Efficacy of nimodipine in the prophylaxis of migraine

The efficacy of nimodipine in the prophylaxis of migraine was assessed in a double-blind, placebo-controlled, cross-over study carried out on 33 patients, 20 of whom suffered from classic and 13 from common migraine. Four patients dropped out, but not as a result of the side effects of the drug. The duration of drug treatment was 8 weeks. The dosage used was 30 mg four times daily. Nimodipine proved to be better than placebo, the number of migraine attacks and severity of headache showing a significant reduction. The drug was well tolerated and no marked side effects were noted. The results suggest that nimodipine is a useful new prophylactic drug for migraine, but further studies are needed before its final value can be evaluated.     

Long Acting Propranolol in the Prophylaxis of Migraine. Comparison of the Daily Doses of 80 mg and 160 mg

SYNOPSIS
The efficacy of long acting propranolol in a dosage of 80 mg once daily in comparison to 160 mg once daily was assessed in the prophylactic treatment of migraine in a double-blind cross-over trial. 48 patients with classic or common migraine were included in the investigation, 6 patients withdrew, but only one because of side-effects. A four week run-in placebo period preceded the drug treatments, the duration of drug treatments was 12 weeks and there was a wash-out placebo period of 4 weeks between the treatments.
The two long acting propranolol doses, 80 mg and 160 mg once daily seemed to be equally effective. There was no difference in the antimigraineous effect. Long acting propranolol decreased both the frequency and severity of migraine attacks. Side-effects reported during the trial were mild, both doses were well tolerated. The treatment compliance during the once daily treatment was very good.     

Flunarizine-pizotifen single-dose double-blind cross-over trial in migraine prophylaxis

The results of a double-blind cross-over clinical trial involving 27 patients with classical or common migraine are described to compare the prophylactic effect of the calcium entry blocker flunarizine with that of pizotifen. Duration of the treatment was two months, with an evening single-dose administration of both drugs. For most parameters, there was no definite difference between flunarizine and pizotifen in migraine prophylaxis. It has been demonstrated previously that pizotifen is an effective drug in migraine prophylaxis, and these results suggest that flunarizine is effective, too. Weight gain as a side effect was less frequent and less severe with flunarizine than with pizotifen; other side effects showed the same incidence with both drugs.     

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.     

Flunarizine in prophylaxis of childhood migraine

An 8-month, double-blind, placebo-controlled, crossover trial of flunarizine in the prophylaxis of migraine has been performed in 70 children. After 4 weeks of medication-free base-line observation, 35 children (group A) received flunarizine (5 mg/day) and 35 (group B) received placebo over a 12-week period. After a 4-week washout they crossed treatments for another 12 weeks. Sixty-three patients completed the trial. In both groups flunarizine significantly reduced the frequency and average duration of headache attacks. In group A efficacy was maintained after placebo crossover for the last 4 months of the study. Five subjects in group B stopped placebo because of ineffectiveness; two children in group A discontinued flunarizine treatment, one because of excessive daytime sedation and the other because therapy was ineffective. The main side effects were daytime sedation and weight gain. It is concluded that flunarizine is an effective drug for the treatment of childhood migraine. In a study of this length no serious side effects were discovered.     

A Placebo-Controlled Crossover Trial of Nimodipine in Pediatric Migraine

An 8-month, double-blind, placebo-controlled crossover trial was carried out on the use of nimodipine in migraine prophylaxis in 37 patients aged 7 to 18 years old. After a 4-week medication-free run-in period, 19 subjects (Group 1) received a placebo while 18 (Group 2) received nimodipine (10-20 mg t.i.d., according to body weight), for 12 weeks. After a 4-week wash-out period, the groups switched therapy for a further 12 weeks. 30 patients completed the trial and the number of dropouts was comparable in the 2 groups. The only side-effect during nimodipine treatment was mild abdominal discomfort (3 cases). The treatments were evaluated on the basis of frequency and duration of attacks. There was a significant reduction in both parameters during the first period of treatment. During the second period of treatment, nimodipine proved to have a significantly greater effect than the placebo with regard to frequency, whereas the response was similar with the placebo as regards duration of attacks. The latter parameter shows a significant decrease during the treatment periods, regardless of type of therapy.     

Prophylaxis of Migraine: A Comparison Between Naproxen Sodium and Pizotifen

SYNOPSIS
Seventy-four migraine sufferers were entered into a randomized, single-blind study to compare the prophylactic effects of naproxen sodium and pizotifen. 550 mg naproxen sodium twice daily or 0.5 mg pizotifen three times daily were given for up to three months. Response to treatment was determined by monthly clinical assessments and daily patient self-assessment.
Both groups showed a significant decline in both the severity of migraine (p=0.001) and in the frequency of attacks (p = 0.02). No significant differences were detected between groups.
Tolerance to both treatments was good. The most common adverse experience reported by the naproxen sodium treated patients was nausea (6 patients), whereas pizotifen gave rise to weight gain in five patients.
The study has shown that naproxen sodium is a useful prophylactic agent for migraine.     

Telmisartan in migraine prophylaxis: a randomized, placebo-controlled trial

We evaluated telmisartan 80 mg for migraine prophylaxis. Migraine patients ( n  = 95) with three to seven migraine attacks in 3 months were randomized, double-blind to telmisartan or placebo. The primary end-point was the reduction in the number of migraine days (i.e. a day with ≥ 1 h of symptoms) between the 4-week baseline period and the last 4 weeks of the 12-week treatment period. A responder was recorded when there was a symptom reduction of ≥ 50% in these 4-week baseline and treatment periods. The reduction in migraine days was 1.65 with telmisartan and 1.14 with placebo ( P  > 0.05). Post hoc analyses adjusting for baseline and centre showed a 38% reduction in migraine days with telmisartan vs. 15% with placebo ( P  = 0.03), and a borderline significant difference in responders (40% vs. 25%, P  = 0.07). The incidence of adverse events was similar between treatments. This study indicates that telmisartan might be effective in migraine prophylaxis.     

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.     

Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine. A double-blind investigation

The prophylactic anti-migraine effect of the serotonin antagonist pizotifen and the beta 1-selective beta-adrenoceptor antagonist metoprolol was compared in a double-blind cross-over study. The dosage of pizotifen was 0.5 mg t.i.d. and that of metoprolol 50 mg b.i.d. Thirty-five patients with classical or common migraine were included in the investigation. Five patients withdrew during the course of the study; four because of side effects (three on pizotifen, one on metoprolol) and one because of unassociated illness. The results show that there was no statistically significant difference in efficacy between metoprolol and pizotifen. The tolerance, especially regarding weight gain, was the major drawback with pizotifen, while metoprolol was generally well tolerated.     

A comparative study of oral acetylsalicyclic acid and metoprolol for the prophylactic treatment of migraine. A randomized, controlled, double-blind, parallel group phase III study

This study was a multinational, multicentre, double-blind, active controlled phase III trial designed to investigate efficacy and safety of 300 mg acetylsalicyclic acid (ASA) (n = 135) vs. 200 mg metoprolol (n = 135) in the prophylaxis of migraine. In total 270 (51 male and 219 female) patients, aged 18-65 years, suffering between two and six migraine attacks per month were recruited. The main objective was to show equivalence with respect to efficacy, defined as a 50% reduction in the rate of migraine attacks. A run-in phase was carried out with placebo for 4 weeks, followed by a 16-week drug phase. In both treatment groups the median frequency of migraine attacks improved during the study period, from three to two in the ASA group and from three to one in the metoprolol group; 45.2% of all metoprolol patients were responders compared with 29.6% with ASA. Medication-related adverse events were less frequent in the ASA group (37) than in the metoprolol group (73). The findings from this trial show that metoprolol is superior to ASA for migraine prophylaxis but has more side-effects. Acetylsalicylic acid is better tolerated than metoprolol. Using a strict responder criterion ASA showed a responder rate comparable with the placebo rate in the literature.     

A placebo-controlled, double-blind, cross-over trial of flunarizine in common migraine

After four weeks of medication-free baseline observation, 29 patients with common migraine randomly received flunarizine (10 mg daily) or placebo for a 16-week period. After four weeks wash-out they crossed treatments for another 16 weeks; 27 patients completed the trial. Compared with placebo, flunarizine significantly reduced the frequency of migraine attacks and the derived headache indices, but the duration and severity of single attacks remained unchanged (Mann-Whitney U-test). The effect of flunarizine increased during the 16-week treatment period and during the last four weeks the number of migraine attacks reduced to 50% compared to the wash-out period. The only side-effect of flunarizine was mild daytime sedation in three patients. It is concluded that flunarizine is a valuable new prophylactic agent for common migraine.     

Cyclandelate in the prophylaxis of migraine: a placebo-controlled study

The prophylactic action of cyclandelate was investigated in a multicentre, randomized, placebo-controlled, parallel group study. A 4-week baseline period was followed by a 4-week placebo phase and a 16-week treatment period with either 1600 mg cyclandelate or placebo. Patients (n = 251) with two to six migraine attacks/month were randomized. Neither the primary study endpoint (reduction of migraine days from baseline to the last 28 days) nor most of the secondary endpoints (reduction in the number of migraine attacks, severity or duration of attacks, frequency of autonomic disturbances, medication for treatment of attacks) showed a difference between cyclandelate and placebo. Cyclandelate, however, was superior to placebo in a global impression of efficacy rated by the patients and the treating physicians. Both treatments were well tolerated. In conclusion, cyclandelate was not superior to placebo in the prophylaxis of migraine with regard to parameters usually used in migraine prophylaxis trials.     

Effect of Prophylactic Administration of Nimodipine in Patients with Migraine

SYNOPSIS
The prophylactic effect of nimodipine in the treatment of migraine headache was assessed in a prospective, placebo-controlled, double-blind trial. Twenty-six patients were studied during a 3-month experimental period (placebo vs nimodipine) following a 1-month period during which all patients received placebo. Results were tabulated using a "headache index". A trend in favour of a beneficial nimodipine effect on the headache index was demonstrated which achieved statistical significance during one month of the follow-up period. A similar trend with respect to the overall number of headaches was demonstrated and achieved statistical significance during two months of the follow-up period. We conclude that nimodipine is a potentially useful agent in the prophylaxis of migraine headache.     

Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study

In order to evaluate the prophylactic effect of oral magnesium, 81 patients aged 18–65 years with migraine according to the International Headache Society (IHS) criteria (mean attack frequency 3.6 per month) were examined. After a prospective baseline period of 4 weeks they received oral 600 mg (24 mmol) magnesium (trimagnesium dicitrate) daily for 12 weeks or placebo. In weeks 9–12 the attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared to the baseline (p <0.05). The number of days with migraine and the drug consumption for symptomatic treatment per patient also decreased significantly in the magnesium group. Duration and intensity of the attacks and the drug consumption per attack also tended to decrease compared to placebo but failed to be significant. Adverse events were diarrhea (18.6%) and gastric irritation (4.7%). High-dose oral magnesium appears to be effective in migraine prophylaxis.     

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.     

Nimodipine, a New Calcium Antagonist, in the Prophylactic Treatment of Migraine

SYNOPSIS
The prophylactic effect of the calcium antagonist nimodipine was assessed in a double-blind placebo controlled parallel design study in 60 patients. After a drug-free interval of two weeks, placebo or nimodipine were given for 13 weeks each. The dose of nimodipine was 40 mg t.i.d. Ten patients (eight on placebo, two on nimodipine) withdrew because of therapeutic failure. In the 50 patients who completed the trial there was a significant beneficial effect in the nimodipine treated group, with regard to number of migraine attacks and duration during the last two months of treatment. Side effects were negligible.     

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.     

L-5-Hydroxytryptophan versus placebo in childhood migraine prophylaxis: a double-blind crossover study

L-5HTP was tested versus placebo in a double-blind crossover study of 27 migraine children aged 6-12 years, who recorded their headaches in a headache diary for 1 month. Twenty-one patients subsequently started the trial. The mean daily dose of L-5HTP was 5 mg/kg body weight, and each treatment period with either L-5HTP or placebo lasted 12 weeks. In group A (L-5HTP-placebo; 10 patients) and group B (placebo-L-5HTP; 11 patients) both L-5HTP and placebo led to a significant reduction of the migraine index and frequency of migraine attacks during the 3rd month of each treatment period. However, we found a treatment X period interaction because the efficacy determinants decreased significantly during the first and the second treatment periods in both groups irrespective of the sequence of treatments. No differences were found between L-5HTP (first period of group A) and placebo (first period of group B).     

Fluoxetine Prophylaxis of Migraine

Many patients with severe migraine remain refractory to the current treatment regimens or cannot tolerate the side effects. Since current research implicates serotonin dysregulation in migraine pathogenesis, we investigated in a double blind, placebo controlled study the prophylactic effect of the serotonergic drug fluoxetine. Sixteen subjects were randomly assigned to 8 week fluoxetine treatment and 16 to the placebo group; nine subjects in each group completed the study. Migraine headache scores were obtained for two weeks prior to commencement of treatment, and then for each successive two week period. Zung depression scores were obtained before and after completion of the study. Fluoxetine caused significant reduction in headache scores starting with weeks 3-4 of treatment; there was no significant change with placebo. Depression scores did not differ between groups before treatment, and did not significantly change with either treatment. Fluoxetine appears to be a safe and effective drug for migraine prophylaxis, and deserves further therapeutic trials with larger groups for longer periods of time.