Permanent non-progressive cinnarizine and flunarizine-induced parkinsonism: An under-recognized tardive syndrome in the elderly?

Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.

[Systematic review and Meta-analysis on randomized controlled trial of efficacy and safety for acupuncture versus Flunarizine in treatment of migraine].

To systematically evaluate the efficacy and safety of acupuncture versus Flunarizine hydrochloride in the treatment of migraine. Four Chinese databases(CNKI, VIP, WanFang, CBM), three English databases(Cochrane Library, EMbase, Medline) and ClinicalTrail.gov were systematically and comprehensively retrieved. The retrieval time was from the establishment of each database to January 8, 2020. Randomized controlled trial(RCT) for acupuncture versus Flunarizine in the treatment of migraine were screened out according to inclusion criteria and exclusion criteria. The included studies were evaluated with the Cochrane bias risk assessment tool. The included studies was conducted by RevMan 5.3, and the outcome indicators were evaluated for evidence quality and strength of recommendation by the GRADE system. A total of 1 033 literatures were retrieved, and 23 studies were finally included. Except for 4 multiarm tests, the total sample size was 1 548, including 785 in acupuncture group and 763 in Flunarizine group. The overall quality of the included studies was not high. Meta-analysis results showed that the acupuncture group was superior to the Flunarizine group in reduction of headache frequency(SMD=-1.00, 95%CI[-1.45,-0.54], P<0.000 1). In reduction of headache intensity, acupuncture group was superior to Flunarizine group(SMD=-1.05, 95%CI[-1.41,-0.68], P<0.000 01). In reduction of headache duration, acupuncture group was superior to Flunarizine group(SMD=-1.42, 95%CI[-1.83,-1.02], P<0.000 1). The acupuncture group was superior to Flunarizine group(MD=-0.17, 95%CI[-0.21,-0.13], P<0.000 01) in reduction of the painkillers taking frequency. The acupuncture group was superior to Flunarizine group(SMD=-0.94, 95%CI[-1.35,-0.52], P<0.000 1) in allevia-tion of paroxysmal symptoms, such as nausea and vomiting. The GRADE system showed that the evidence level of the above indicators was extremely low, and the strength of recommendation was low. As for the occurrence of adverse reactions, the adverse reactions reported in the acupuncture group included in the study were all mild adverse reactions, like drowsiness, subcutaneous bleeding, local pain, subcutaneous hematoma and dizziness needle. The available evidence showed that acupuncture has a better efficacy than Flunarizine hydrochloride in the treatment of migraine in adult patients. However, due to the high bias risk in the included studies, the conclusions of this study shall be adopted with caution, and more high-quality studies shall be carried out for verification in the future.

Flunarizine related movement disorders: a nationwide population-based study.

Flunarizine (fz) causes side effects such as movement disorders (MDs). We investigated risk factors associated with fz-related MDs. Participants were recruited from the longitudinal health insurance databases and included patients who took fz for more than 1 month. Patients with one of the underlying diseases, or with concomitant drug use (antipsychotics, metoclopramide or reserpine), and those diagnosed with MDs before fz use were excluded. Fz-related MD was defined as a new diagnosis of parkinsonism or hyperkinetic syndrome including dyskinesia or secondary dystonia during fz use or within 3 months after drug discontinuation. After exposure, 288 individuals had fz-related MDs (parkinsonism, n = 240; hyperkinesia, n = 48). Risk factors associated with these disorders were higher-dose exposure (cumulative defined daily dose [cDDD] ≥87.75, odds ratio [OR]: 3.80; 95% CI: 2.61-5.52), older age (OR: 1.07; 95% CI: 1.06-1.09), history of essential tremor (OR: 6.39; 95% CI: 2.29-17.78) and cardiovascular disease (CVD) (OR: 1.47; 95% CI: 1.14-1.9). The optimal value of cDDD to predict MDs was 58.5 (sensitivity: 0.67, specificity: 0.60), indicating an overall exposure of 585 mg. Higher exposure dose and duration, older age, history of essential tremor, and CVD were associated with fz-associated MDs. Clinicians ought to watch for extrapyramidal side effects when prescribing fz.

Calcium antagonists for acute ischemic stroke.

BACKGROUND: The sudden loss of blood supply in ischemic stroke is associated with an increase of calcium ions within neurons. Inhibiting this increase could protect neurons and might reduce neurological impairment, disability, and handicap after stroke. OBJECTIVES: To assess the effects of calcium antagonists for reducing the risk of death or dependency after acute ischemic stroke. We investigated the influence of different drugs, dosages, routes of administration, time intervals after stroke, and trial design on the outcomes. SEARCH METHODS: The evidence is current to 6 February 2018. We searched the Cochrane Stroke Group Trials Register (6 February 2018), Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2), MEDLINE Ovid (1950 to 6 February 2018), Embase Ovid (1980 to 6 February 2018), and four Chinese databases (6 February 2018): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure (CNKI), Chinese Scientific Periodical Database of VIP information, and Wanfang Data. We also searched the following trials registers: ClinicalTrials.gov, EU Clinical Trials Register, Stroke Trials Registry, ISRCTN registry, WHO International Clinical Trials Registry Platform, and Chinese Clinical Trial Registry, and we contacted trialists and researchers. SELECTION CRITERIA: Randomized controlled trials comparing a calcium antagonist versus control in people with acute ischemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the quality of the evidence. We used death or dependency at the end of long-term follow-up (at least three months) in activities of daily living as the primary outcome. We used standard Cochrane methodological procedures. MAIN RESULTS: We included 34 trials involving 7731 participants. All the participants were in the acute stage of ischemic stroke, and their age ranged from 18 to 85 years, with the average age ranging from 52.3 to 74.6 years across different trials. There were more men than women in most trials. Twenty-six trials tested nimodipine, and three trials assessed flunarizine. One trial each used isradipine, nicardipine, PY108-608, fasudil, and lifarizine. More than half of these trials followed participants for at least three months. Calcium antagonists showed no effects on the primary outcome (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.98 to 1.13; 22 trials; 22 studies; 6684 participants; moderate-quality evidence) or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17; 31 trials; 7483 participants; moderate-quality evidence). Thirteen trials reported adverse events, finding no significant differences between groups. Most trials did not report the allocation process or how they managed missing data, so we considered these at high risk of selection and attrition bias. Most trials reported double-blind methods but did not state who was blinded, and none of the trial protocols were available. AUTHORS' CONCLUSIONS: We found no evidence to support the use of calcium antagonists in people with acute ischemic stroke.

Flunarizine for Headache Prophylaxis in Children With Sturge-Weber Syndrome.

BACKGROUND: Children with Sturge-Weber syndrome can experience severe headache with or without transient hemiparesis. Flunarizine, a calcium antagonist, has been used for migraine. The experience with flunarizine for headache in a cohort of children at a national center for Sturge-Weber syndrome is reviewed, reporting its efficacy and adverse effect in this population. METHODS: We collected data from health care professionals' documentation on headache (severity, frequency, duration) before and on flunarizine in 20 children with Sturge-Weber syndrome. Adverse effects reported during flunarizine treatment were collated. The Wilcoxon signed rank test was used to determine the significance of pre- versus post-treatment effect. RESULTS: Flunarizine was used for headache alone (13) or mixed migrainous episodes and vascular events (7). The median duration of treatment was 145 days (range 43 to 1864 days). Flunarizine reduced headache severity (z = -3.354, P = 0.001), monthly frequency (z = -2.585, P = 0.01), and duration (z = -2.549, P = 0.01). Flunarizine was discontinued owing to intolerable adverse effects in a minority (2). Sedation and weight gain were the most common side effects. There were no reports of behavior change or extrapyramidal features. CONCLUSIONS: The most effective management for headaches in patients with Sturge-Weber syndrome has not been established. This retrospective observational study found benefit of flunarizine prophylaxis on headache severity, frequency, and duration in children with Sturge-Weber syndrome without severe side effects. Flunarizine is not licensed for use in the United Kingdom, but these data support its off-license specialist use for headache prophylaxis in Sturge-Weber syndrome.

Flunarizine and the risk of parkinsonism in a newly diagnosed type 2 diabetic population in Taiwan: A nested case-control study.

Previous studies demonstrated that both diabetes and flunarizine use can increase the risk of parkinsonism. The aim of the current study was to investigate the risk of developing parkinsonism after flunarizine treatment, in a cohort of patients newly diagnosed with type 2 diabetes. We conducted a nested case-control study of a type 2 diabetic cohort from the Taiwan Longitudinal Health Insurance Database 2005 (LHID 2005). Each incident case of parkinsonism, during the period from 2001 to 2013, was randomly matched with 3-10 controls, according to age, sex, calendar year of cohort entry, and the duration of follow-up. Conditional logistic regression was used to estimate the odds ratio (OR) of parkinsonism associated with flunarizine use. The cohort consisted of 44,644 patients with newly diagnosed type 2 diabetes from 2001 to 2013, of whom 464 patients had a parkinsonism event during the follow-up period. The adjusted OR of parkinsonism with relation to flunarizine use was 2.75 (95% confidence interval: 2.26-3.36). There were also duration- and dose-response effects. Compared to those who had not used it, the OR for developing parkinsonism was 1.77 for patients who used flunarizine for less than 1 month. When the exposure period expanded over 3 months, the OR increased to 7.03. Our findings suggested that flunarizine use is a potential risk factor for parkinsonism in patients with newly diagnosed type 2 diabetes, especially when the drug is persistently used for over 3 months.

Sibelium in combination with dibazole in the treatment of angioneurotic headache.

Angioneurotic headache is a common nerve headache featured by intermittence, repetition, paroxysm and aggravation, which can severely affect the sufferer's quality of life. Currently, there are multiple drugs which can be used for relieving this type of headache, and the effectiveness and safety of drugs have been a subject of interest in clinical practice. To observe the effects of sibelium in combination with dibazole and offer a basis for the clinical treatment, 136 patients with angioneurotic headache who were admitted to hospital between February and September 2015 were selected and randomly divided into a test group and a control group, 68 in each. Patients in the test group were treated with sibelium in combination with dibazole, while patients in the control group were given sibelium only. The effects, adverse reactions, complications and toxic and side effects of the treatment in the two groups were observed. Furthermore, the blood flow speed and hemodynamic changes before and after treatment were compared. The results demonstrated that the hemodynamic indexes and cerebral blood flow speed of the patients in the test group showed obvious changes after treatment, and the difference was statistically significant (P<0.05); the improvement of the above indexes of the test group was superior to that of the control group, and the difference had statistical significance (P<0.05); the overall effective rate of the test group was higher than that of the control group (94.12% vs 76.47%) (P<0.05); the medication safety of the test group was higher than that of the control group (all P<0.05). It can be concluded that sibelium in combination with dibazole has a remarkable effect in treating angioneurotic headache as it can significantly improve hemodynamic indexes and cerebral blood flow speed. Moreover, the therapy seldom induces toxic and side effects, adverse reactions or complications.

Serotonin syndrome in patients with headache disorders.

Serotonin syndrome (SS) is an iatrogenic, drug-induced syndrome caused by serotoninergic agent. Various serotonergic drugs are used in different headache disorders. Therefore, a possibility of developing SS exists in patients with headache. Herein, we are reporting two patients with headache disorders who developed SS.Case 1: a 49-year-old man had a 6-year history of episodic cluster headache (CH). However, he had never been diagnosed with CH before reporting to us. He had been receiving amitriptyline, tramadol/acetaminophen combination and flunarizine. Lithium was started for CH. He developed features consistent with SS. The patient responded to cyprohepatdine.Case 2: a 36-year-old chronic migraineur was on amitriptyline. Addition of sodium valproate led to the development of new features that fulfilled the criteria of SS. The patient responded to cyprohepatdine.As SS may be fatal, there is a need to increase awareness about SS in physicians treating patients with headache.

Extrapyramidal symptoms after exposure to calcium channel blocker-flunarizine or cinnarizine.

PURPOSE: Flunarizine (fz) and cinnarizine (cz) have well-known extrapyramidal side effects (EPSEs). The aim of this study was to evaluate the incidence and occurrence time of cz- and fz-related EPSEs. METHOD: Patients who took fz or cz for more than 1 month were identified from the longitudinal health insurance database 2005 and 2010. Excluded were patients with any of the underlying diseases that may cause parkinsonism. Drug-induced EPSEs were defined as the new diagnosis of parkinsonism, dyskinesia, or secondary dystonia during drug use or within 3 months after discontinuing the medication. Age- and sex-matched controls were included in this study. RESULTS: Recruited for analysis were individuals who took fz (n = 26,133) and cz (n = 7186). The incidence rates of fz- and cz-induced EPSEs were 21.03 and 10.3 per 10,000 person-months, respectively. The hazard ratios (HRs) of EPSEs among fz and cz subjects were 8.03 (95% CI 6.55-9.84) and 3.41 (95% CI 2.50-4.63) when compared with the control individuals. Both fz and cz patients had a higher cumulative incidence of EPSEs than their control individuals (p < 0.001). Among subjects who took fz, the incidence of EPSEs was higher in the second than first year of drug exposure (45.59 vs 21.03 per 10,000 person-months). CONCLUSIONS: Fz and cz significantly increased the risk of parkinsonism, dyskinesia, and dystonia. Potential benefits and risks should be weighed when considering long-term use of these drugs especially fz.

Flunarizine versus topiramate for chronic migraine prophylaxis: a randomized trial.

OBJECTIVES: Chronic migraine (CM) is a prevalent and devastating disorder with limited therapeutic options. This study explored the efficacy of 10 mg/d flunarizine for CM prophylaxis as compared with 50 mg/d topiramate. METHODS: We conducted a prospective, randomized, open-label, blinded-endpoint trial. Patients with CM were randomized to flunarizine and topiramate treatment. The primary outcomes assessed were the reductions in the total numbers of headache days and migraine days after 8 weeks of treatment. Secondary outcomes were reductions in the numbers of days of acute abortive medication intake and acute abortive medication tablets taken, and the 50% responder rate. RESULTS: Sixty-two subjects were randomized (n=31/group). Patients treated with flunarizine showed significant reductions in the numbers of total headache days (-4.9 vs -2.3, P=.012) and migraine days (-4.3 vs -1.4, P=.001) compared with those treated with topiramate. Patients treated with flunarizine also showed significant reductions in the numbers of days of acute abortive medication intake (-2.3 vs -0.2, P=.005) and acute abortive medication tablets taken (-4.6 vs -0.5, P=.005) and had a higher 50% responder rate in terms of total headache days (58.6% vs 25.9%, P=.013) and migraine days (75.9% vs 29.6%, P=.001), compared with topiramate-treated patients. Flunarizine was generally well tolerated and had a safety profile comparable to that of topiramate. CONCLUSIONS: Our results suggest that, in an 8-week study, 10 mg/d flunarizine is more effective than 50 mg/d topiramate for CM prophylaxis.

Risk of parkinsonism induced by flunarizine or cinnarizine: a population-based study.

PURPOSE: This retrospective cohort study used a population-based dataset to test the risk for parkinsonism in patients receiving flunarizine and cinnarizine, compared with matched controls. METHODS: Data were obtained from the National Health Insurance Research Dataset of Taiwan. Patients receiving flunarizine or cinnarizine for more than 1 month between 2000 and 2005 were enrolled. Exclusion criteria included receiving flunarizine, cinnarizine, or antipsychotics for more than 1 month during 1997-1999, a history of neurodegenerative diseases, and an age of less than 30 years. One matched control for each patient was selected. Each participant was followed for diagnosis of parkinsonism within a 3-year observation period. Stroke, diabetes mellitus, total prescription days, and doses of flunarizine or cinnarizine were recorded. RESULTS: The study and control groups consisted of 9830 subjects. In the study group, 280 patients (2.9 %) were diagnosed with parkinsonism with a median observation period of 1.2 years, and 49 participants (0.5 %) were diagnosed in the control group with a median observation period of 1.9 years. The adjusted hazard ratio for parkinsonism among patients receiving flunarizine and cinnarizine was 5.117 (95 % CI = 3.758-6.967). Age, stroke, and diabetes mellitus were significant risk factors, but female sex and total doses of the study drugs were not. CONCLUSIONS: This study demonstrates that flunarizine and cinnarizine significantly increase the risk for parkinsonism. The treatment benefits of these two agents should be balanced with this adverse effect. Physicians must look carefully for early signs of parkinsonism in patients treated with flunarizine and cinnarizine.

Zhengtian Capsule versus flunarizine in patients with migraine: a multi-center, double-blind, double-dummy, randomized controlled, non-inferior clinical trial.

BACKGROUND: The primary objective of this study was to assess whether Zhengtian Capsule was non-inferior to flunarizine in efficacy and safety profile for prevention of migraine in adults. METHODS: This was a double-dummy, double-blind, multicenter, positive drug (flunarizine), parallel randomized controlled, non-inferior clinical trial. Patients (n = 360) were randomized in a 1:1 to receive either Zhengtian Capsule or flunarizine, including 12 weeks' intervention and 4 weeks' follow-up. The primary outcome measure was responder rate (defined as the percentage of subjects in a treatment group with 50 % or greater reduction in attack frequency during treatment compared with the baseline period). The secondary outcome measures included migraine attack frequency, the number of migraine days, pain evaluated by visual analogue scale (VAS) score, duration of migraine attacks, the times of using analgesics, patient-reported outcome (PRO) measure of migraine and the scores of short-form 36 Health Survey Scale (SF-36). Weight variation in both groups was also evaluated. Adverse events were monitored throughout the trial. RESULTS: Zhengtian Capsule was non-inferior to flunarizine in responder rate at week 12 and follow-up period (P = 0.002, P < 0.001). There was fewer migraine days in Zhengtian Capsule group at follow-up period compared with flunarizine (P = 0.001). For the total duration of migraine attacks, there was significant group difference at week 4 which favored the control group (P = 0.009). For the total score of PRO scale, there was statistical difference between the two groups at follow-up period (P = 0.021). There were also group differences between the two groups in the dimensions of somatization symptoms at week 4 (P = 0.022) and functional status at week 12 and follow-up period (P < 0.001, P < 0.001). However, there were no significant differences between the two groups in migraine attack frequency, VAS scores reduction, consumption of acute pain drugs and the dimension scores of SF-36 at any time interval of the treatment period (P > 0.05). No severe adverse events occurred in the trial. Flunarizine was found associated with a weight gain. CONCLUSION: Zhengtian Capsule was non-inferior to flunarizine with regard to the primary endpoint. In addition, it could reduce migraine days and improve the functional status and somatization symptoms of migraine patients with good safety profile. TRIAL REGISTRATION: This trial was registered at Chinese Clinical Trial Register (ChiCTR), ChiCTR-TRC-13004412.

Iatrogenic parkinsonism: the role of flunarizine and cinnarizine.

We performed a clinical report based, descriptive and retrospective study, aimed at comparing Flunarizine/Cinnarizine-induced parkinsonism (FCIP) patients and Parkinson's disease (PD) patients. The FCIP group (n = 30) presented a lower frequency of rigidity and unilateral tremor than the PD group (n = 70). All FCIP patients improved, 13 after dopaminergic treatment. FCIP patients who improved spontaneously presented lower frequency of rigidity, compared with the other FCIP subgroup and PD group. FCIP patients who did not improve spontaneously showed a clinical pattern similar to PD patients.

Flunarizine in the prophylaxis of migrainous vertigo: a randomized controlled trial.

Migrainous vertigo is a common cause of dizziness presenting to an otorhinolaryngology/otoneurology clinic. Although it causes a substantial burden to the individual and society there are no randomized controlled trails on prophylactic medication for this condition. Flunarizine, a calcium channel blocker has been used effectively in both migraine and vestibular conditions. This randomized control trial was undertaken in a tertiary academic referral center to evaluate the efficacy of flunarizine in patients with migrainous vertigo when compared to non-specific vestibular treatment of betahistine and vestibular exercises. The effect of flunarizine on two particularly disabling symptoms of vertigo and headache was studied. A total of 48 patients who were diagnosed with definitive migrainous vertigo completed the study of 12 weeks duration. Patients in arm A received 10-mg flunarizine daily along with betahistine 16 mg and paracetamol 1 gm during episodes, and arm B received only betahistine and paracetamol during episodes. Symptom scores were noted at the start of the study and at the end of 12 weeks. Analysis of the frequency of vertiginous episodes showed a significant difference between arm A and arm B (p = 0.010) and improvement in severity of vertigo between the two groups (p = 0.046). Headache frequency and severity did not improve to a significant degree in arm A as compared to arm B. The main side effects were weight gain and somnolence and this was not significantly different between the two groups. Flunarizine (10 mg) is effective in patients with migrainous vertigo who suffer from considerable vestibular symptoms.

[A comparative study of the effectiveness of topiramate and flunarizine in independent series of chronic migraine patients without medication abuse]. / Estudio comparativo de la efectividad del topiramato y la flunaricina en series independientes de pacientes con migraña cronica sin abuso de medicacion.

INTRODUCTION: Topiramate and onabotulinumtoxin A have proven to be effective in chronic migraine with or without medication abuse according to recent criteria of the International Headache Society's Headache Classification. AIMS: To show that flunarizine is as effective as topiramate in cases of chronic migraine without medication abuse. PATIENTS AND METHODS: We conducted a prospective, non-randomised, comparative study of two groups of patients paired by age and sex, with chronic migraine without abuse, who had been treated preventively for the first time with topiramate or flunarizine. RESULTS: Forty patients treated with flunarizine were assigned a patient of their same sex and age who was being treated with topiramate. The mean rate of reduction in intense migraines in the topiramate group was 59% and in the flunarizine group, 58.5% (p = 0.9444); the responder rate at four months of treatment did not show any significant differences either, the figures being 75% for topiramate and 70% for flunarizine (p = 0.6236). The mean reduction of other headaches in the topiramate group was 57% and in the flunarizine group, 64% (p = 0.4261); the responder rate at four months of treatment was similar in the two groups: 76%. The percentage of dropouts from treatment was higher with topiramate (19.5%) than with flunarizine (10%) (p = 0.3493). No serious side effects occurred in either of the groups. In all, 78.9% of the patients who took topiramate said they were satisfied with the drug versus 75% of those in the flunarizine group (p = 0.7903). CONCLUSIONS: Flunarizine proved to be as effective as topiramate in the treatment of chronic migraine without medication abuse.

TITLE: Estudio comparativo de la efectividad del topiramato y la flunaricina en series independientes de pacientes con migraña cronica sin abuso de medicacion.Introduccion. El topiramato y la onabotulinumtoxina A han mostrado ser eficaces en la migraña cronica con o sin abuso de farmacos segun los criterios recientes de la Clasificacion de Cefaleas de la Sociedad Internacional de Cefaleas. Objetivo. Demostrar que la flunaricina es tan efectiva como el topiramato en la migraña cronica sin abuso de farmacos. Pacientes y metodos. Estudio prospectivo, no aleatorizado, comparativo de dos grupos de pacientes con similar edad y sexo, con migraña cronica sin abuso, tratados preventivamente por primera vez con topiramato o flunaricina. Resultados. A 40 pacientes tratados con flunaricina se les asigno un paciente del mismo sexo y edad tratado con topiramato. La media de reduccion de las migrañas intensas en el grupo del topiramato fue del 59% y en el grupo de la flunaricina, del 58,5% (p = 0,9444); la tasa de respondedores al cuarto mes de tratamiento tampoco mostro diferencias significativas, ya que fue del 75% para el topiramato y del 70% para la flunaricina (p = 0,6236). La media de reduccion de otras cefaleas en el grupo del topiramato fue del 57%, y en el grupo de la flunaricina, del 64% (p = 0,4261); la tasa de respondedores al cuarto mes de tratamiento fue del 76%, similar en ambos grupos. El porcentaje de abandonos del tratamiento fue mayor con el topiramato (19,5%) que con la flunaricina (10%) (p = 0,3493). En ninguno de los dos grupos hubo efectos adversos graves. Un 78,9% de los pacientes que tomo topiramato presento satisfaccion con el farmaco frente al 75% del grupo de la flunaricina (p = 0,7903). Conclusion. La flunaricina mostro ser tan efectiva como el topiramato en el tratamiento de la migraña cronica sin abuso de farmacos.

Calcium antagonists as an add-on therapy for drug-resistant epilepsy.

BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Nearly a third of people with epilepsy do not have their seizures controlled with current treatments. Continuous attempts have been made to find new antiepileptic drugs based on increasing knowledge of the cellular and molecular biology involved in the genesis of epilepsy and seizures. Therefore, calcium antagonists that can alter the effects of calcium on brain cells have been investigated for their effect on epileptic seizures. OBJECTIVES: To evaluate the effects of calcium antagonists when used as an add-on therapy for people with drug-resistant epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (29 January 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12), MEDLINE (1948 to 29 January 2013) and SCOPUS (all years to 29 January 2013). SELECTION CRITERIA: Randomised placebo-controlled or active-controlled add-on trials of any calcium antagonist in people with drug-resistant epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors (MH and JP) independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, cognition and quality of life. Analyses were by intention to treat. MAIN RESULTS: Eleven trials were included with a total of 424 participants, one parallel-group and seven cross-over trials of flunarizine, two cross-over trials of nimodipine and one cross-over trial of nifedipine.For flunarizine, the risk ratio (RR) with 95% confidence interval (CI) for a 50% or greater reduction in seizure frequency in a single parallel trial was 1.53 (95% CI 0.59 to 3.96) indicating a non-significant advantage of flunarizine. We were unable to acquire data for this outcome from the other seven cross-over trials. The overall RR for treatment withdrawal of flunarizine was 7.11 (95% CI 1.73 to 29.30) indicating individuals were significantly more likely to have flunarizine withdrawn than placebo. No adverse effects were associated statistically with flunarizine.For nifedipine, we were unable to acquire the data we required for our specified outcomes.For nimodipine, we had data only from the first treatment period from one of the two cross-over trials (17 participants). The RR for a 50% or greater reduction in seizure frequency was 7.78 (99% CI 0.46 to 130.88) and for treatment withdrawal the RR was 2.25 (99% CI 0.25 to 20.38). AUTHORS' CONCLUSIONS: Flunarizine may have a weak effect on seizure frequency but had a significant withdrawal rate, probably due to adverse effects, and should not be recommended for use as an add-on treatment. Similarly, there is no convincing evidence to support the use of nifedipine or nimodipine as add-on treatments for epilepsy.

Safety and efficacy of flunarizine in childhood migraine: 11 years' experience, with emphasis on its effect in hemiplegic migraine.

AIM: The aim of this study was to report a single-centre experience of flunarizine in childhood migraine with focus on safety and efficacy. METHOD: We conducted a retrospective observational audit of 72 individuals (40 male, 32 female; mean age 13y; age range 1y 6mo-17y) at a tertiary paediatric neurology unit between 1998 and 2009. Children were included if they had a diagnosis of migraine and at least one follow-up assessment and a minimum of 3 months' treatment with flunarizine. RESULTS: Of 102 individuals identified, 30 were excluded for the following reasons: no outcome data (n=13), non-migraineurs (n=9), missing records (n=4), or inadequate treatment duration (n=4). Of the final cohort (72 individuals), 44 had migraine without aura, 15 had migraine with aura or childhood migraine equivalents, eight had sporadic hemiplegic migraine, and five had familial hemiplegic migraine. The median age was 13 years (1y 6mo-17y) and median duration of migraine was 48 months. Starting dose was 5mg. Other doses used were 2.5mg (three individuals), 7.5mg (one individual), and 10mg (six individuals). Treatment duration was 12 months. Successful prophylaxis, defined as at least a 50% reduction in attack frequency, was observed in 57% (41/72). Response rate was higher among those with hemiplegic migraines (85%) than in those who did not have hemiplegic migraines (51%). Side effects were noted in 15 (21%) individuals (depression, n=6; weight gain/increased appetite, n=5; tiredness/sedation, n=2; and worsening headache, n=2), and led to discontinuation of treatment in 13. INTERPRETATION: In our cohort of children with migraine, flunarizine appears to be more effective in the hemiplegic migraine group. Adverse effects were seen in one-fifth of the individuals, leading to discontinuation in 18%.