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.     

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.     

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 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.     

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 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.     

Flunarizine in Migraine: A Double-blind Placebo-controlled Study (in a Saudi Population)

We evaluated the effect of flunarizine (Fz) (10 mg/d) on migraine in a double-blind placebo-controlled design. The attacks' frequency, duration, severity and associated symptoms were compared before and after treatment. Forty-two patients completed a three-month trial period; 21 patients received Fz and 21 placebo. Statistical analysis showed no significant difference between Fz and placebo (p > 0.05). In this study Fz was not more efficient than placebo in migraine.     

Efficacy and safety of intravenous acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the acute treatment of migraine. A double-blind, double-dummy, randomized, multicenter, parallel group study

Two-hundred-and-seventy-eight patients with acute migraine attacks with or without aura were treated in 17 centers with 1.8 g lysine acetylsalicylate i.v. (Aspisol®;=1 g acetylsalicylic acid), 6 mg sumatriptan s.c. or placebo using a double-blind, double-dummy, randomized, multicenter parallel group study design. Two-hundred-and-seventy-five of them fulfilled the criteria for efficacy analysis, corresponding to 119 patients treated with lysine acetylsalicylate (L-ASA), 114 with sumatriptan and 42 with placebo injections. Both treatments were highly effective compared to placebo ( p <0.0001) in decreasing headache from severe or moderate to mild or none (verbal rating scale, VRS, placebo=23.8%). Sumatriptan showed a significantly ( p =0.001) better response (91.2%) compared to L-ASA (response 73.9%). Of the patients in the L-ASA-group, 43.7% were pain-free after 2 h; 76.3% after sumatriptan and 14.3%, after placebo. It took patients on average 12.6 (L-ASA), 8.2 (sumatriptan), and 19.4 h (placebo) to be able to work again. There was no significant difference between treatment groups in recurrence of headache in responders within 24 h (18.2% L-ASA, 23.1%, sumatriptan, 20% placebo). Accompanying symptoms (nausea, vomiting, photophobia, phonophohia, and visual disturbances) improved with both verum treatments to a similar extent. L-ASA was significantly better tolerated than sumatriptan (adverse events L-ASA 7.6%, sumatriptan 37.8%). In conclusion, subcutaneous sumatriptan and lysine acetvlsalicylate i.v. are effective treatments for patients suffering from migraine attacks. Sumatriptan is more effective, but resulted in more adverse events.     

Therapie des akuten Migräneanfalls mit intravenös applizierter Acetylsalicylsäure

INTRODUCTION: The empirical use of oral acetylsalicylic acid (ASA) in the treatment of acute migraine attacks has led to the recommendation of ASA as a basic treatment of migraine. However, there are no controlled studies on the intravenous use of acetylsalicylic acid. METHODS: Forty patients with a 1- to 12-year history of migraine were included in this placebo-controlled trial. The sociodemographic data of patients receiving placebo or 500 mg ASA i.v. and migraine symptoms before treatment were identically distributed. Pain relief during attacks was documented by the Visual Analogue Scale (VAS) for 1 h at 5-min intervals. Furthermore, the change of concurrent non-pain symptoms was evaluated by self-rating (worse-unchanged-better-absent). RESULTS: The VAS showed a mean pain reduction of about 60% after 1 h versus placebo. Efficacy varied significantly between patients. We observed a small number of socalled non-responders as well as patients with complete pain relief. The most common concomitant symptoms were nausea, photophobia, vertigo, vomiting and sweating. During the time of observation these symptoms were significantly reduced compared to placebo. The study shows a maximum placebo effect of about 17% (mean value). Significant differences in pain ratings were measured 25-30 min after application (P=0.0008). CONCLUSIONS: In this study i.v. ASA showed a significant reduction in pain intensity during migraine attacks. In addition, most concomitant non-pain symptoms were equally reduced. The onset of pain relief did not correspond with the inhibition of platelet aggregation (after 2-4 min) or with peak plasma concentrations of ASA (immediately after application) or salicylic acid (after 2-3 h). More efficacy studies with higher doses and longer periods of observation are necessary to optimize the treatment of migraine attacks with intravenous ASA. Studies including neurophysiological and vascular parameters are recommended to confirm the results of this study.     

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.     

Efficacy,safety, and tolerability of oral eletriptan for treatment of acute migraine: a multicenter,double-blind,placebo-controlled study conducted in the United States

OBJECTIVE: To investigate the efficacy, consistency, safety, and tolerability of oral eletriptan in the acute treatment of three migraine attacks. BACKGROUND: Eletriptan is a selective 5-HT1B/1D agonist member of a class of agents known to be effective in the acute treatment of migraine. METHODS: Thirteen hundred thirty-four patients were randomized to 20 mg, 40 mg, or 80 mg of eletriptan, or placebo and could treat up to three attacks. The primary efficacy endpoint was 2-hour headache response for the first attack. Secondary endpoints included associated symptom relief, and pain-free, sustained pain-free, and consistency of response. RESULTS: Eletriptan 20 mg, 40 mg, and 80 mg achieved significantly (P <.0001) better headache response rates than placebo at 2 hours (47%, 62%, and 59%, respectively, versus 22%) and 4 hours (64%, 76%, and 79%, respectively, versus 25%). Headache response was observed to be rapid, showing improvement at 0.5 hour and 1 hour. Two-hour pain-free response rates for eletriptan 20 mg, 40 mg, and 80 mg were 14%, 27%, and 27%, respectively, compared with 4% for placebo. Sustained pain-free response rates were significantly (P <.001) better for eletriptan 20 mg (10%), 40 mg (20%), and 80 mg (18%) compared with placebo (3%). Eletriptan had a higher consistency of intrapatient response than placebo in two of three (68% to 82%) and three of three attacks (32% to 60%) versus 16% and 8%, respectively. All eletriptan doses yielded significant functional improvement at 2 hours. Adverse events were generally mild or moderate and transient, with eletriptan 20 mg having an adverse event profile comparable to placebo. CONCLUSIONS: Eletriptan is efficacious, displaying high consistency of response over multiple attacks, and is well tolerated for the acute treatment of migraine.     

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.     

Differences of anti-nociceptive mechanisms of migraine drugs on the trigeminal pain processing during and outside acute migraine attacks

The aim of this study was to investigate central anti-nociceptive mechanisms of i.v. acetylsalicylic acid (ASA) and oral zolmitriptan (ZOL) in migraine patients and healthy subjects using the 'nociceptive' blink reflex (nBR). Twenty-eight migraine patients received ASA (n = 14, 1000 mg i.v) or ZOL (n = 14, 5 mg p.o) during the acute migraine attack and interictally. Thirty healthy subjects received either ASA or ZOL vs. placebo using a double blind cross over design. nBR was recorded in all patients and subjects before, 60 and 90 min after treatment. ASA and ZOL did not inhibit nBR responses in healthy subjects. Both ASA and ZOL suppressed nBR responses (ASA by 68%, ZOL by 78%) only during the acute attack but not interictally. The data suggest, that the anti-nociceptive effects of migraine drugs on the trigeminal nociceptive processing are different during and outside an acute migraine attack.     

Chlormezanone in the treatment of migraine attacks: A double blind comparison with diazepam and placebo

One hundred and fifty patients treated for an acute migraine attack all received a standard regimen consisting of metoclopramide 10 mg i.m. and--20 min later--paracetamol 1 g orally. Simultaneous trial medication was given. This consisted of placebo, diazepam 5 mg as tablets, or chlormezanone 400 mg as capsules given in a double dummy fashion. A successful treatment result was defined as a decrease of two or three steps on a four-point verbal pain report scale, and no need for further treatment. Patients with severe pain (all three treatment groups together) showed significantly better treatment results (p less than 0.001) than patients with pain of medium severity. In the group with severe pain there was no significant difference between diazepam, chlormezanone or placebo. In the group with pain of medium severity there was a significant (p less than 0.01) effect of chlormezanone, but no significant effect of diazepam. Chlormezanone may possibly be a valuable addition to antiemetic and analgesic therapy of migraine attacks.     

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.     

A Double-blind Placebo-controlled Prophylactic Study of Flunarizine (Sibelium®) in Migraine

SYNOPSIS
The potential prophylactic value of a daily dose of 10 mg flunarizine, a calcium antagonist with anti-vasospastic properties was studied in a 3-month double-blind placebo-controlled trial in 58 migraineurs. With an almost perfect mutual correlation, both the patients' overall appreciation of the treatment and the reduction of migraine attacks proved flunarizine to be effective (p<0.001). Half of the flunarizine-patients considered the treatment certainly beneficial in contrast to none of the placebo-patients. In 21 of the 29 flunarizine-patients the attack rate was lower than expected in 20 of the 29 controls it was not. Younger patients appeared to respond better to the treatment. Flunarizine displayed a gradually increasing effect; during the third month 83% of the treated patients were completely attack-free. The drug did not appear to influence the severity and duration of attacks, however. Treatment was very well tolerated. Flunarizine, therefore, appears to be a very suitable agent for migraine prophylaxis but it should be given for more than two months in order to obtain full effectiveness with this dosage.     

Comparison of the Efficacy Between Flunarizine and Nifedipine in the Prophylaxis of Migraine

SYNOPSIS
Background. Several calcium channel blockers have been evaluated in controlled clinical studies and some holdconsiderable promise for future. Efficacy in migraine prophylaxis has been claimed for drugs belonging to all threeclasses of calcium channel blockers (nifedipine-like, verapamil-like, and flunarizine-like), but the extent and quality of theevidence varies, and a comparison of efficacy between different calcium channel blockers has not been reported. Objective. The objective of the study is to assess the comparison of efficacy and safety of flunarizine and nifedipinein migraine prophylaxis. Patients and methods. The study was conducted in a prospective, double-blind, randomized controlled trial, parallelgroup design. 78 patients were studied for a 1-month period during which all patients received placebo followed by a3-month experimental period. Headache response to medication was measured monthly by compilation ofmigraine-scores derived from quantitative data recorded by patients in a daily diary.¹ Student's t-test was used tocompare results from the flunarizine (10 mg) and nifedipine (20 mg) group for each month. Results. Both groups showed a significant reduction in the migraine-scores after 3-months. No significantdifferences were detected between groups, but there was a clinical significantly different reduction of migraine-scoresbetween the groups in the first month after the run-in period (58% vs 38%). It shows that the beneficial effect offlunarizine was more rapidly manifest than that of flunarizine. Tachycardia more frequently occurred in the nifedipinegroup than in the flunarizine treatment group. Conclusion. It concluded that flunarizine is a potentially more useful agent in the prophylaxis of migraine headache.     

Evaluation of the efficacy of intravenous acetaminophen in the treatment of acute migraine attacks: a double-blind, placebo-controlled parallel group multicenter study

The efficacy of intravenous acetaminophen (1000mg) in the treatment of acute migraine attacks as an alternative to parenteral application of lysine acetylsalicylate or triptans was investigated, using a multi-center, randomized, double-blind, placebo controlled study design. Migraine diagnosis was made according to the International Headache Society Classification. Sixty patients were included in three headache outpatient centers (Neurology Departments of the Universities of Regensburg, Münster and München). In the acute migraine attack patients were treated intravenously with either 1000mg paracetamol (acetaminophen) or placebo. The primary end point was pain-free after 2h. Secondary efficacy criteria were pain-free after 24h or pain relief after 2hours and after 24hours. With regard to the efficacy criteria, 37% of patients reported pain relief or painfree after two hours, 12 patients after treatment with acetaminophen and 10 patients after treatment with placebo. Out of these, 3 patients in the acetaminophen and 4 patients in the placebo group were painfree. After 24hours 86% of the patients reported pain relief: 24 treated with acetaminophen and 27 treated with placebo. The results indicate, that 1000mg intravenous acetaminophen is not superior to placebo in treating severe acute migraine attacks.     

Flunarizine, a Calcium Entry Blocker in Migraine Prophylaxis

SYNOPSIS
To obtain a sample size sufficiently large to enable valid statistical analysis, patients with common or classical migraine treated in different centres with the calcium-entry blocker flunarizine, 10 mg daily, were pooled into 2 sets. In a first group of 202 patients, flunarizine was shown to reduce the frequency of attacks in 83%. Improvement was more marked when the duration of the disease was shorter and was more rapid when the pretreatment frequency of attacks was high. Somnolence and weight gain, sometimes labeled increased appetite, were the main adverse reactions but rarely caused withdrawal of the drug. Weight gain was significantly correlated with the global result and occurred more in patients with a low pre-treatment weight. In a second group of 125 patients, most of them being treated for a year, the effect of flunarizine was fully sustained at the 4-month level, i.e., at a median reduction in attacks by 51% to 60%.     

Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks

OBJECTIVE: To study the efficacy and tolerability of 1 g of intravenous magnesium sulfate as acute treatment of moderate or severe migraine attacks. BACKGROUND: Migraine is a common disorder in which not only the pain but also the accompanying symptoms such as nausea and vomiting reduce activity and productivity of sufferers. Many drugs used for the treatment of acute migraine attacks have many side effects, are not well tolerated, are ineffective in some patients, or cannot be used during pregnancy or in patients with ischemic heart disease. Magnesium deficiency has been proposed to play a role in the pathophysiology of migraine, and recently treatment of migraine with magnesium has gained considerable interest. METHODS: This was a randomized, single-blind, placebo-controlled trial including 30 patients with moderate or severe migraine attacks. Fifteen patients received 1 g intravenous magnesium sulfate given over 15 minutes. The next 15 patients received 10 mL of 0.9% saline intravenously. Those in the placebo group with persisting complaints of pain or nausea and vomiting after 30 minutes also received 1 g magnesium sulfate intravenously over 15 minutes. The patients were assessed immediately after treatment, and then 30 minutes and 2 hours later. Intensity of pain, accompanying symptoms, and side effects were noted. RESULTS: All patients in the treatment group responded to treatment with magnesium sulfate. The pain disappeared in 13 patients (86.6%); it was diminished in 2 patients (13.4%); and in all 15 patients (100%), accompanying symptoms disappeared. In the placebo group, a decrease in pain severity but persisting nausea, irritability, and photophobia were noted in 1 patient (6.6%). Accompanying symptoms disappeared in 3 patients (20%) 30 minutes after placebo administration. All patients initially receiving placebo were subsequently given magnesium sulfate. All of these patients responded to magnesium sulfate. In 14 patients (93.3%), the attack ended; in 1 patient (6.6%), pain intensity decreased; and in all 15 patients (100%), accompanying symptoms disappeared. Both the response rate (100% for magnesium sulfate and 7% for placebo) and the pain-free rate (87% for magnesium sulfate and 0% for placebo) showed that magnesium sulfate was superior to placebo. Twenty-six patients (86.6%) had mild side effects which did not necessitate discontinuing treatment during magnesium sulfate administration. CONCLUSION: Our results show that 1 g intravenous magnesium sulfate is an efficient, safe, and well-tolerated drug in the treatment of migraine attacks. It is possible that magnesium sulfate could be used in a broader spectrum of patients than other drugs commonly used for attack treatment. In view of these results, the effect of magnesium sulfate in acute migraine should be examined in large-scale studies.