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.     

Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370

This study investigated whether the selective 5HT1F receptor agonist LY334370 has other possible antimigraine mechanisms in addition to the proposed inhibition of dural plasma extravasation. LY334370 (up to 10(-5) M) had no vasoconstrictor effects on human cerebral arteries in vitro. It had no effect (up to 10 mg kg-1, i.v.) on neurogenic vasodilation of dural blood vessels produced by electrical stimulation of the dura mater in anesthetized rats. Nor had it any effect (at 3 mg kg-1, i.v.) on the hyperalgesia produced by injection of carrageenan into the paw of conscious rats or on nociceptive reflex responses in the spinalized, decerebrate rabbit (up to 3 mg kg-1, i.v.), indicating that it has no general analgesic properties. However, it significantly inhibited activation of second-order neurons in the trigeminal nucleus caudalis produced by electrical stimulation of the dura mater in anesthetised rats at 3 mg kg-1, i.v. These results provide evidence to suggest that LY334370 has a central mechanism of action in blocking the transmission of nociceptive impulses within the trigeminal nucleus caudalis and that this may represent a mechanism through which it has its antimigraine effect.     

Alpha-dihydroergocryptine in the prophylaxis of migraine: a multicenter double-blind study versus flunarizine

This multicenter, double-blind, clinical study was designed to compare the efficacy and safety of alpha-dihydroergocryptine and flunarizine in the prophylaxis of migraine without aura. One hundred thirty-five patients fulfilling the diagnostic criteria of the International Headache Society were enrolled at five neurologic centers. The study design included a 1-month pretreatment phase with placebo; a 6-month, double-blind, double-dummy treatment phase with alpha-dihydroergocryptine (10 mg twice daily) or flunarizine (5 mg once daily); a further 3-month follow-up phase without treatment. Efficacy was assessed using the patient's diary. Laboratory tests, vital signs, and adverse events were monitored. Analysis of covariance for repeated measures was performed on the intent-to-treat sample. Both treatments led to a significant reduction in the frequency of migraine, days with headache, and use of relief medication. Overall, 51% of those treated with alpha-dihydroergocryptine and 49% of those treated with flunarizine were responders (50% or greater reduction in attack frequency), the average percentage of reduction being 64% with alpha-dihydroergocryptine and 51% with flunarizine. There was no significant difference between the two groups in terms of incidence of adverse events; dizziness and weight gain were the most frequent observed adverse events with alpha-dihydroergocryptine and flunarizine, respectively. Based on the overall improvement in migraine parameters, alpha-dihydroergocryptine can be recommended for use in migraine prophylaxis.     

Acupuncture in the prophylactic treatment of migraine without aura: a comparison with flunarizine

OBJECTIVES: In a randomized controlled trial extending over 6 months, we evaluated the effectiveness of acupuncture versus flunarizine in the prophylactic treatment of migraine without aura. METHODS: One hundred sixty women with migraines were randomly assigned to acupuncture treatment (group A, n = 80) or to an oral therapy with flunarizine (group F, n = 80). In group A, acupuncture was carried out in weekly sessions for the first 2 months and then once a month for the next 4 months. The same acupoints were used at each treatment: LR3 Taichong, SP6 Sanyinjiao, ST36 Zusanli, CV12 Zhongwan, LI4 Hegu, PC6 Neiguan, GB20 Fengchi, GB14 Yangbai, EX-HN5 Taiyang, GV20 Baihui. In group F, 10 mg flunarizine were given daily for the first 2 months and then for 20 days per month for the next 4 months. RESULTS: The frequency of attacks and use of symptomatic drugs significantly decreased during treatment in both groups. The number of attacks after 2 and 4 months of therapy was significantly lower in group A than in group F, and analgesic consumption was significantly lower in group A at 2 months of treatment. At 6 months no such differences existed between the two treatment groups. Pain intensity was significantly reduced only by acupuncture treatment. Side effects were significantly less frequent in group A. CONCLUSIONS: Acupuncture proved to be adequate for migraine prophylaxis. Relative to flunarizine, acupuncture treatment exhibited greater effectiveness in the first months of therapy and superior tolerability.     

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.     

天麻钩藤饮与氟桂利嗪治疗偏头痛有效性及安全性的Meta分析

目的 使用Meta分析评价天麻钩藤饮与氟桂利嗪治疗偏头痛有效性及安全性.方法 采用PubMed、Cochrane Li-brary、知网(CNKI)、维普(VIP)和万方数据库进行文献检索.根据纳入及排除标准筛选出天麻钩藤饮与氟桂利嗪治疗偏头痛的随机对照试验(RCTs),采用RevMan 5.4软件进行Meta分析.结...     

Long-term results of migraine prophylaxis with flunarizine and beta-blockers

We followed-up 64 migraine patients after discontinuation of successful interval prophylaxis with flunarizine, propranolol or metoprolol, to investigate how long the therapeutic success would last, if further prophylaxis would be successful again, and what factors would influence the prognosis. We found that 16 out of 64 patients experienced a lasting reduction of migraine frequency, whereas 48 patients did improve initially, but later experienced a relapse. Further prophylaxis was effective in 29, poorly effective in 11, and ineffective in 8 of these patients; in 7 of the 8 non-responders prophylaxis was not changed. Negative prognostic factors were frequent attacks, a history of analgesic abuse and/or analgesic withdrawal therapy and ineffective previous prophylaxis. In conclusion, the therapeutic success decreases dramatically in the majority of patients several months after discontinuation of prophylaxis; further prophylaxis is more effective if the substance class is changed; increased analgesic intake is the most important prognostic factor. As a strategy for migraine prophylaxis we propose sequential changing of interval prophylaxis or--in patients with negative prognostic factors--long-term prophylaxis.     

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).     

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.     

Transcranial Doppler evaluation of cerebral hemodynamics in migraineurs during prophylactic treatment with flunarizine

Transcranial Doppler (TCD) recording was used to evaluate the mean flow velocity (MFV) and cerebrovascular reactivity to CO2 in 21 migraineurs during the interictal phase. Nine were affected by migraine with aura (MwA) and 12 by migraine without aura (MwoA). During each session the middle cerebral artery (MCA) flow velocity was examined in basal conditions, in hypocapnia after a 3-min period of hyperventilation, in basal conditions a second time, and in hypercapnia after breath-holding. The same procedure was followed in a group of 21 age- and sex-matched volunteers. Recordings were performed before (T1), during (T2), and after (T3) prophylactic treatment with flunarizine (10 mg/day for 2 months) to assess the possible effect of this drug on cerebral hemodynamics. In basal condition, increased MFV values were found in both MwA and MwoA patients. In MwA patients the reactivity index (RI) to hypocapnia was significantly increased in T1 (p < 0.05). This abnormal cerebrovascular reactivity disappeared during flunarizine treatment (T2) and in the post-therapy period (T3).     

甲磺酸倍他司汀联合盐酸氟桂利嗪治疗前庭性偏头痛的临床效果

目的 观察甲磺酸倍他司汀联合盐酸氟桂利嗪治疗前庭性偏头痛的临床效果.方法 选择2018年2月至2020年10月我院收治的100例前庭性偏头痛患者为研究对象,按治疗方式的不同将其分为对照组和观察组,每组50例.对照组采取甲磺酸倍他司汀治疗,观察组采取倍他司汀联合盐酸氟桂利嗪治疗.比较两组的临床效果.结果 观察组的头痛、眩晕发作次数、累积发作时间以及疼痛强度评分均优于对照组,差异具有统计学意义(P<0.05).两组患者的不良反应总发生率无显著差异(P>0.05).治疗后,两组患者的PSQI、WHOQOL-BREF评分及血清CGRP、5-HT水平均较治疗前明显改善,且观察组优于对照组,差异具有统计学意义(P<0.05).观察组的治疗总有效率高于对照组,差异具有统计学意义(P<0.05).结论 甲磺酸倍他司汀联合盐酸氟桂利嗪治疗前庭性头痛能有效改善患者偏头痛及眩晕等临床症状,提高其睡眠质量和生活质量,且安全性良好,值得临床推广应用.     

Normalization of high interictal cerebrovascular reactivity in migraine without aura by treatment with flunarizine

BACKGROUND: Modification of migraine-associated cerebrovascular reactivity may provide insight into the mechanism of action of a given therapeutic intervention. METHODS: With transcranial Doppler and a breath-holding index, cerebrovascular reactivity to hypercapnia was evaluated in 20 patients with migraine without aura interictally and in 11 healthy controls. Patients were started on prophylactic treatment with flunarizine 10 mg per day, and measurements were repeated at the end of every month for 3 months. Headache status was evaluated clinically via a headache index. Headache index; breath-holding index; systolic, diastolic, and mean blood flow velocities; and pulsatility index measurements were recorded at every session. RESULTS: The baseline breath-holding index was significantly higher in the migraine group compared to the control group (P =.002). No difference in other parameters was found between the groups. The change in the headache index was significant (P<.001), indicating a beneficial effect from flunarizine. The breath-holding index improved significantly after treatment (P<.001), and the baseline difference in the breath-holding index between the pretreatment migraine group and the control group was no longer evident at 3 months. There was no significant change with treatment in the other transcranial Doppler parameters. CONCLUSIONS: Our finding of unchanged blood flow velocities but normalized cerebrovascular reactivity after treatment suggests that the mechanism of action of flunarizine in migraine does not involve a vasodilatory effect on cerebral vessels. It may be instead that flunarizine modifies cerebrovascular reactivity through its action on centrally located structures that subserve autonomic vascular control.     

Changes in the dopaminergic control of prolactin secretion and in ovarian steroids in migraine

Prolactin (PRL) responses to dopamine (DA) blockers and to direct and indirect DA agonists have been studied in 23 healthy women, 17 women with catamenial migraine and 17 with non-catamenial migraine in both their follicular and luteal phases. PRL responses to the DA blockers were greater in the follicular phase of both migraine groups than in controls. The inhibitory effect of nomifensine on PRL secretion was dampened in the follicular phase of both migraine groups. These findings demonstrate an increased PRL reserve in migraine and suggest the existence of a dopaminergic supersensitivity of the lactotrophic postsynaptic DA receptors. The impaired inhibitory effect of nomifensine on PRL secretion hints at a decrease of the presynaptic DA content in tuberoinfundibular DA neurons. In migrainous women 17-beta-oestradiol levels are higher in both ovarian phases, whereas progesterone concentrations and the progesterone to oestradiol ratio are lower than in healthy subjects in the luteal phase. These data suggest the existence of a change in the oestrogen-dependent modulation of pituitary DA receptors.     

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.     

Flunarizine and migraine in childhood

Flunarizine was tested for prophylactic efficacy and for side effects in 10- to 13-year-old patients with severe migraine (greater than 2 attacks per month). The 13 preadolescents received a single 5-mg dose at night for 2 months. The attack frequency decreased significantly, and the effect was maintained over time. The endocrine status, investigated before and after treatment, showed no significant interference with pituitary, beta-pancreatic, or gonadal function.     

氟桂利嗪添加治疗难治性癫痫的临床研究

目的探讨氟桂利嗪添加治疗难治性癫痫的疗效。方法随机、双盲对照添加治疗,从我院癫痫病人数据库中随机抽取确诊为难治性癫痫患者52例,随机分配入氟桂利嗪添加活疗组（n=26）与安慰剂组（n=26）。疗程1月后,分别比较两组疗效差别及每组自身治疗前后差别。结果两组于受试期结束后发作频率比较,差异有统计学意义（x^2=5．20,P〈0．05）。治疗组在第二周末、第四周末与基线期自身比较,差异有统计学意义（t=2．40、2．81,P均〈0．05）。结论氟桂利嗪作为难治性癫痫的添加治疗有一定疗效,无明显不良反应,但需进一步扩大样本深入研究。     

氟哌噻吨与普利曲新合剂治疗偏头痛的对照研究

目的:为探索不同的治疗偏头痛的有效方法,观察氟哌塞吨与普利曲新合剂(商品名黛力新)对不伴有抑郁和/或焦虑的偏头痛的治疗效果。方法:将114例不伴有抑郁和焦虑的偏头痛患者按随机数字表法分为两组。治疗组用黛力新,对照组用氟苯桂嗪,共治疗8周,观察两组头痛发作次数和头痛持续时间及头痛程度。结果:对照组2例,治疗组3例因症状减轻两周后自行停药而脱落犤脱落率4%(2/54),5%(3/60)犦。治疗组8周后头痛发作次数(0.5±0.5)次/周和持续时间(0.5±0.5)h较治疗前犤(1.6±0.8)次/周,(6.9±3.1)h犦明显好转(t=5.5,3.4,P<0.01);对照组8周后头痛发作次数(0.6±0.5)次/周较治疗前(1.2±0.8)次/周好转(t=3.2,P<0.01),持续时间(1.7±1.7)h较前(6.0±3.6)h缩短(t=2.01,P<0.05)。两组治疗后比较,治疗组发作次数(t=2.12,P<0.05)和持续时间(t=2.09,P<0.05)均优于对照组。治疗后对照组头痛程度分级要低于治疗组(z=3.56,P<0.01)。结论:对不伴有焦虑和/或抑郁的偏头痛患者使用氟哌噻吨与普利曲新合剂能取得较好的疗效。     

Flunarizine in Migraine: A Minireview

Flunarizine is a non-selective calcium antagonist. It distributes preferentially in the adipose tissue and passes the blood brain barrier. Numerous controlled clinical studies have established that flunarizine is efficacious in migraine prophylaxis, including double-blind studies in which the drug was compared with placebo or other antimigraine drugs. To avoid side effects a special schedule or administration is necessary. Flunarizine has no myogenic effect on smooth muscle cells of the vessles. It is said to be the only calcium antagonist able to protect brain cells against hypoxic damage. In addition, the considerable body of information which shows flunarizine capable of directly influencing the central nervous system, suggests that the drug's anti-migraine action may depend on its ability to influence central phenomena.     

氟桂利嗪预防脑梗死再发298例临床研究

目的探讨加用氟桂利嗪预防脑梗死再发的临床效果。方法 298例脑梗死患者随机分为2组,均给予相同的基础治疗。观察组(n=150)再给予阿司匹林及盐酸氟桂利嗪;对照组则单用阿司匹林。比较治疗6个月后2组的总体疗效、血液流变学指标、不良反应及1年内的再发率。结果治疗6个月时观察组显效率显著高于对照组;观察组1年内脑梗死再发率明显低于对照组;2组患者治疗后血液流变学各项指标均较治疗前显著改善,而观察组改善情况显著优于对照组。随访1年,观察组不良反应发生率为11.3%,继续用药后逐渐消失。结论加用氟桂利嗪能显著降低脑梗死再发率,且不良反应轻微,值得推广。     

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.