Low Dose Flunarizine in the Prophylaxis of Migraine

P. Bassi, L. Brunati B. Rapuzzi, E. Alberti A. Mangoni

Department of Neurology, University of Milan, Luigl Sacco Hospital, Milan, Italy. Reprint requests to: Dr. Pietro Bassi, Clinica Neurologica, Ospedale Luigi Sacco, Via G.B. Grassi 74, 1-20157 Milan, Italy. Accepted for publication May 6, 1992 SYNOPSIS

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 10 mg 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. Key words: Migraine, flunarizine, side effects. Abbreviations: HI migraine index (Headache 1992; 32:390-392) INTRODUCTION

Migraine is one of the most prevalent disorders, affecting approximately 15% of adults of working age,1 and it is one of the most frequent causes for seeking medical attention, absence from work and use of medication. Migraine is a chronic disease, usually persisting for a lifetime. One of the most efficacious prophylactic treatments is flunarizine, a calcium antagonist. Flunarizine is a piperazine difluoridate derivative that is not selective for slow calcium channels.2-3 The efficacy of Ca++ antagonists, particularly of flunarizine, in the prophylaxis of migraine is well documented; flunarizine is usually prescribed at a dosage of 5-10 mg per day as a single evening dosage.4-9 It is considered particularly effective in long term therapy4 and in young subjects.4-6 Both the efficacy and the side effects of flunarizine have been studied comparatively for the 5 and 10 mg dosages, and it has been noted that while the efficacy is similar, the side effects are reduced with the lower dosage.7 Flunarizine, following oral administration, shows a rise in plasma concentration, reaching the steady state in five weeks;3 it is then distributed in the various tissues, including adipose tissue which acts as a deposit for subsequent gradual release.3 Flunarizine is not free of side effects; the most serious being the extrapyramidal (parkinsonism, akathesia, tardive dyskinesia) and depressive syndromes, especially after long term treatment10-14 when they are not always reversible after stopping the therapy.11-14 Other less important but poorly tolerated side effects, are sleepiness and weight gain, which sometimes cause patients to interrupt the therapy.5 The aim of our study was to evaluate the efficacy and the side effects of flunarizine administered chronically at 3 mg per day, and to compare these results with those obtained using the usual dosage of 10 mg per day. MATERIAL AND METHODS

In a period of one year we selected 40 consecutive patients from those seen at the "Headache Dispensary of the Luigi Sacco Hospital". The subjects comprised 33 females and 7 males with an average age of 30 years (range 18-50 years); 37 suffered from migraine without aura and 3 from migraine with aura. The patients had suffered from migraine from an average of 140 months (range 2-35 years) and reported an average of 6.8 (range 2-18) attacks per month. (Table 1). Table 1 Distribution of patients by sex, age and diagnosis Flunarizine 3 mg Flurarizine 10 mg Men 4 (20%) 3 (15%) Women 16 (80%) 17 (85%) Age (years) media 29.6 (±8.19) 31.5 (±9.11) Migraine without aura 17 (85%) 20 (100%) Migraine with aura 3 (15%) 0 (0%) Duration of the disease median (months) 141 (±113.03) 138.7 (±112.92) Number of attacks (1 month) median 7.65 (±5.967) 6.05 (±3.236)

The criteria for inclusion were the following: • Patients suffering from migraine with or without aura classified according to the criteria proposed by the IHS committee on classification of headache;15 • Clinical history of at least two years; • Monthly attack frequency of two or more; • Absence of prophylactic therapy during the 3 months preceding the study;

• Age between 18 and 50 years; • Absence of associated pathology with particular attention to: hypertension, diabetes mellitus, hepatic and renal failure, circulatory ischemic diseases; • Absence of depression (Hamilton Rating Scale Score below 22); •Regular life and working habits. Within an open randomized study there were two groups, each of 20 patients; to the first group flunarizine was administered orally at the dosage of 10 mg per day, while the second was treated with an oral dosage of flunarizine of 3 mg per day. In consideration of the substance's kinetic characteristics,3 during the first week both groups were given flunarizine at a dosage of 10 mg per day. The overall duration of the study was 18 months; each patient was followed for 5 months; during the first month no prophylactic therapy was administered and the patients continued with their usual symptomatic therapy. Each patient completed the headache diary form during the run-in period (first month) and during the subsequent 4 months of therapy; the forms contained information on the number of attacks per month, their duration in hours, their intensity, the use of analgesic drugs and presence of side effects; the latter were taken in to consideration if they were present for more than three days. The Migraine Index (HI) was then calculated by multiplying the number of hours of headache per month with the intensity of the pain for both groups at the end of each of the four months of therapy. The Headache's subjective intensity was classified as follows: 0 = Absence of pain; 1 = Slight pain without need of analgesic drugs; 2 = Pain of medium intensity regressing with analgesic drugs; 3 = Strong pain with partial incapacity even after administration of analgesic drugs. RESULTS

Of the 40 randomized patients, 11 (27.5%) were not considered in the results; 9 for poor compliance and two who discontinued treatment before the end of the fifth month because of side effects (1 patient in each group). Of the 29 patients who completed the study, 15 were treated with flunarizine at a dosage of 10 mg per day and 14 with 3 mg per day. The average HI Scores are shown in Table 2. Applying the Student T-test, it can be seen that both groups showed a statistically significant reduction of the migraine index from the first to the fourth month (as shown in Table 3). In Figure 1, the linear repression of the reduction of the migraine indices for the two different Table 2 HI value in the two groups of patients High dose patients HI basal median: 147,7

2 month 113,9

3 month 95,2

4 month 67

5 month 43,7

Low dose patients HI basal median: 239,3

2 month 97,2

3 month 100,3

4 month 62

5 month 44,1

Table 3 Median, Standard error and significance of the HI in the two treated groups HI in the group treated with 3 mg of flunarizine 1st month 2nd month 3rd month 4th month MEDIAN -33.73 -66.87 -80.87 -103.93 Standard Error 18.48 28.64 31.48 30.09 Number 15.00 15.00 15.00 15.00 Max. 46.00 57.00 41.00 56.00 Min. -214.00 -346.00 -368.00 -385.00 t-test -1.82562 -2.33480 -2.56242 -3.4544450 NS P

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 firs...
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