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.     

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

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

Topiramate as an adjunctive treatment in migraine prophylaxis

BACKGROUND: Anticonvulsants now are commonly used for headache prevention. Topiramate, one of the newer anticonvulsants, recently has been demonstrated to be effective as monotherapy for migraine prophylaxis. OBJECTIVE: To assess the efficacy, safety, and tolerability of topiramate as adjunctive prophylactic therapy for migraine. MATERIAL AND METHODS: A prospective trial involving patients with more than 3 migraine attacks per month was performed. Patients continued their usual prophylactic treatment. Baseline analgesic use and frequency and duration of migraine attacks were recorded. A 4-point visual analog scale evaluated severity. Laboratory tests, electrocardiogram, and computed tomography or magnetic resonance imaging were performed before study entry. After informed consent was obtained, patients were instructed to take 25 mg of topiramate per day, with 25- to 50-mg weekly increments to a maximum of 100 mg per day. Safety was assessed at the first month; tolerability and efficacy were assessed every week for the first month and then every month for 3 months. Effectiveness was assessed by comparing baseline and on-treatment migraine status, and data were analyzed by the Fisher exact test. RESULTS: Twenty-five women and 11 men (mean age, 44 years) were evaluated. Existing prophylactic treatment was either propranolol or flunarizine (or both) in 80% of the patients. At 3 months of therapy with topiramate, headache frequency decreased from 17 to 3 episodes per month, headache duration from 559 to 32 minutes, and intensity from 9 to 1 by visual analog scale (P <.001). Improvement in frequency and severity of migraine was observed in 83% of patients. Slight or no changes in headache were observed in 6 patients. Tolerability was good in 30 patients. The most common side effects were acroparesthesias, weight loss, sleepiness, and headache worsening. No adverse interaction with propranolol or flunarizine was observed. CONCLUSIONS: These results suggest that topiramate is efficacious and safe as an adjunctive treatment in patients with migraine whose prior response to prophylactic management has been less than satisfactory.     

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.     

Variation in Almotriptan Effectiveness According to Different Prophylactic Treatments

Objective.— To evaluate the effect of different migraine prophylaxis medications on subject responsiveness to almotriptan.
Background.— There is evidence supporting an increase of responsiveness of symptomatic medications for migraine attacks by some prophylactic treatments although this has not been probed.
Methods.— A total of 345 patients (230 women, mean age 37.3) with episodic or chronic migraine were classified according to the prophylaxis they were taking in the following groups: (1) no prophylactic medication; (2) propranolol; (3) topiramate; (4) flunarizine. Decrease in Analogical Visual Scale and pain-free at 2 hours after almotriptan intake was assessed at 2 months. Side effects and discontinuation or treatment were also assessed.
Results.— Headache severity was reduced 4.2 in control group, 5.3 in propranolol group, 4.1 in topiramate group, and 4.0 in flunarizine group, whereas pain-free status was achieved in 37.3%, 48.7%, 36.1%, and 38.1% respectively. These two parameters were statistically significative between propranolol and control groups. Side effects were similar in all groups.
Conclusions.— Our results displayed a higher efficacy of almotriptan in propranolol group and we hypothesized it may be due to a common mechanism of action at serotoninergic 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 (10 and 20 mg) i.v. versus placebo in the treatment of acute migraine attacks: a multi-centre double-blind study

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

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.     

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.     

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

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

Flunarizine in migraine prophylaxis: predictive factors for a positive response

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

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.     

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).     

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.     

Flunarizine, the vestibular system and migraine

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

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).     

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.     

Magnesium Prophylaxis of Menstrual Migraine: Effects on Intracellular Magnesium

The effects of oral Magnesium (Mg) pyrrolidone carboxylic acid were evaluated in 20 patients affected by menstrual migraine, in a double-blind, placebo controlled study. After a two cycles run-in period, the treatment (360 mg/day of Mg or placebo) started on the 15th day of the cycle and continued till the next menses, for two months. Oral Mg was then supplemented in an open design for the next two months. At the 2nd month, the Pain Total Index was decreased by both Placebo and Mg, with patients receiving active drug showing the lowest values (P less than 0.03). The number of days with headache was reduced only in the patients on active drug. Mg treatment also improved premenstrual complaints, as demonstrated by the significant reduction of Menstrual Distress Questionnaire (MDQ) scores. The reduction of PTI and MDQ scores was observed also at the 4th month of treatment, when Mg was supplemented in all the patients. Intracellular Mg++ levels in patients with menstrual migraine were reduced compared to controls. During oral Mg treatment, the Mg++ content of Lymphocytes (LC) and Polymorphonucleated cells (PMN) significantly increased, while no changes in plasma or Red Blood Cells were found. An inverse correlation between PTI and Mg++ content in PMN was demonstrated. These data point to magnesium supplementation as a further means for menstrual migraine prophylaxis, and support the possibility that a lower migraine threshold could be related to magnesium deficiency.     

Effectiveness of lamotrigine in the prophylaxis of migraine with aura: an open pilot study

We report a small open pilot study to evaluate the efficacy of lamotrigine (100 mg/day) in the prevention of migraine with aura attacks. We studied 24 patients affected by migraine with aura with a high frequency of attacks. Following a 1-month run-in period, the patients took lamotrigine for 3 months. Mean attack number per month was reduced from 6.1 +/- 4.1 during the run-in period to 0.7 +/- 1.3 at the 3rd month of treatment (p < 0.0001). In 13 out of 21 patients who completed the study, the attacks were completely abolished at the 3rd month of treatment, while only one patient was completely unresponsive to the drug. Lamotrigine seems worthy of a controlled trial as prophylaxis of a migraine with aura.     

Preventing disturbing migraine aura with lamotrigine: an open study

BACKGROUND: Lamotrigine has been suggested as possibly effective for preventing migraine aura. OBJECTIVE: To describe our experience with a series of patients with disturbing migraine aura treated with lamotrigine. METHODS: The members of the Headache Group of the Spanish Society of Neurology were sent an ad hoc questionnaire to collect patients treated with lamotrigine due to disturbing migraine aura. The main outcome parameter ("response") was a >50% reduction in the mean frequency of migraine auras at 3 to 6 months of treatment. RESULTS: A total of 47 patients had been treated with lamotrigine due to severe migraine aura. Three could not complete the protocol as a result of developing skin rashes. Thirty (68%) patients responded. These were 21 females and 9 males whose ages ranged from 19 to 71 years. Eight suffered from migraine with "prolonged" aura, 8 typical aura with migraine headache (but had frequent episodes including speech symptoms), 6 basilar-type migraine, 6 typical aura without headache, and 2 hemiplegic migraine. Fifteen had been previously treated, without response, with other preventatives. The mean monthly frequency of migraine auras in these 30 patients changed from 4.2 (range: 1 to 15) to 0.7 (range: 0 to 6). Response was considered as excellent (>75% reduction) in 21 cases (70% of responders). Auras reappeared in 2 months in 9 out of 13 patients where lamotrigine was stopped, and ceased as soon as this drug was reintroduced. CONCLUSIONS: Lamotrigine should be considered in clinical practice for the preventive treatment of selected patients with disturbing migraine auras. Lamotrigine seems worthy of a controlled trial as prophylaxis of migraine aura.