Dihydroergotamine nasal spray in the treatment of acute migraine

OBJECTIVE: To evaluate the efficacy and safety of dihydroergotamine (DHE) nasal spray in patients suffering from common or classical migraine. METHODS: In a double-blind parallel-group study, 52 outpatients with migraine were randomly allocated to DHE nasal spray or to placebo. Two puffs, one in each nostril, was taken as an initial dose (resulting in either 0.5 or 1 mg of DHE), followed by another puff (0.5 mg) after 30 and 60 minutes, if necessary, achieving a maximum dose of 2 mg for patients of the DHE 1-mg group or of 1.5 mg for patients of the 0.5-mg group. Four consecutive attacks were thus treated. The efficacy analysis was done for observed cases. The main outcome measure was reduction of the severity of the attacks. RESULTS: No differences were observed in the migraine characteristics or the number of treatments of the patients from the different groups. Dihydroergotamine 1 mg tended to provide better relief than 0.5 mg, although the effect was not statistically significant. Patients taking DHE used less rescue medications, with a dose-dependent effect. Side effects were reported by four patients receiving DHE but not placebo. The tolerability of the drug was assessed as good by 94% of the patients. CONCLUSION: These findings suggest that DHE nasal spray is well tolerated and has dose-dependent efficacy in migraine.     

A Controlled Study of Dihydroergotamine in the Treatment of Acute Migraine Headache

SYNOPSIS
A prospective, double-blind, crossover study was conducted of the effectiveness of dihydroergotamine (DHE) vs. placebo in the treatment of acute migraine in the emergency department. Thirty-seven patients were enrolled. By 60 minutes after treatment, those receiving DHE first had significantly better relief of pain than those receiving it later. Side effects were fairly common but were minor and did not necessitate terminating treatment. Eleven per cent of patients had significant relief of pain with prochlorperazine pre-treatment alone. Only 13.5% of patients treated with this DHE regimen required narcotics at the end of the study for relief of pain, compared to 45% of migraine headache patients seen concurrently in the same emergency department who were not enrolled in the study. We conclude that treatment with intravenous prochlorperazine and DHE is a safe and effective treatment and a useful alternative to narcotics.     

Combined low-dose acetylsalicylic acid and dihydroergotamine in migraine prophylaxis

The efficacy of the combination of dihydroergotamine (10 mg) with acetylsalicylic acid (80 mg) (DHE + ASA) in the prophylaxis of migraine was studied in a double-blind, placebo-controlled crossover trial (8 weeks twice). Of 45 patients who entered the study, 38 completed it. The number of attacks was significantly (p = 0.003) reduced during active treatment (11.5 +/- 6.2) compared with placebo (16.6 +/- 9.9). The mean duration, the mean severity, and the mean score for symptomatic acute medication of attacks did not differ significantly. The overall assessment made by the patients themselves was in favor of DHE + ASA (p = 0.001). These results indicate a moderately beneficial effect of the dihydroergotamine/low-dose acetylsalicylic acid combination in migraine prophylaxis.     

Clinical Experience With Patient Administered Subcutaneous Dihydroergotamine Mesylate in Refractory Headaches

This study examines the practicality and efficacy of dihydroergotamine mesylate (DHE) when self-administered subcutaneously in a population of refractory headache patients. Forty-three patients with chronic daily headache or migraine headache without aura, who had been taught self-injection of DHE either through the Raskin Protocol or in an outpatient headache clinic, were contacted by telephone and administered a questionnaire regarding usage and results from DHE injection. Ninety-two percent of patients could successfully administer DHE. Forty-six percent of patients experienced 90% or greater relief of pain and the majority of patients (77%) had greater than 50% relief. Emergency room use was decreased in 83% and 80% preferred DHE to their previous therapy. While side effects were common (79%), only four patients (9%) stopped DHE for this reason. No convincing evidence for the development of rebound headaches due to DHE was found in this sample.     

Treatment of Childhood Headache with Dihydroergotamine Mesylate

SYNOPSIS
This study was undertaken to determine whether pediatric patients with migraine without aura who have failed standard outpatient regimens including intravenous dihydroergotamine mesylate (DHE) in conjunction with oral metoclopramide would respond to an inpatient treatment protocol of intravenous DHE and oral metoclopramide. Thirty patients were evaluated in this study which was an open label, retrospective review of treatment. Independent of the duration of the refractory migraine, 80% of the patients responded to the protocol with only minimal side effect. The dose of DHE mesylate ranged from 0.1 to 0.5 mg. The dose of DHE is lower than is typically utilized in standard adult protocols. The patients received an average of five doses of DHE.     

A clinical comparison of sumatriptan nasal spray and dihydroergotamine nasal spray in the acute treatment of migraine

A multinational, multicentre, randomised, double-blind, double-dummy, crossover study (368 patients treating two attacks) was conducted to compare the efficacy and tolerability of sumatriptan nasal spray (20 mg) with dihydroergotamine (DHE) nasal spray (1 mg plus optional 1 mg). At the primary efficacy time point of 60 minutes after dosing, significantly more patients obtained headache relief (change from moderate or severe to none or mild) after treatment with sumatriptan than with DHE (53% sumatriptan, 41% DHE, p < 0.001). Significantly more patients reported relief of nausea after sumatriptan than after DHE at 60 minutes (64% sumatriptan, 49% DHE, p = 0.006). A significant difference between the two treatments was first observed at 45 minutes with respect to both headache relief (38% sumatriptan, 31% DHE, p = 0.037) and relief of nausea (55% sumatriptan, 40% DHE, p = 0.014). There were no significant differences between the two treatments for other measures of efficacy. Both treatments were well tolerated, with only 10% of patients in each group reporting one or more adverse events. The most frequently reported adverse event after sumatriptan was a bad or bitter taste, which was reported by 5% of patients. After DHE, 4% of patients reported symptoms of the nasal cavity/sinuses and 3% reported nausea and/or vomiting as adverse events. It is concluded that sumatriptan nasal spray is superior to DHE nasal spray in the relief of pain and nausea associated with acute migraine headache.     

Rescue therapy for acute migraine, part 3: opioids, NSAIDs, steroids, and post-discharge medications

Objective.— The final section of this 3‐part review analyzes published reports involving the acute treatment of migraine with opioids, non‐steroidal anti‐inflammatory drugs (NSAIDs), and steroids in the emergency department (ED), urgent care, and headache clinic settings, as well as post‐discharge medications. In the Conclusion, there is a general discussion of all the therapies presented in the 3 sections. Method.— Using the terms (“migraine” AND “emergency”) AND (“therapy” OR “treatment”), the author searched MEDLINE for reports from ED and urgent care settings that involved all routes of medication delivery. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Results.— Seventy‐five reports were identified that compared the efficacy and safety of multiple acute migraine medications for rescue. Of the medications reviewed in Part 3, opioids, NSAIDs, and steroids all demonstrated some effectiveness. When used alone, nalbuphine and metamizole were superior to placebo. NSAIDs were inferior to the combination of metoclopramide and diphenhydramine. Meperidine was arguably equivalent when compared with ketorolac and dihydroergotamine (DHE) but was inferior to chlorpromazine and equivalent to the other dopamine antagonists. Steroids afford some protection against headache recurrence after the patient leaves the treatment center. Conclusions.— All 3 opioids most frequently studied – meperidine, tramadol, and nalbuphine – were superior to placebo in relieving migraine pain, although meperidine combined with promethazine was not. Opioid side effects included dizziness, sedation, and nausea. With ketorolac being the most frequently studied drug in the class, NSAIDs were generally well tolerated, and they may provide benefit even when given late in the migraine attack. The rate of headache recurrence within 24‐72 hours after discharge from the ED can be greater than 50%. Corticosteroids can be useful in reducing headache recurrence after discharge. As discussed in Parts 1, 2, and 3, there are effective medications for provider‐administered “rescue” in all the classes discussed. Prochlorperazine and metoclopramide are the most frequently studied of the anti‐migraine medications in the emergent setting, and their effectiveness is superior to placebo. Prochlorperazine is superior or equivalent to all other classes of medications in migraine pain relief. Although there are fewer studies involving sumatriptan and DHE, relatively “migraine‐specific” medications, they appear to be equivalent to the dopamine antagonists for migraine pain relief. Lack of comparisons with placebo and the frequent use of combinations of medications in treatment arms complicate the comparison of single agents to one another. When used alone, prochlorperazine, promethazine, metoclopramide, nalbuphine, and metamizole were superior to placebo. Droperidol and prochlorperazine were superior or equal in efficacy to all other treatments, although they also are more likely to produce side effects that are difficult for a patient to tolerate (especially akathisia). Metoclopramide was equivalent to prochlorperazine, and, when combined with diphenhydramine, was superior in efficacy to triptans and NSAIDs. Meperidine was arguably equivalent when compared with ketorolac and DHE but was inferior to chlorpromazine and equivalent to the other neuroleptics. Sumatriptan was inferior or equivalent to the neuroleptics and equivalent to DHE when only paired comparisons were considered. The overall percentage of patients with pain relief after taking sumatriptan was equivalent to that observed with droperidol or prochlorperazine. (Headache 2012;52:467‐482)     

Continuous Intravenous Dihydroergotamine in the Treatment of Intractable Headache

We reviewed data on 171 patients with refractory headache treated by continuous intravenous dihydroergotamine mesylate (IV DHE 45 ÒÒ ) and repetitive IV DHE and compared the efficacy of continuous IV DHE to repetitive IV DHE. One hundred (58.5%) patients had refractory chronic daily headache. Seventy-one (42%) had drug rebound headache. One hundred thirty-eight (81%) had refractory migraine without aura, and 28 (16%) had migraine with aura. Treatment consisted of either continuous IV DHE by infusion pump or repetitive IV DHE and withdrawal of excessively used analgesics, analgesic narcotics, ergotamines, or benzodiazepines. Eighty-nine (92.5%) patients treated with continuous IV DHE became headache-free; the majority, 62 (64.5%), within 3 days. Sixty-five (86.5%) patients treated by repetitive IV DHE became headache-free, 50 (66.5%) within three days. The average hospital stay for both treatment groups was 4 days. Twelve (12.5%) of the continuous group and 12 (16%) of the repetitive group were headache-free within 24 hours. The average length of time to become headache-free was similar for the two groups, 3.06 days for continuous IV DHE and 2.94 days for repetitive IV DHE. The most common side effect was nausea, followed by diarrhea, vomiting, and leg cramps.
We conclude that DHE can be accurately and easily administered by continuous IV infusion pump, and that continuous IV DHE is a safe and efficacious mode of treatment producing results similar to repetitive IV DHE.     

A Randomized, Double Blind, Placebo-Controlled Study of MAP0004 in Adult Patients With Migraine

Background.— Dihydroergotamine mesylate (DHE) is an effective treatment for acute migraine, but its effective use is often limited by the inconvenience and inconsistency of intranasal, intramuscular, or subcutaneous routes of administration. A new formulation of DHE delivered through the lungs by the novel Tempo^® inhaler is being developed and is designed to offer fast onset, consistent dosing, and sustained response. Objective.— This proof of principle and dose setting study evaluated the efficacy and tolerability of inhaled DHE delivered by a breath‐synchronized, plume‐controlled inhaler (Tempo) in adult migraineurs. Methods.— This was a randomized, double blind, placebo‐controlled, 2‐period study conducted at 9 headache centers in the United States. Adult men and women with a documented history of acute migraine for at least 12 months, with an average of 2 to 8 attacks per month in the preceding 6 months were treated with MAP0004 0.5 or 1.0 mg systemic equivalent dose (1.0 or 2.0 mg nominal dose) or matching placebo during Treatment Period 1 (TP1). Patients who responded to treatment during TP1 were re‐randomized in Treatment Period 2 (TP2) to receive MAP0004 0.25 mg systemic equivalent dose or placebo. Results.— Of 86 patients randomized to treatment, 69 were included in the As‐Treated population in TP1. Pain relief at 2 hours was greater for MAP0004 0.5 mg (72%, P = .019) and 1.0 mg (65%, P = .071) than for placebo (33%). Pain relief at 10 (32%), 15 (46%), and 30 (55%) minutes was significantly (P < .05) greater with MAP0004 0.5 mg than with placebo (0%, 7% and 14%, respectively). Pain‐free at 2 hours was significantly greater with MAP0004 0.5 mg (44%, P = .015) and 1.0 mg (35%, P = .050) than with placebo (7%). Total migraine relief at 2 hours was significantly (P = .019) greater with MAP0004 0.5 mg (72%) than with placebo (33%). Sustained pain relief and pain‐free rates exhibited a therapeutic gain of 30% (P = .066) and 31% (P = .037) at 24 hours and 28% (P = .096) and 30% (P = .057) at 48 hours with MAP0004 0.5 mg vs placebo. MAP0004 was well tolerated with no serious or severe adverse events. Dysgeusia was reported as treatment‐related in 2 patients on placebo, 0 patients on MAP0004 0.5 mg, and 6 patients on MAP0004 1.0 mg. No clinically relevant changes were noted in spirometry, vital signs, electrocardiogram, or clinical laboratory values. No significant differences between treatments were observed in TP2. Conclusions.— In this study MAP0004 0.5 mg and 1.0 mg were well tolerated and effective at delivering clinically significant, rapid, and sustained pain relief in adult migraine patients. No additional benefit was observed with the higher dose, thus the MAP0004 0.5 mg systemic equivalent dose has been selected as the dose for further clinical study.     

Home Administration of Intramuscular DHE for the Treatment of Acute Migraine Headache

SYNOPSIS
Dihydroergotamine (DHE) has been used for the treatment of acute migraine headache for almost 50 years. Previous studies have emphasized use in emergency room, inpatient, or office settings. Twenty-nine patients with migraine headache who had failed to obtain relief with conventional therapy were trained to self-administer intramuscular DHE. The patients administered 0.5 mg DHE and 100 mg trimethobenzamide at the onset of their headache and an additional O.5mg DHE if satisfactory headache relief was not obtained. Twenty patients were successfully contacted and interviewed. Forty-five percent of the patients had at least 50% relief of headache and continued to use the protocol. Eighty-two percent of patients who initially had at least 50% headache relief continued to use the drug, whereas none of the patients who initially had less than 10% relief continued the protocol. Sixty-one percent of patients whose headaches precluded continuation of activity had at least 50% response to initial treatment, whereas only 29% whose headaches were less severe had this response. Initial response to therapy was predictive of continued use of the treatment protocol and patients who described more severe headache had a higher response to the initial treatment. Thus, home administration of I.M. DHE offers an additional treatment regimen for patients with migraine headache.     

Montelukast for migraine prophylaxis: a randomized, double-blind, placebo-controlled study

OBJECTIVE: To evaluate the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine. BACKGROUND: A previous small open-label study in migraine patients suggested prophylactic efficacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used in the treatment of asthma. We sought to confirm these findings in a randomized controlled trial. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-groups study enrolled adult migraine outpatients who experienced > or =3 and < or =8 migraine attacks per month for the last 6 months. Patients were entered into a 2-month, single-blind, placebo run-in phase. Only patients who experienced > or =3 migraine attacks in the second month were eligible to enter the subsequent 3-month, double-blind treatment phase of the study. The primary efficacy endpoint was the percentage of patients reporting at least a 50% decrease in migraine attack frequency per month during the double-blind treatment period (months 3-5) compared to baseline (run-in month 2). RESULTS: A total of 93 patients were randomized to montelukast 20 mg and 84 patients to placebo at the end of the placebo run-in month 2; 76 patients on montelukast and 72 patients on placebo completed the double-blind treatment period. Over 3 months of treatment, there was no significant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15.4% for montelukast versus 10.3% for placebo (P= .304). In addition, montelukast 20 mg was not significantly superior to placebo on any of the secondary endpoints. There were no differences between treatment groups for adverse events. CONCLUSION: Montelukast 20 mg was well tolerated in migraine patients but was not an effective prophylactic for prevention of migraine.     

Benefits of treating highly disabled migraine patients with zolmitriptan while pain is mild

Clinical trials of migraine therapy often require treatment when migraine pain intensity is moderate or severe, but many physicians find this practice artificial and patients often prefer to treat while pain is mild. This randomized, placebo-controlled study assessed the efficacy of zolmitriptan 2.5 mg in treating migraine while pain is mild, in patients who typically experience migraine attacks that are initially mild, but progress to moderate or severe. The intent-to-treat population comprised 280 patients (138 zolmitriptan; 148 placebo), with mean MIDAS grades of 29.6 (zolmitriptan) and 27.6 (placebo). Zolmitriptan 2.5 mg provided a significantly higher pain-free rate at 2 h (43.4% vs. 18.4% placebo; P < 0.0001). Significantly fewer zolmitriptan patients reported progression of headache pain to moderate or severe intensity 2 h postdose (53.7% vs. 70.4% placebo; P < 0.01), or required further medication within 24 h (46.4% vs. 71.1% placebo; P < 0.0001). The efficacy of zolmitriptan was more pronounced in patients treating during the first 15 min following pain onset. Adverse events were reported in 31.2% of patients treated with zolmitriptan (vs. 11.3% for placebo), and the incidence was lower in patients who treated early after attack onset. Zolmitriptan provides high efficacy when treating migraine while pain is mild, with the clinical benefits being more pronounced when treating early after migraine onset.     

MIGRAINE TREATMENT

Clinical trials of migraine therapy often require treatment when migraine pain intensity is moderate or severe, but many physicians find this practice artificial and patients often prefer to treat while pain is mild. This randomized, placebo-controlled study assessed the efficacy of zolmitriptan 2.5 mg in treating migraine while pain is mild, in patients who typically experience migraine attacks that are initially mild, but progress to moderate or severe. The intent-to-treat population comprised 280 patients (138 zolmitriptan; 148 placebo), with mean MIDAS grades of 29.6 (zolmitriptan) and 27.6 (placebo). Zolmitriptan 2.5 mg provided a significantly higher pain-free rate at 2 hours (43.4% vs 18.4% placebo; P < .0001). Significantly fewer zolmitriptan patients reported progression of headache pain to moderate or severe intensity 2 hours postdose (53.7% vs 70.4% placebo; P < .01), or required further medication within 24 hours (46.4% vs 71.1% placebo; P < .0001). The efficacy of zolmitriptan was more pronounced in patients treating during the first 15 minutes following pain onset. Adverse events were reported in 31.2% of patients treated with zolmitriptan (vs 11.3% for placebo), and the incidence was lower in patients who treated early after attack onset. Zolmitriptan provides high efficacy when treating migraine while pain is mild, with the clinical benefits being more pronounced when treating early after migraine onset.     

Langzeitwirksamkeit und Nebenwirkungen verschiedener Migräneprophylaktika—eine retrospektive Analyse

Introduction

Drug therapy for the prevention of migraine attacks is becoming more and attacks is becoming more and more important. The aims of such prophylactic treatment are to reach a lower frequency, shorter duration and milder intensity of migraine attacks, and to reduce the intake of anti-migraine medication, to improve the quality of life and working ability. The question of efficacy and tolerance of established migraine prophylactics [1] has been thoroughly investigated in many studies. So far the question of sustained efficacy after a successful prophylactic treatment completion has not been a research priority, but it is nonetheless of great importance. Researchers at the neurologic scientific research institute of the university of Naples have followed up migraine out-patients after successful prophylactic treatment and observed that prophylactic agents differ not only in their immediate efficacy and safety, but also in long-term efficacy. Therefore, an open pilot study was performed with the prophylactic agents propranolol, flunarizine, pizotifen, DHE retard, methysergide and cyclandelate in the recommended dossages (Tabe 1).

Objective and methods

The aim of this study was to determine whether the various prophylactic agents available differ in active and long-term efficacy (at the end of a period after a successful prophylaxis=follow-up) and in the distribution of long-term responders at the end of the follow-up. The side effects of all prophylactic agents during active prophylaxis were also compared. Initially, 387 outpatients who had successfully completed a period of prophylactic treatment were recruited, and 208 were included in the study. At the time of follow-up a further period of prophylactic treatment was recommended if the efficacy rate was lower than 40% of the baseline at the end of the active prophylaxis period. The patients kept migraine headache daries (MHD) during the active prophylaxis and the follow-up, recording the following migraine objectives: number of attacks, pain total index (PTI), frequency of awakening with headache, and use of analgesics.

Results

The results showed that cyclandelate—actually a drug that is not yet officially accepted—had especially good results from the aspects of immediate efficacy, long-term efficacy and tolerance, compared with all other prophylactic agents. Significant differences were found in the duration of active prophylaxis. The mean monthly duration for patients treated with pizotifen (4.2), cyclandelate (3.9), and DHE retard (3.8) was longer than for those treated with flunarizine (2.8), and for patients treated with pizotifen it was longer than for those receiving propranolol (3.4). The mean duration (in months) of the postprophylactic period was distinctly longer for patients treated with cyclandelate (18.2) than for patients treated with DHE retard (12.9), flunarizine (13.1), propranolol (13.3) or pizotifen (13.8), but comparable with that after methysergide (17.2). Among the 208 patients, 85 were long-term responders (with no indication for repeated prophylaxis). No significant differences were found between the various groups, but the group of patients treated with cyclandelate was the only one with more than 50% long-term responders (18 vs 14). In general, the side effects of pizotifen, flunarizine and DHE retard seemed to be most pronounced. For cyclandelate, propranolol and methysergide fewer side effects were reported.

Conclusion

In spite of the uncontrolled pilot design, it can be said in summary that all prophylactic drugs were effective. Cyclandelate had a good safety profile, and in efficacy it was at least comparable to the other prophylactic drugs. Patients treated with cyclandelate had a longer duration of active treatment and likewise a longer period of follow up. In addition, the proportion of patients with “no indication for repeated prophylaxis” at follow up was higher than for any of the other drugs. The results are interesting for medical practice and suggest replication in a randomized blind study. If the results yielded by the present study are confirmed, cyclandelate should be classified as a drug of first choice for migraine prophylaxis.     

Topiramate in migraine prevention: a double-blind, placebo-controlled study

OBJECTIVE: To evaluate the efficacy of topiramate in the preventative treatment of episodic migraine. BACKGROUND: Topiramate is a broad-spectrum antiepileptic drug effective for treatment of multiple seizure types in adults and children. Antiepileptic agents have demonstrated efficacy in migraine prevention, and open-label experience from our clinic has suggested that topiramate might be effective for this use. We consequently conducted a single-center, double-blind, placebo-controlled trial to evaluate the efficacy and safety of topiramate for the preventative treatment of migraine. METHODS: Forty patients, aged 19 to 62 years (mean, 38.2 years), were randomly assigned in a 1:1 ratio to receive topiramate (n = 19; all women) or placebo (n = 21; 20 women, 1 man). Following a prospective baseline phase of 4 weeks, the study drug dose was titrated weekly in 25-mg increments over 8 weeks to 200 mg per day or to the maximum tolerated dose. The titration phase was followed by an 8-week maintenance phase. RESULTS: During the entire double-blind phase, topiramate-treated patients experienced a significantly lower 28-day migraine frequency (3.31 +/- 1.7 versus 3.83 +/- 2.1; P =.002) compared to placebo, irrespective of use of concomitant migraine prevention medications. The mean 28-day migraine frequency was reduced by 36% in patients receiving topiramate as compared with 14% in patients receiving placebo (P =.004). Twenty-six percent of the patients on topiramate and 9.5% of the patients on placebo achieved a 50% reduction in migraine frequency (P >.05). The mean dose of topiramate was 125 mg per day (range, 25 to 200 mg per day). Topiramate was well tolerated; 2 of 19 topiramate-treated patients discontinued treatment due to adverse events. Adverse effects that occurred more frequently in topiramate-treated patients included paresthesia, weight loss, altered taste, anorexia, and memory impairment. CONCLUSIONS: Preventative therapy with topiramate significantly reduced migraine frequency. Larger multicenter clinical studies may further delineate the role of topiramate in migraine prevention.     

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.     

A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial

OBJECTIVE: To determine the efficacy for migraine prophylaxis of a compound containing a combination of riboflavin, magnesium, and feverfew. BACKGROUND: Previous studies of magnesium and feverfew for migraine prophylaxis have found conflicting results, and there has been only a single placebo-controlled trial of riboflavin. DESIGN/METHODS: Randomized double-blind placebo-controlled trial of a compound providing a daily dose of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg. The placebo contained 25 mg riboflavin. The study included a 1-month run-in phase and 3-month trial. The protocol allowed for 120 patients to be randomized, with a preplanned interim analysis of the data after 48 patients had completed the trial. RESULTS: Forty-nine patients completed the 3-month trial. For the primary outcome measure, a 50% or greater reduction in migraines, there was no difference between active and "placebo" groups, achieved by 10 (42%) and 11 (44%), respectively (P=.87). Similarly, there was no significant difference in secondary outcome measures, for active versus placebo groups, respectively: 50% or greater reduction in migraine days (33% and 40%, P=.63); or change in mean number of migraines, migraine days, migraine index, or triptan doses. Compared to baseline, however, both groups showed a significant reduction in number of migraines, migraine days, and migraine index. This effect exceeds that reported for placebo agents in previous migraine trials. CONCLUSION: Riboflavin 25 mg showed an effect comparable to a combination of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg. The placebo response exceeds that reported for any other placebo in trials of migraine prophylaxis, and suggests that riboflavin 25 mg may be an active comparator. There is at present conflicting scientific evidence with regard to the efficacy of these compounds for migraine prophylaxis.     

European Multicenter Trial of Nimodipine in the Prophylaxis of Common Migraine (Migraine Without Aura)

SYNOPSIS
This double blind, randomized study of the calcium antagonist Nimodipine 40 mg t.i.d. vs placebo in the prophylaxis of common migraine (migraine without aura) included 192 patients. Patients with 2–8 migraine days/4 weeks, age 18–60, who had no other types of recurring headaches except up to 6 interval headaches/4 weeks were included. 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 19 drop-outs, 12 on Nimodipine and 7 on placebo, A gradual and marked improvement was seen both with Nimodipine and with placebo amounting to approximately 60% during the last 4 weeks. Statistical analysis on all included patients (intention to treat) revealed no difference between Nimodipine and placebo for migraine days (P = 0.69) or migraine index (p = 0.91). In patients "valid for analysis of efficacy" there were also no significant differences. Due to a very marked placebo effect and use of the parallel groups design, the present trial was not very powerful despite the large number of patients and a satisfactory compliance. We cannot rule out that Nimodipine might have up to 30% effect on a single main outcome parameter, but the uniform lack of response in all tested parameters makes this unlikely. Therefore Nimodipine probably has only a small or no effect in common migraine (migraine without aura).     

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 with sumatriptan 50 mg in the mild phase of migraine attacks in patients with infrequent attacks: a randomised, double-blind, placebo-controlled study

Most migraine patients with infrequent attacks are currently not treated with migrainespecific medication such as triptans. The response of these patients to triptans is unknown. The objective of this study was to investigate the efficacy and tolerability of sumatriptan 50 mg vs. placebo in migraine patents with infrequent migraine attacks when medication is taken during the mild phase of an attack. The study design was double-blind, placebocontrolled, parallel-group and randomised. Migraine patients were recruited by general practitioners and referred to one of 4 study centres. Additional patients were recruited by advertising. The patients were eligible for the study if they had between 6 and 12 migraine attacks with or without aura per year. The patients were instructed to take the medication during the mild phase of a single attack. The primary efficacy measure was the percentage of patients pain-free after 2 h. Fortysix percent of treated attacks were moderate or severe. In the intention-to-treat analysis, sumatriptan was superior (20/51 patients were pain-free) to placebo (8/47 patients pain-free) (p=0.03). Adverse events (AEs) occurred more frequently after sumatriptan (40%) than after placebo (13%) (p=0.003) and most AEs were mild or moderate. In this migraine population with infrequent attacks, sumatriptan was superior to placebo and was generally well tolerated.