Flunarizine I.V. in the Acute Treatment of Common or Classical Migraine Attacks A Placebo-Controlled Double Blind Trial

The efficacy and tolerance of 20 mg flunarizine i.v. were tested in comparison with placebo in a multicentre randomised double-blind trial in the acute treatment of migraine attacks. Sixty case reports were included in the evaluation; 31 patients were treated with flunarizine and 29 with placebo. Flunarizine proved to be significantly superior in its effect on the intensity of pain and the typical concomitant symptoms of the attacks. Patients were classed as responders who displayed a reduction in pain intensity by at least 50% within 60 minutes after the administration of flunarizine. 23 patients (= 74.2%) were responders, including 11 patients being without pain after 60 minutes. In the placebo group the responder rate was 27.6% The fact that both groups were comparable in all respects should be emphasized. The tolerance of intravenously administered flunarizine was excellent and corresponded to that of placebo. Apart from a sedative effect reported by 9 patients there were no side-effects. The circulatory conditions remained largely stable. The result of this study seems to indicate that an intravenous injection of 20 mg flunarizine might represent a genuine alternative, and as regards tolerance even a superior one, to the parenteral administration of ergotamine in migraine attacks.     

Sublingual Flunarizine: a New Effective Management of the Migraine Attack. A Comparison versus Ergotamine

SYNOPSIS
Flunarizine was found to be effective in the acute treatment of isosorbide dinitrate induced migraine attacks, when given in a dosage of 10 mg sublingually.
The present study consists of two parts: in the first preliminary investigation, 7 out of 8 migraine patients who developed a typical migraine attack after isosorbide dinitrate were relieved of pain within about 10 minutes. On the basis of this result a second, randomized controlled open trial was performed, in which the acute efficacy of flunarizine was compared with ergotamine tartrate, 0.25 mg i.m., on 40 migraine patients. Flunarizine was found as effective as ergotamine (75% positive responses in the flunarizine group, 70% in the ergotamine group). The mean latency of the flunarizine effect was significantly lower than that of the ergotamine ( r < 0.001, Student's t test). Moreover sublingual flunarizine was found to be virtually devoid of side effects.     

Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation

Pharmacological data and early clinical experience have suggested that the calcium entry blocker flunarizine may be a valuable gain in the prophylaxis of migraine. This was supported by a study in 20 patients with classical migraine who were, after a drug free run-in phase, orally treated with either placebo or flunarizine (10 mg at night) for 3 to 4 months. Flunarizine significantly reduced the frequency, duration and severity of the migraine attacks. A corrected migraine index, based on these 3 variables was reduced by 82% in the drug group but increased by 66% in the control patients. Only 1 patient did not clearly benefit from flunarizine. In some cases flunarizine should be administered for at least 4 months before judging its efficacy. No side-effects occurred.     

Flunarizine in Migraine Prophylaxis: An Indian Trial

Flunarizine, a calcium channel blocker is considered useful in migraine prophylaxis. We report the first Indian trial with this drug. Fifteen patients with migraine were studied in a 6 months double-blind, placebo-controlled crossover trial. Flunarizine was superior to placebo in reducing the severity and duration of the individual attacks though there was no statistically significant effect on frequency of migraine attacks. The side effects most frequently caused by flunarizine were weight gain and daytime sleepiness.     

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.     

Long-term follow-up after flunarizine or nimodipine discontinuation in migraine patients

Various open and controlled studies have confirmed the antimigraine action of flunarizine, while the antimigraine properties of nimodipine are still open to controversy. Moreover, only a few studies include an additional follow-up after discontinuation of migraine prophylaxis with either drug. We carried out a single blind evaluation of the efficacy and tolerance of flunarizine (25 patients) in comparison with nimodipine (25 patients) and the long-term effect after discontinuation of a 6-month treatment. Both medications significantly reduced migraine frequency and severity. Flunarizine was more efficacious than nimodipine in reducing migraine frequency ( p < 0.001), pain severity ( p < 0.05), migraine index ( p < 0.05) and corrected migraine index ( p < 0.05). The positive effect lasted 8.4 ± 4.0 months after discontinuation of flunarizine and 4.9 ± 3.5 months after nimodipine ( p < 0.05). Our results suggest that flunarizine is more effective than nimodipine in the prophylactic treatment of migraine. The positive effect after drug discontinuation lasts longer with flunarizine, compared to nimodipine.     

Possible involvement of dopaminergic mechanisms in the antimigraine action of flunarizine

Flunarizine, a calcium antagonist widely used in the prophylactic treatment of migraine, may interfere with dopaminergic systems. Flunarizine therapy can in fact induce extrapyramidal side effects and can increase basal as well as stimulated prolactin levels. To better define the mechanism of flunarizine action in migraine, we studied prolactin and growth hormone responses to thyrotropin releasing hormone and sulpiride in 13 female migraineurs before and after 60 days of flunarizine therapy. The treatment did not modify basal prolactin and growth hormone levels, but prolactin response to thyrotropin releasing hormone was enhanced. A paradoxical increase of growth hormone to thyrotropin releasing hormone observed before therapy was blunted after flunarizine treatment. These data indicate a modulatory action of flunarizine on dopaminergic systems which might to some extent explain the antimigraine action of this drug.     

Flunarizine Plasma Concentrations and Side Effects in Migraine Patients

Flunarizine plasma concentrations and side effects were evaluated in migraine patients during a 3 month course of prophylactic treatment. Plasma concentrations did not correlate with daily dose (in mg/kg). Mean flunarizine levels were higher in patients showing sleepiness or sedation. Weight gain was independent of plasma concentrations. Future clinical trials of flunarizine should be supported by drug monitoring in order to clarify the relationship between plasma levels and drug effects.     

Classic Migraine and Intercalated Seizures in a Young Woman: Efficacy of Flunarizine

SYNOPSIS
A case of a young woman suffering from both migraine and epilepsy is reported. Since the age of 28, she complained of classic migraine attacks and of generalized or partial seizures. The seizures often intercalated themselves between the visual prodrome and the painful phase of her attacks. She came to our observation at the age of 31. Neurological examination, laboratory work and CT-scan were normal. The EEG showed an asymmetry of the background activity between the two hemispheres and medium-voltage sharp waves, not blocking upon eye opening, in the left parieto-temporel leads. Flunarizine was added to her anti-convulsant therapy. It remarkably reduced the migraine attacks and controlled the intercalated seizures. After one year, flunarizine was discontinued and two intercalated seizures occurred four months later. The efficacy of flunarizine and its hypothetical mechanism of action in such a clinical condition is discussed.     

Flunarizine in migraine prophylaxis: predictive factors for a positive response

The efficacy o flunarizine in migraine prophylaxis is confirmed in both open and controlled trials. However, it is unknown what factors may influence a good response to prophylaxis with flunarizine. The aim of this study was to determine the possible predictive factors for therapeutic responsiveness to 3 months' treatment with flunarizine. One-hundred headache patients treated with flunarizine were evaluated. We considered "responders" those patients who recorded a reduction in migraine frequency of 75% after treatment. Statistical analysis revealed four factors which might influence therapeutic responsiveness in our patients. Positive factors were a family history ( p <0.0l) and high intensity of pain ( p <0.0l); negative factors were frequent attacks ( p <0.0l) and a history of analgesic abuse ( p <0.001). Patients with no previous history of analgesic abuse, low frequency of attacks at baseline, higher levels of migraine pain, and positive family history constitute the prototype of flunarizine long-term treatment responders.     

Post-marketing cohort study comparing the safety and efficacy of flunarizine and propranolol in the prophylaxis of migraine

A comparative post-marketing surveillance study of the safety and efficacy of flunarizine and propranolol in the treatment of migraine was carried out. General practitioners in Belgium and the Netherlands each recruited patients for whom they would prescribe one of the study medications in the normal course of their treatment and recorded all medical events on follow-up forms for up to 8 months. A total of 1601 migraine patients were enrolled; 838 in the flunarizine cohort and 763 in the propranolol cohort. Propranolol was somewhat better than flunarizine in reducing the severity of migraine attacks, although this may have been due to a selection bias. Discontinuations of therapy due to events considered likely to be treatment-related were mostly due to the recognized side effects of the two drugs. As regards the occurrence of depressions, a total of 58 patients had depressive events, 34 in the flunarizine cohort and 24 in the propranolol cohort. Whereas migraine itself appears to be associated with an increased risk of depression, the number of previous migraine treatments was shown to be an additional risk factor for the development of depression in patients receiving flunarizine as was a history of depression. Overall, there was no appreciable difference in the risk/benefit ratio between flunarizine and propranolol.     

Flunarizine (10 and 20 mg) i.v. versus placebo in the treatment of acute migraine attacks: a multi-centre double-blind study

In a multi-centre, randomized double-blind study, the effect and tolerance of 10 and 20 mg flunarizine i.v. versus placebo was tested on 102 migraineurs with acute migraine attacks with and/or without aura. Thirty-seven patients received 10 mg flunarizine, 32 received 20 mg and 33 received placebo. The groups were comparable. Response to treatment was defined as pain reduction of at least 50% within 60 min on a visual analogue scale after i.v. drug administration. This effect was noted on 59.4% with 20 mg flunarizine, on 24.3% with 10 mg flunarizine and on 30.3% with placebo. The tolerance of flunarizine i.v. was similar to placebo. Blood pressure and pulse rate were not affected by flunarizine. All in all, 20 mg flunarizine i.v. appeared to be a suitable alternative for treatment of acute migraine attacks.     

Comparison of flunarizine (Sibelium®) and pizotifen (Sandomigran®) in migraine treatment: A double-blind study

In this double-blind, randomized multicenter study involving 75 patients, the calcium-entry blocker flunarizine (10 mg nocte) was compared with pizotifen (2–3 mg per day in three administrations). Duration of treatment was four months. The results suggest that, in the dosage used, flunarizine is at least as effective as pizotifen in both classical and common migraine as regards effect on attack frequency. Flunarizine might tend to more markedly suppress severity of the attack, though. The weight gain seen with both drugs might be slightly less with flunarizine. A practical advantage of flunarizine is its simple dosage schedule (one intake per day).     

盐酸氟桂利嗪预防性治疗偏头痛的疗效和安全性

目的：探讨盐酸氟桂利嗪预防性治疗偏头痛的有效性及安全性.方法：采用开放性研究,2120例偏头痛患者每日口服盐酸氟桂利嗪5～10 mg,治疗时间为12周,在治疗开始及4周末、8周末、12周末分别记录患者的头痛程度、频率、服药剂量、不良事件发生情况以及血压.结果：治疗后4周末、8周末及12周末与治疗前相比,头痛程度明显减轻（均P＜0.05）,频率明显减少（均P＜0.05）,盐酸氟桂利嗪用量亦明显减少（均P＜0.05）,未发现严重不良事件,治疗前后血压无明显变化（均P＞0.05）.结论：盐酸氟桂利嗪是一种安全有效的偏头痛预防性治疗药物.     

Therapie idiopathischer Kopfschmerzen im Kindesalter

According to the principles of evidence-based medicine, the controlled studies on the treatment of idiopathic headache in childhood have been analysed and compiled to treatment recommendations. For the acute treatment of migraine attacks or tension-type headache, ibuprofen (10 mg per kg body weight) or acetaminophen (15 mg per kg body weight) are recommended with highest evidence, intranasal sumatriptan (10 to 20 mg) can be given as second choice. For the prophylaxis of migraine, betablockers (propranolol and metoprolol), flunarizine, and valproic acid are recommended. Flunarizine is the drug of first choice in the treatment of migraine-related disorders. No controlled studies are available for the treatment of further headache types. First line methods for the non-drug treatment of headache in childhood are relaxation therapies, biofeedback, and specific training schedules.     

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.     

A Case of Hemiplegic Migraine Treated with Flunarizine

SYNOPSIS
A patient with hemiplegic migraine who was treated successfully with flunarizine is presented. A fifteen-year-old boy developed right hemiparesis during several migraine attacks. Regional cerebral blood flow (CBF) measurement using intravenously injected xenon 133 showed that the CBF was about 10-15% lower in left fronto-temporo-parietal regions than that on the contra-lateral side. After the treatment with flunarizine at a dose of 10 mg/day, he has been free of migraine attacks and hemiparesis disappeared. Regional CBF 1 month after treatment showed no decrease in any region of the brain. The findings indicate that flunarizine reversed the neurological deficits by increasing CBF by its vasodilating action.     

Sublingual Administration of Flunarizine for Acute Migraine: Will Flunarizine Take the Place of Ergotamine?

SYNOPSIS
Clinical effectiveness of 10 mg sublingual flunarizine during 89 headache attacks was observed in 68 chronic headache patients. The study population consisted of 36 patients with migraine, 12 with combined headache, 11 with muscle contraction headache (MCH) and nine with cluster headache. Improved cases, defined as cases showing more than moderate improvement, were 75.0% in the migraine group, 50.0% in the combined headache group, 18.2% in the MCH group and 33.3% in the cluster headache group. The migraine group showed a significantly higher percentage of improved cases than did the MCH group (p<0.002). The group in which subjects received flunarizine within 10 min. from the beginning of headache, showed significantly better improvement than did the group in which subjects were treated after 10 min. (p<0.01). No remarkable side effects were observed except for transient numbness of the tongue and a feeling of sleepiness. Four typical case histories utilizing flunarizine administration, and a case showing recovery from angiospasm after sublingual flunarizine administration during an angiographic examination, are reported. A possible favorable role of flunarizine during migraine attacks is discussed. Double blind studies based on the present observations are necessary.     

Flunarizine, the vestibular system and migraine

The vestibular function was extensively investigated in 75 patients suffering from migraine. Pathological findings were present in 62 patients (82.6%). With the exception of position nystagmus, vestibular abnormalities were not related to migraine characteristics. Fifty-six patients were treated with flunarizine 10 mg daily for three months. A favourable effect on headache was obtained in 44 patients (78.5%). Flunarizine therapy influenced significantly gaze nystagmus and position nystagmus. The latter tended to be related to anti-migraine efficacy. Other electronystagmographic parameters were not substantially influenced. The authors assume that the vestibular abnormalities in migraine are side phenomena, the clinical relevance of which, at least during the headache-free phase, is not yet well understood.     

Flunarizine Versus Metoprolol in Migraine Prophylaxis: A Double-Blind, Randomized Parallel Group Study of Efficacy and Tolerability

The prophylactic effect of flunarizine and metoprolol was studied in a multi-center randomized, double-blind trial of 149 patients with migraine with or without aura. After a 4-week placebo run-in period, patients were randomly allocated to treatment with flunarizine 10 mg daily or metoprolol 200 mg daily for 16 weeks (parallel group design). Both drugs reduced the number of migraine days per month by 37% (95% confidence interval 21-53%) compared with the placebo run-in period. All efficacy parameters were significantly reduced by both drugs and no significant difference was found between the two drugs at any time of the treatment period. However, calculation of the 95% confidence limits showed that each drug may have a superiority of more than 100% on a single main effect parameter. The most common adverse experiences were day-time sedation (both drugs) and weight gain (flunarizine). Depression was the most serious side-effect occurring in 8% on flunarizine and 3% on metoprolol. We conclude that both drugs are effective in the prevention of migraine attacks but a higher number of dropouts occurred on flunarizine because of depression or weight gain.