished at the 3rd month of treatment, while only one patient was completely unresponsive to the drug. Lamotrigine seems worthy of a controlled trial as prophylaxis of a migraine with aura.     

Normobaric hypoxia and nitroglycerin as trigger factors for migraine

Migraine prevalence is increased in high-altitude populations and symptoms of acute mountain sickness mimic migraine symptoms. Here we tested whether normobaric hypoxia may trigger migraine attacks. As positive control we used nitrolgycerin (NTG), which has been shown to induce migraine attacks in up to 80% of migraineurs. Sixteen patients (12 females, mean age 28.9 +/- 7.2 years) suffering from migraine with (n = 8) and without aura (n = 8) underwent three different provocations (normobaric hypoxia, NTG and placebo) in a randomized, cross-over, double dummy design. Each provocation was performed on a separate day. The primary outcome measure was the proportion of patients developing a migraine attack according to the criteria of the International Headache Society within 8 h after provocation onset. Fourteen patients completed all three provocations. Migraine was provoked in six (42%) patients by hypoxia, in three (21%) by NTG and in two (14%) by placebo. The differences among groups were not significant (P = 0.197). The median time to attacks was 5 h. In conclusion, the (remarkably) low response rate to NTG is surprising in view of previous data. Further studies are required to establish fully the potency of hypoxia in triggering migraine attacks.     

Migraine Warnings

SYNOPSIS
The early prodromal phase of a migraine attack, poorly documented yet conceivably relevant to the pathogenesisof the attack, was studied in 149 patients, mainly female, with classic or common migraine who were aware ofthese prodromal phenomena. On a questionnaire a variety of prodromes, nearly all well reproduceable, werereported. Day-before and day-of-attack symptoms were noticed by 79% and 88% of the patients, respectively. Inthe other 12–21% signs were mainly observed by the partner. Some prodromes invoked the "cause orconsequence?" question as to certain trigger factors. Others bore rather striking similarities to the classic aura, sothat evolutive symptoms seemed to merge with the early part of the migraine attack. The incidence, or at least theawareness of prodromes was correlated with the occurrence of some factors aggravating the headache and withpost-attack symptoms, was higher in women, in patients with long-standing disease and frequent attacks, inpatients who had other types of headaches as well, and in classic migraine sufferers.     

Sumatriptan in the treatment of acute migraine with aura

The efficacy of the selective 5HT1-like agonist sumatriptan in acute treatment of classical migraine (i.e. migraine with aura) was assessed in a double-blind, placebo-controlled, parallel group randomized trial. An oral dose of 200 mg was chosen on the basis of the efficacy rates achieved (70-85%) with 70-280 mg in open studies (1, 2). The dose of 200 mg was also chosen for the study because preliminary data from an oral pilot study indicated that efficacy increased with increasing dose up to 200 mg. Each patient was treated for a maximum of three separate attacks of migraine with aura within a three months' period. Three attacks were treated so that we could examine consistency of response across more than one attack. For attack 1, 200 mg sumatriptan was significantly more effective, safe and well tolerated than placebo at relieving headache 2 h after treatment was given (p = 0.023). In subsequent attacks, i.e. in attacks 2 and 3, there was no such significant effect of sumatriptan compared with placebo in relieving headache. This reduced efficacy of sumatriptan in the second and third attacks may be due to a high incidence of vomiting induced by the high dose of dispersible formulation and also by the bitter taste of the tablets. In addition, there was an increase in placebo response in attacks 2 and 3 compared to the first attack.