Flunarizine, a Calcium Channel Blocker: a New Prophylactic Drug in Migraine

SYNOPSIS
The postulated pivotal role of focal brain hypoxia in the genesis of the migraine attack and the anti-hypoxic properties of flunarizine, have led to the use of the selective calcium-entry blocker in the treatment of migraine. Clinical experience is reviewed. Open findings, confirmed by double-blind placebo-controlled studies and comparisons with pizotifen and cinnarizine, have shown that flunarizine, given at 10 mg daily, is a safe and effective prophylactic drug for both common and classical migraine. Factors determining the efficacy of flunarizine are discussed.     

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.     

Low Dose Flunarizine in the Prophylaxis of Migraine

In a period of one year (1990) we selected 40 patients suffering from migraine. For an open randomized study there were 2 groups of patients: the first were treated with 10mg of flunarizine per day and the second with 3 mg per day. The patients were treated for 4 months consecutively. There were 11 drop outs (27.5%): nine for poor compliance and 2 due to side effects. The efficacy of flunarizine in the prophylaxis of migraine was essentially identical in the two dosage groups while the incidence of side effects was considerably reduced in the patients treated with the lower dose.     

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 Pizotifen: A Double-Blind Study in the Prophylaxis of Migraine

SYNOPSISThe calcium entry blocker flunarizine was compared with an antiserotonin agent, pizotifen, in the prophylaxis ofmigraine. Thirty-five patients were treated under double-blind conditions for four months. The number of migraineattacks gradually declined in both groups with an eventual mean reduction of 65% and 45% in the flunarizine andpizotifen groups respectively. The efficacy of the former drug developed somewhat faster but no statisticallysignificant differences between the groups were found. Weight gain was the main side effect in both groups. Otherside effects were rare.It is concluded that flunarizine is a useful alternative for the prophylactic treatment of migraine.     

不同剂量的钙离子通道拮抗剂对面神经损害的保护作用

背景应用Ca2+通道拮抗剂对周围神经损害保护作用的实验研究较多,但在临床应用中其剂量大小对受损神经保护作用的效果差异尚需探讨.目的应用不同剂量Ca2+通道拮抗剂氟桂利嗪治疗面神经麻痹(简称面瘫),观察治疗1个月后电生理学量化评估结果.设计随机分组,空白对照,随访1个月.单位南京医科大学第一附属医院神经科.对象1999-11/2001-05南京医科大学第一附属医院神经内科门诊面瘫患者35例,男19例,女16例,年龄16～58岁,病程≤3 d,未经过任何治疗且瘫痪均为完全性.采用随机抽样方法将初诊患者分为对照组12例、治疗Ⅰ组10例,治疗Ⅱ组13例.方法对照组采用基础治疗,强的松1 mg/(kg·d),1次/d,晨服,最大剂量≤60 mg/d,每隔5 d减半量,1个疗程15 d,甲钴胺口服500μg,3次/d.呋喃硫胺口服25 mg,3次/d.超短波理疗,1次/d,治疗15 d.共治疗1个疗程.治疗Ⅰ组和治疗Ⅱ组在此基础上进行Ca2+通道拮抗剂治疗治疗Ⅰ组氟桂利嗪5 mg,1次/晚,治疗Ⅱ组氟桂利嗪10 mg,1次/晚.治疗前及治疗后1个月分别检测各组患者的Blink反射潜伏期及波幅的变化.主要观察指标各组患者治疗1个月后Blink反射潜伏期和波幅.结果按意向处理分析,35例患者均进入结果分析.①治疗前3组患者Blink反射均呈现面瘫侧传出型阻断,R1,R2均消失.②治疗后1个月Blink反射R1,R2出现,治疗Ⅱ组R1及R2的潜伏期恢复显著优于对照组[(9 608±0.575)ms,(31.869±2.934)ms,(11.208±1 490)ms,(37.583±5.408)ms,P＜0.01],而治疗Ⅰ组与对照组比较,R1,R2潜伏期恢复无差异.③治疗后1个月3组Blink反射同侧波幅变化比较无差异. 结论较大剂量(10 mg/d)氟桂嗪治疗1个月,可促进面瘫患者面神经功能的恢复,而日剂量5 mg时,氟桂嗪对周围神经的保护作用不优于常规治疗,其机制和最适剂量本文未做进一步观察.     

Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily

This was a phase-IV double-blind equivalence trial designed to assess the efficacy and tolerability of two doses of flunarizine (10 mg o.d.=FLU 10 mg and 5 mg o.d.=FLU 5 mg) in the prophylaxis of migraine, in comparison with slow-release propranolol (160 mg o.d.). A total of 808 subjects were treated in a treatment period of 16 weeks. 142 subjects discontinued the trial prematurely, mainly because of adverse events (n=58). The mean attack frequency in the double-blind period was 2.0 for the FLU 5 mg group, 1.9 for the FLU 10 mg group, and 1.9 for the propranolol group. The mean attack frequency in the last 28 days of the double-blind period was 1.8 for FLU 5 mg, 1.6 for FLU 10 mg, and 1.7 for propranolol. Both flunarizine groups were at least as effective as propranolol (P<0.001 in one-sided test). The percentage of responders (defined as subjects for whom attack frequency decreased by at least 50% compared to run-in) in the last 28 days of the double-blind period was 46% (118/259) for FLU 5 mg, 53% (141/264) for FLU 10 mg, and 48% (125/258) for propranolol. Statistical analysis showed that FLU 10 mg is at least as effective as propranolol (P<0.001) and showed a trend for noninferiority of FLU5 and propranolol (P=0.053). No statistically significant differences between the treatment groups were found for any of the secondary parameters. Overall, 190 subjects reported one or more adverse events during the run-in phase: 54 (20.5%) in the FLU 5 mg group, 76 (27.7%) in the FLU 10 mg group and 60 (22.3%) in the propranolol group. The results of this equivalence trial show that 10 mg flunarizine daily with a drug-free weekend is at least as effective as 160 mg propranolol in the prophylaxis of migraine for all evaluated parameters (one-sided equivalence tests) after 16 weeks of treatment. In addition, 5 mg flunarizine proves to be at least as effective as 160 mg propranolol when looking at the mean attack frequency for both the whole double-blind period and the last 28 days of treatment. However, in the analysis of responders, 160 mg propranolol seems to be slightly better than 5 mg flunarizine. In addition, no significant differences between the three treatments were found with regard to safety: all three treatments were generally well-tolerated and safe.     

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.     

Single-dose Pizotifen, 1.5 mg Nocte: A New Approach in the Prophylaxis of Migraine

SYNOPSIS
Seventeen patients have taken part in a double-blind, controlled, randomized, cross-over trial, completing four months, two months on each arm of the trial, in which pizotifen 0.5 mg t.d.s. has been compared with 1.5 pizotifen at night. Sixteen patients improved significantly. No significant difference was noted between patients on 0.5 mg t.d.s. compared with 1.5 mg nocte but there was a trend to suggest that initially patients may respond better to the t.d.s. dosage but then maintenance would be more easily carried out on a once nightly regime of pizotifen 1.5 mg nocte. Weight gain appeared to be related to the t.d.s. dosage regime and if this finding is confirmed in subsequent studies then the single dosage at night would certainly be preferable to a t.d.s. dosage regime. We confirm previous studies which show that pizotifen is extremely useful in the prophylaxis of migraine.     

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.     

Monodrug efficacies of sulfonamides in prophylaxis for Pneumocystis carinii pneumonia.

A remarkably high rate of adverse events is associated with the use of trimethoprim-sulfamethoxazole in patients with human immunodeficiency virus type 1 infection. We examined the efficacies of sulfonamides alone in the prevention of Pneumocystis carinii pneumonitis, with the assumption that at least some of the adverse events with the drug combination might be due to trimethoprim. With the immunosuppressed rat model, eight sulfonamides were studied at 100, 10, and 1.0 mg/kg/day (10 rats per dosage and drug). P. carinii infection was prevented in all animals (100%) receiving dosages of as little as 1.0 mg of sulfamethoxazole, sulfamethoxypyridazine, and sulfadimethoxine per kg per day, as little as 10 mg of sulfameter, sulfachlorpyridazine, and sulfaquinoxaline per kg per day; and 100 mg of sulfaguanidine and sulfanilamide per kg per day. These studies suggest that a sulfonamide, such as sulfamethoxazole, might provide effective prophylaxis for P. carinii pneumonitis without trimethoprim.     

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.     

Efficacy of accelerated dose titration of olanzapine with adjunctive lorazepam to treat acute agitation in schizophrenia

We conducted a prospective double-blind study of accelerated dose titration of olanzapine in the treatment of newly admitted acutely agitated patients with schizophrenia. Patients were randomized to either oral olanzapine (10 mg per day) or oral haloperidol (10 mg per day), plus lorazepam as needed (up to 12 mg per day). Antipsychotic dosage was increased to 20 mg per day as early as day 3. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) Agitation subscale during the first 24 hours of treatment, daily for the first week, then weekly until study completion. Significant within-group improvement was demonstrated in PANSS Agitation scores for both groups as early as 1 hour after initiating therapy (-5.79 +/- 6.30 for olanzapine and -4.89 +/- 6.05 for haloperidol, P <.001). This study demonstrated that accelerated dose titration of oral olanzapine is as efficacious as oral haloperidol in reducing acute agitation in patients with schizophrenia.     

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.     

Flunarizine effects on oxidative stress in migraine patients

Prophylactic activity of flunarizine in migraine is attributed to its antioxidant properties and to the relief of cerebral vasospasm in which nitric oxide (NO) is involved. We investigated the antimigraine activity of flunarizine and its influence on NO and oxidative marker bioavailability in 25 subjects suffering from migraine without aura and in 25 healthy controls. Urinary samples collected before and after treatment with flunarizine (5 mg orally per day for 6 months) were assayed for NO stable metabolites (NOx) and thiobarbituric acid reactive substances (TBARS). Urinary levels of NOx and TBARS were higher in migraine sufferers before treatment than in healthy controls. No differences were observed in NOx levels in migraine sufferers, before and after flunarizine treatment; urinary TBARS levels were decreased after flunarizine treatment (P < 0.05) and remained persistently higher than in healthy controls (P < 0.05). Our results suggest that flunarizine did not prevent NO-mediated vasodilatation, while it proved effective in limiting the oxidative reactions occurring in migraine sufferers.     

Dopamine D2 receptor blockade and antimigraine action of flunarizine

We studied in vivo the influence of flunarizine on dopamine D2 receptors and investigated whether dopamine D2 receptor blockade is involved in its antimigraine action. Eleven migraine patients, treated with flunarizine, 10 mg per day, underwent single photon emission computer tomography (SPECT) using [¹²³I] labeled iodobenzamide, a ligand with high affinity and high specificity for D2 receptors. There was a reduction of the dopamine D2 receptor binding potential in all patients compared to age-matched controls. The efficacy of flunarizine in migraine prophylaxis failed to correlate with the degree of the dopamine D2 receptor blockade. The antimigraine action of flunarizine may not involve antidopaminergic mechanisms.     

倍他乐克和小剂量胺碘酮对维持房颤复律后窦律的疗效观察

目的：应用倍他乐克和小剂量胺碘酮，观察对房颤转复及维持窦性心律的效果。方法：开始用胺碘酮持续静注，48h后改用口服，按每天600mg，400mg，200mg每周减量；倍他乐克每天25～50mg起始，每周25～50mg增量，以心率和血压作为控制标准。结果：23例药物转复成功，6例电转复成功；0．5a、1a、2a有效率93．31％(27／29)，89．66％(26／29)，86．21％(25／29)，无明显副作用发生。结论：联合小剂量胺碘酮和倍他乐克维持房颤转复后的窦性心律．比单用胺碘酮疗效好，观察2a未发现明显副作用。认为：除两药的抗心律失常作用外，长期应用更有综合改善心功能的作用，更有利于对冠心病、高血压心脏病、心肌病合并房颤的治疗。     

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.     

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.     

A comparative study of magnesium, flunarizine and amitriptyline in the prophylaxis of migraine

Circumstantial evidence points to the possible role of magnesium (Mg⁺²) deficiency in the pathogenesis of migraine and has raised questions about the clinical utility of magnesium as a therapeutic regimen in migraine. This was a prospective, randomized, double-blind, placebo-controlled trial comparing the efficacy and tolerability of 1830 mg magnesium citrate (23 patients), 10 mg flunarizine (22 patients) and 10 amitriptyline (20 patients) in the prophylaxis of migraine diagnosed according to the criteria of the International Headache Society. Patients were evaluated for attack frequency, severity and drug side effects monthly for 3 months. Magnesium, flunarizine and amitriptyline were all superior to placebo (p<0.001) in reducint both attack frequency and severity after the first month. There was no significant difference between the 3 active drugs in reduction of attack frequency and severity. No serious side effects were observed and the frequencies of side effects were not significantly different in all treatment groups. Our results show that oral magnesium is an effective and well tolerated drug in the prophylaxis of migraine and compares well to established drugs like flunarizine and amitriptyline both in effectiveness and occurence of side effects. Magnesium may be an alternative drug in migraine prophylaxis, but more and larger comparative trials are needed to confirm these results. Received: 28 August 2000 / Accepted in revised form: 10 January 2001