Original Articles

Flunarizine Versus Metoprolol in Migraine Prophylaxis: A Double-Blind, Randomized Parallel Group Study of Efficacy and Tolerability

P. Soelberg Sørensen, M.D., Ph.D.,1 B.H. Larsen, M.D.,1 M.J.K. Rasmussen, M.D.,2 E. Kinge, M.D.,2 H. Iversen, M.D.,3 T. Alslev, M.D.,4 P. Nøhr, M.D.,5 K.K. Pedersen, M.D.,5 P. Schrøder, M.D.,6 A. Lademann, M.D., Ph.D.6 and J. Olesen, M.D., Ph.D.3 1Department 2Department

of Neurology, Rigshospitalet, Copenhagen, Denmark.

of Neurology, Sønderborg Sygehus, Sønderborg, Denmark.

3Department

of Neurology, Gentofte Hospital, Copenhagen, Denmark.

4Department

of Neurology, Esbjerg Sygehus, Esbjerg, Denmark.

5Department

of Neurology, Hjørring Sygehus, Hjørring, Denmark.

6Department

of Neurology, Aalborg Sygehus, Aalborg, Denmark.

Reprint requests to: Per Soelberg Sørensen, M.D., Ph.D., University Department of Neurology, Rigshospitalet, DK-2100 Copenhagen, Denmark. Accepted for Publication: September 10, 1991. SYNOPSIS

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. Key words: flunarizine, metoprolol, migraine prophylaxis, side effects. (Headache 31:650-657, 1991) INTRODUCTION

Calcium-antagonists were introduced for the prophylactic treatment of migraine on the theoretical basis of being protective against cerebral vasoconstriction and brain hypoxia.1 Flunarizine has been the most extensively studied in migraine prophylaxis: four double-blind studies have been published in which the prophylactic effect of flunarizine has been compared to that of placebo. Three studies used parallel comparison2-4 and one study employed the crossover design.5 In all 4 studies flunarizine was convincingly superior to placebo. Only a small number of studies with a limited number of patients have compared flunarizine with the currently used standard treatment in migraine prophylaxis: beta-blockers as propranolol6-8 and metoprolol,9 and 5-HT antagonists.10-12 In previous controlled trials of flunarizine side-effects seemed to be mild and infrequent but the studies have been too small to provide a reliable assessment of the frequency of adverse effects. The present study was undertaken in order to provide a large controlled trial comparing the efficacy and side-effects of flunarizine with one of the most commonly used beta-blockers, metoprolol, in migraine prophylaxis. PATIENTS AND METHODS

Patients. Patients suffering from migraine with or without aura, diagnosed according to the criteria of the Headache Classification Committee of the International Headache Society13 were eligible for admission to the study. Other criteria for inclusion were age between 18 and 65 years, a history of migraine of at least one year's duration, and a frequency of migraine attacks, defined as days with migraine, from 2 to 8 per month, based on the average of the last three months before admission. Excluded were patients with other types of headache, although occurrence of tension-type headache was accepted if the patient was able to distinguish these headaches from migraine, Further, we excluded patients with serious somatic diseases, hepatic or renal dysfunction, patients with diabetes mellitus, heart disease, hypertension, orthostatic hypotension, psychiatric disorders, glaucoma, or other diseases contra-indicating treatment with beta-blockers

or calcium-blockers. Fertile women who did not use a medically accepted method of contraception, pregnant or nursing women werenot admitted to the study. Furthermore, we excluded patients who daily required beta-blockers, ergot alkaloids, antidepressants, phenothiazines, NSAID-drugs, or any other drugs used in the prophylaxis of migraine. Patients who used more than 20 mg ergotamine per month or regularly took opioid drugs for treatment of migraine attacks were also excluded. Study Design. The study was a multicenter trial conducted in out-patients by 11 neurologists in 6 Departments of Neurology. The study design was a randomized double-blind parallel group comparison. Before randomization the patients were stratified according to: 1) type of migraine: migraine with aura or migraine without aura; 2) sex; 3) number of migraine days per month: 4 or less, or more than 4; and 4) age: matched with another patient ± 10 years of age. After stratification patients were randomized to treatment with either flunarizine or metoprolol (Fig. 1). During the first month (=4 weeks) all patients were treated with 2 placebo tablets (one tablet appearing identical to flunarizine and one tablet appearing identical to metoprolol tablets. After one month of placebo treatment group 1 was treated with one tablet of flunarizine 10 mg and one tablet of placebo appearing identical to metoprolol tablets. Group 2 was treated with one tablet of metoprolol 200 mg (slow-release formulation) and one placebo tablet appearing identical to flunarizine tablets. The tablets were to be taken in the evening for a period of 5 months. In order to disguise the trial design and achieve maximum blindness of doctors and patients, two patients were treated according to a cross-over trial design: after 4 weeks of placebo run-in one patient was treated with metoprolol for 2 months and after 1 month placebo wash-out flunarizine was given for 2 months. The other patient was treated according to the same design with the sequence flunarizine followed by metoprolol. These patients were not included in the statistical analysis. All patients were informed that the majority of the patients would be treated with one of the two active drugs and a small

number with both drugs. They were also informed that placebo treatment for 1 or 2 months would be included in the trial, but they were not informed about the time of placebo treatment. Symptomatic treatment of each migraine attack was allowed and had to be reported. Concomitant medicine given for other medical reasons than migraine was allowed for up to 1 month. All patients gave their informed consent before entering the study and the trial was approved by the local Committee on Ethics and the Danish National Board of Health and Welfare. Baseline Evaluations and Follow-up. Before entering the study each patient had a complete physical and neurological examination, an ECG was recorded and the blood pressure, orthostatic blood pressure, and body weight were measured. Laboratory examinations included Hb, white cell count, platelet count, plasma creatinine, electrolytes, coagulation status, alanine-amino-transaminase, phosphatase, thyroxine, and triiodothyronine. During the trial, each patient kept a headache diary which recorded the number, intensity and duration of migraine attacks, the presence of nausea and vomiting, the occurrence of interval headaches (tension-type headache), and the amount of drugs taken to relieve headache attacks. Follow-up visits took place every month and included an interview, check of the headache diary, counting of left-over medicine as a check of compliance, and questioning about any adverse effect of the drug. Blood pressure and pulse rate were not measured by the investigator unless the patient reported side effects indicating a fall in blood pressure or bradycardia. Body weight was not measured until the end of the study. Each patient was seen by the same neurologist throughout the trial. Evaluation of Effect. The main efficacy parameter was the attack frequency defined as days with migraine per month. Other parameters recorded for assessment of the therapeutic effect were attack duration (if a patient want to sleep with migraine and woke up with migraine on the following morning the attack on the first day was recorded from start of the attack to midnight and the attack on the second day from midnight to cessation); attack severity as judged by the patient on a scale from I to 3; the presence or absence of nausea or vomiting; the number of days with tension-type headache; and the overall assessment of treatment. The assessment of efficacy included both an explanatory analysis of patients who had completed all 5 months of active treatment, and an intention-to-treat analysis of all patients who had accomplished one month of active treatment. The effect of flunarizine is slow in onset, due to its pharmacokinetics, and, therefore, it was decided to leave out the first month of active treatment from the main efficacy analysis.

Patients who discontinued the treatment prematurely because of insufficient effect or because of side effects were included in the adverse experience analysis. Drop-outs during the run-in period were excluded from the analysis and replaced. Statistical Methods. A sample size of 75 patients in each group was assessed to provide an 80% power of detecting of treatment difference of 25% in reduction of attack frequency at p = 0.05.14,15 This calculation was based on pooled data from earlier clinical trials with flunarizine and metoprolol. Non-parametric statistical tests were used in the analysis of ordinal and continuous variables, changes and percentage changes within groups were tested with the Wilcoxon matched pair signed ranks test and differences between groups with the Mann-Whitney U-test. In the nominal analysis, Fishers exact probability test was used for 2 x 2-contingency tables, and the Chi-square test for N x K-tables. RESULTS

Admissions and Patient Characteristics. A total of 149 patients were randomized to treatment with flunarizine (74 patients) or metoprolol (75 patients). They were 31 men and 118 women aged 20 to 64 years, median age 42 years. Thirty-nine patients had migraine with aura (classical migraine) and 110 migraine without aura (common migraine). The median duration of migraine illness was 18 years, range 1 to 50 years. The median frequency of migraine attacks during the last 3 months before admission was 4.3 per month. A family history of migraine was reported by 109 (73%) of the patients. Regarding the pain quality and accompanying symptoms of the migraine attacks 135 (90%) had unilateral pain localization; 111 (75%) had pulsating pain; 137 (92%) had phono- and photophobia; and 136 (91%) had nausea and/or vomiting accompanying the attack. One hundred and eleven (74%) reported provocative factors; most frequently alcoholic beverages, different kinds of food, stress, and menstruation. Oral contraceptives or estrogens were used by 28 (24%) of the women. Interval headaches were present several days per week in 24 patients (16%), weekly in 56 (38%), monthly in 20 (13%), and less than monthly or never in 49 (33%) of the patients. A total of 81 (64%) of the patients had tried prophylactic treatment for migraine before; 56 patients (38%) had tried one drug, 14 (9%) two drugs, and 11 (7%) three or four drugs for prevention of migraine attacks. The most commonly used drugs were beta-blockers (60 patients), ergot alkaloids (28 patients), pizotifen (15 patients), antidepressants (8 patients), and phenothiazines (8 patients). No difference in patient characteristics were found between the two treatment groups (Table 1). Adverse Experiences and Withdrawals. One hundred and forty-seven patients were included in the analysis of adverse experiences while 2 patients left the study so early that no data were collected (Fig 1). The 10 most frequently reported adverse experiences are listed in Table 2. The majority of side Table 1 Characteristics of the patients by treatment group. Total Flunarizine Metoprolol population

Group difference

Number of patients

74

75

149

N.S.

Sex+ Males Females

16 (22%) 58 (78%)

15 (20%) 60 (80%)

31 (21%) 118 (79%)

N.S.

Age; median (range) (yrs)

42 (20-64)

42 (20-63)

42 (20-64)

N.S.

Type of migraine+ With aura (classical) Without aura (common)

17 (23%) 57 (77%)

22 (29%) 53 (71%)

39 (26%) 110 (74%)

N.S.

Duration of migraine disease Median (range) (yrs)

15 (2-50)

18 (1-50)

17 (1-50)

N.S.

Days with migraine per month+ 2-4 5-8

37 (50%) 37 (50%)

39 (52%) 36 (48%)

76 (51%) 73 (49%)

N.S.

Family history of migraine+

48 (65%)

61 (81%)

109 (73%)

N.S.

Provocative factors+

53 (72%)

58 (77%)

111 (74%)

N.S.

38 (51%) 14 (19%) 26 (35%) 4 ( 5%) 6 ( 8%) 4 ( 5%)

43 (57%) 14 (19%) 34 (45%) 4 ( 5%) 9 (12%) 4 ( 5%)

81 (54%) 28 (19%) 60 (40%) 8 ( 5%) 15 (10%) 8 ( 5%)

N.S.

Previous prophylactive treatment+ Ergot alkaloids Betablockers Antidepressants Pizotifen Phenothiazines + No. of patients (%)

Table 2 Adverse effects during study period by treatment group. Metoprolol (N = 75)

Flunarizine (N = 72)

Run Month Month Month -in 1 2 3

Month Month 4 5

Anytime No.% (95%)cf. L)

Run Month Month -in 1 2

Month Month Month Anytime 3 4 5 No.%

Drowsiness/ sedation

4

13

12

14

12

8

26 36%

(25-48 %)

8

12

10

7

7

5

21

28%

(18-40%)

Weight gain

1

6

11

9

9

12

23 32%

(21-44 %)

0

2

1

2

4

6

9

12%

( 6-22%)

Gastrointestinal symptoms

2

2

1

2

1

1

5 7%

( 2-15%)

1

3

5

2

1

1

10

13%

( 7-23%)

Sleep disturbances/ vivid dreams

0

2

3

2

2

1

4 6%

( 2-14%)

1

4

4

4

3

3

10

13%

( 7-23%)

Muscle fatiguability/ cold paresthesia

0

1

1

1

0

0

3 4%

( 1-12%)

1

2

1

4

4

4

10

13%

( 7-23%)

Depression

0

0

0

2

2

2

6 8%

( 3-17%)

0

1

2

0

0

0

2

3%

( 0- 9%)

Dizziness/ vertigo

0

1

0

0

0

0

1 1%

( 08%)

3

3

0

1

0

0

4

5%

( 1-13%)

Cardiovascular symptoms/ hypotension

2

1

0

0

0

0

2 3%

( 0-10%)

0

0

0

1

1

0

1

1%

( 0- 7%)

Extrapyramidal symptoms

2

1

0

0

0

0

2 3%

( 0-10%)

0

0

0

1

1

0

1

1%

( 0- 7%)

Respiratory system symptoms 0

0

0

0

0

0

0 0%

( 0- 5%)

0

0

1

0

0

0

1

1%

( 0- 7%)

(95%cf.L.)

cf.L. = confidence limits effects were mild and transient and some of them were reported with the same frequency during the run-in period and the period of active treatment. The most common side-effect was drowsiness or sedation reported in 36% of patients treated with flunarizine and 28% of patients treated with metoprolol. Weight gain was a major complaint in patients treated with flunarizine of whom 32% reported weight gain as a problem compared with 12% of the patients treated with metoprolol. The mean increase in weight from start to completion of the study after five months was 1.9 kg ± 0.4 in patients treated with flunarizine and 1.4 kg ± 0.3 in patients treated with metoprolol. Gastrointestinal symptoms, sleep disturbances, vivid dreams, muscle fatiguability, and cold paresthesia were more frequently reported by patients taking metoprolol than by patients treated with flunarizine. Development of depression was the most serious side-effect which occurred in 6 patients (8%) treated with flunarizine and 2 patients (3%) treated with metoprolol. The depression in patients treated with flunarizine appeared during the third to fifth month of treatment. None of the patients had a history of previous depression, but one of the patients had a family history of severe depression. Three of the depressions were characterized as mild and required no treatment with antidepressant medicine and no sick leave. These depressions resolved within one month after discontinuation of flunarizine. In 3 patients the depression was major according to the diagnostic criteria of Diagnostic and Statistic Manual of Mental Disorders (DSM-III), lasted from 2 to 5 months and required antidepressant medicine and sick leave from I to 21/2 months. The depressions during treatment with metoprolol occurred during the first and second month of treatment and were both mild requiring no medicine or sick leave. As it can be seen from the 95% confidence intervals for various adverse experiences, no significant differences in frequency for any of the reported side effects could be detected between patients treated with flunarizine and patients treated with metoprolol. Twenty-two patients (15%) discontinued treatment before the end of the trial: 16 patients on flunarizine (22%) and 6 patients on metoprolol (9%). The reasons for premature discontinuation of study medicine are shown in Table 3. Ten patients treated Table 3 Reasons for premature discontinuation of study medicine. Flunarizine Metoprolol Adverse effects 10 1 Incompliance/lack of motivation 3 2 Died from accident 1 Inefficacy of medicine 2 2 Protocol violation 1 Total 16 6

with flunarizine discontinued treatment because of adverse experiences (depression: 4, weight gain: 4, drowsiness/sedation: 1, unknown: 1). One patient on metoprolol discontinued the treatment because of depression. Efficacy of Treatment. Both drugs significantly reduced the number of migraine days per month compared with the placebo run-in period. The reduction was significant already during the first month of treatment (p

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 ...
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