A placebo-controlled, double-blind, cross-over trial of flunarizine incommon migraine

Per Soelberg Sørensen, Klaus Hansen, Jes Olesen

CEPHALALGIA

Sørensen PS, Hansen K, Olesen J. A placebo-controlled, double-blind, cross-over trial of flunarizine incommon migraine. Cephalalgia 1986;6:7-14. Oslo. ISSN 0333-1024

After four weeks of medication-free baseline observation, 29 patients with common migraine randomlyreceived flunarizine (10 mg daily) or placebo for a 16-week period. After four weeks wash-out they crossedtreatments for another 16 weeks; 27 patients completed the trial. Compared with placebo, flunarizinesignificantly reduced the frequency of migraine attacks and the derived headache indices, but the durationand severity of single attacks remained unchanged (Mann-Whitney U-test). The effect of flunarizineincreased during the 16-week treatment period and during the last four weeks the number of migraineattacks was reduced to 50% compared to the wash-out period. The only side-effect of flunarizine was milddaytime sedation in three patients. It is concluded that flunarizine is a valuable new prophylactic agent forcommon migraine. • Calcium blockers, controlled trials, interval headache, pain, prophylactic treatment,time-effect

Per Soelberg Sørensen, Klaus Hansen, Jes Olesen, Department of Neurology, Rigshospitalet andDepartment of Neurology, Gentofte University Hospital, Copenhagen, Denmark; Correspondence to: PerSoelberg Sørensen, Department of Neurology, Rigshospitalet, 2100 Copenhagen, Denmark; Received 26December 1984, accepted 3 July 1985

Although a great number of drugs from different pharmacological classes have been used in the prophylactictreatment of migraine, only a limited number have been found effective in double-blind trials (1). The searchfor the ideal drug for migraine prophylaxis, i.e. a drug that is highly effective in reducing migraine attacks anddevoid of side-effects, has not yet been successfully concluded.

Flunarizine, a difluorinated piperazine derivate, is a long-acting calcium-channel blocker. Thepharmacological properties of flunarizine and the theoretical considerations underlying its application inmigraine prophylaxis have recently been reviewed (2). A number of studies have suggested a beneficialeffect of flunarizine in migraine patients (3-6). Methodological objections such as lack of a placebo controlgroup and small number of patients may, however, be raised against the design of some of these trials.

The purpose of the present study was to evaluate the prophylactic effect of flunarizine 10 mg daily inmigraine patients. As recent studies have indicated pathophysiological differences between classic andcommon migraine (7-9), only patients with common migraine were included in the trial. The study design andstatistical evaluation of the results were made in accordance with the methodological aspects of prophylacticdrug trials in migraine previously discussed by Olesen et al. (10).

Patients and methods

Eligible for admission to the study were patients between the ages of 18 and 65 years with common migrainedefined according to the criteria given by the Ad Hoc Committee on the Classification of Headache (11)modified by Olesen et al. (10). Other criteria for inclusion were a history of migraine of at least one year'sduration and a frequency of attacks between two and six per month. The basis population consisted ofpatients treated as out-patients at the Copenhagen Acute Headache Clinic, Rigshospitalet, Copenhagen.

Excluded were patients with classic migraine and other types of headache (weekly but not dailyoccurrence of interval

headache was accepted); also excluded were patients suffering from renal or hepatic dysfunction, heartdisease, arterial hypertension, glaucoma, psychiatric disorders, or other brain diseases. Fertile women, whodid not use a medically accepted method of contraception, pregnant women and nursing women were notadmitted to the study. Furthermore, we excluded patients who used beta-blockers, psychotropic drugs andother drugs used in the prophylaxis of migraine, and patients taking more than 20 mg ergot-amine a month ormorphinomimetic drugs for treatment of attacks.

The study design was a double-blind, randomized, placebo-controlled, cross-over trial (Fig. 1). Thepatients were informed of the inclusion of placebo in the study but did not receive information about thenumber and duration of treatment periods. Blindness of doctors and patients was maintained throughout thestudy period. All patients gave their informed consent before entering the study and the trial was approved bythe local Ethics Committee.

Before entering the trial, each patient was given a complete physical and neurological examination; alaboratory examination was also carried out. Each patient kept a headache diary during the trial (described indetail previously (10)), which records the number, intensity and duration of migraine attacks, together with thepresence of nausea and vomiting, and allows to a certain extent a separation of migraine attacks frominterval headaches. The severity of headache is graded from 1 to 3: Grade 1, working capacity not affected;grade 2, inability to work; grade 3, bed rest required. The amounts of drugs taken to relieve the headacheswere monitored, too.

Follow-up visits which took place every four weeks included an interview, checking of the headache diary,counting of left-over medicine as a check on compliance, and questioning about any adverse effect of thedrug. Each patient was seen by the same neurologist throughout the trial.

Efficacy was assessed by comparing flunarizine and placebo treatment periods with regard to number,severity and duration of migraine attacks per four-week period. The number of days with interval headacheand the drug consumption expressed in analgesics units corresponding to 500 mg acetyl-salicylic acid or onedose of an ergot compound (10) were also evaluated. Further, the migraine index, i.e. the product of attackduration in hours times severity, was evaluated. As a slow onset of flunarizine effect was expected a priori (3),it was decided during the planning of the trial to leave out the first four-week period in each treatment period,and to evaluate the data with special reference to the last four weeks of each treatment period.

The efficacy of randomization to the two different treatment sequences was evaluated by comparing thetwo groups of patients regarding the variables given in Table 1 (Chi-square test or Mann-Whitney U-test). Thestatistical analysis of the two-period cross-over trial was performed using parametric and non-parametricmethods. The parametric tests were based on analysis of variance as previously described (10). The non-

parametric methods were based on the Mann-Whitney U-test (two-tailed). The analysis evaluates residual(or: carry-over) effect (e), periodical (or: order, or: time) effect (g), and treatment (or: direct) effect (b). Theprinciples of the method are described in detail by Koch (12). In short, the two treatment sequences(sequence 1: flunarizine (F1) - placebo (P2) and sequence 2: Placebo (P1) - flunarizine (F2)) are comparedwith respect to:

1. Residual effect (e): (F1 + P2) is compared with (P1 + F2). These sums should be similar: if they are not,there is a residual effect and the assumption underlying the statistical calculation of treatment effect mighthave been violated.

2. Periodical effect (g): (F1 - P2) is compared with (F2 - P1). A significant difference indicates a periodicaleffect; it is essential in such cases that the number of patients in each treatment sequence is balanced.

3. Treatment effect (b): In the absence of a residual effect the treatment effect can be assessed bycomparing (F1 - P2) with (P1 - F2).

Results

Admissions

The study included 6 men and 23 women, median age 40 years, range 19-63 years. Nineteen patients had afamily history of migraine. Median duration of migraine illness was 17 years, range 2-30 years. Medianfrequency of migraine attacks per four weeks during the last year was three. Twenty of the patients hadattacks lasting less than 12 h, six between 12 h and 24 h, and three of more than 24 h. All patients had aheadache intensity incompatible with normal work and 20 were forced to stay in bed during the attacks.Twenty-seven had nausea and/or vomiting accompanying the attack and 26 photo- and phonophobia; 27usually had unilateral pain localization; 13 pulsating and 16 pressing pain quality. Ten reported provocativefactors: most frequently menses or stress. Oral contraceptives were used by seven women. Intervalheadaches were present weekly in eight patients, monthly in seven and less than monthly or never in 14. Onepatient did not take medicine for acute treatment of headache attacks, while eight patients used commonanalgesics, six ergot compounds and 14 a combination of common analgesics, ergot compounds and/ortranquilizers. Nineteen patients had tried preventive treatment for migraine before, but only two successfully.Three patients had participated in one clinical trial of migraine prophylaxis previously.

Baseline comparability of treatment groups

Randomization assigned 14 patients to the treatment sequence flunarizine-placebo and 15 patients to thesequence placebo-flunarizine. No significant clinical differences were found between the groups (Table 1).

Side-effects and withdrawals

The only side-effect reported was mild day-time sedation. This adverse effect was experienced by threepatients on flunarizine treatment and by one patient on placebo. Two patients discontinued the trial: Onewithdrew on placebo owing to increasing number of migraine attacks and one patient withdrew on flunarizinebecause of day-time sedation.

Efficacy of treatment

The effect of flunarizine on frequency, duration and severity of migraine attacks, on interval headache and ondrug consumption appears from Table 2 and Fig. 2. Flunarizine significantly decreased the number ofmigraine attacks. During baseline/wash-out period, the median number of migraine attacks per four weekswas 3.5, during placebo treatment 3.2 and on flunarizine 2.0. The total number of hours with migraine andheadache indices were also reduced, whereas the duration of the single attack, the severity of headacheattacks and number of interval headaches remained unchanged.

The cross-over analysis revealed that no residual (or carry-over) effect was present,

and hence the calculation of thetreatment effect of flunarizine v. placebo is valid. The statistical analysis also disclosed a significant periodicaleffect (or time-effect/order-effect) for several of the chosen efficacy parameters; this appears clearly from theevolution of the parameters shown in Fig. 2.

The reduction of migraine attack frequency during treatment with flunarizine was correlated to thepre-treatment frequency. In patients with less than four attacks per four weeks before treatment, thereduction in attacks was only 10%, whereas patients with four or more attacks had a reduction of attacks by44%. During placebo treatment such correlation was not observed. In order to eliminate the effect of thisrelationship, at least to some degree, the results were analysed using percentage changes in the parameters(Table 3). This theoretically more correct method showed that flunarizine was significantly better thanplacebo with regard to number of migraine attacks, hours with migraine, migraine index and reduction ofsymptomatic drug consumption.

The effect of flunarizine increased during the four times four-week treatment period. During the last fourweeks on flunarizine, migraine attack frequency, hours with migraine, and migraine index were reduced by50% or more. Comparison of the last four-week flunarizine treatment period with

Table 3. Percentage reduction in efficacy parameters during flunarizine and placebo treatment.Wash-out period = 100%. Median values of 2nd, 3rd and 4th four-week periods are given, along withthe results of the 4th (and last) four-week period alone (in parentheses).

Flunarizine - wash-outv.

placebo - wash-out (p value*)Flunarizine Placebo

v. v. Periodic Residual Treatmentwash-out wash-out effect (g) effect (e) effect (b)

Number of 39 (50) -1 (15) 0.08 (NS) NS (NS) 0.001 (0.002)migraine attacksHours with migraine 35 (56) 3 (20) 0.02 (0.07) NS (NS) 0.02 (0.007)Severity of 7 (6) 1 (-5) NS (NS) NS (NS) NS (NS)migraine attacks†Migraine index† 36 (56) 6 (13) 0.01 (0.03) NS (NS) 0.01 (0.008)Drug consumption† 37 (49) 10 (10) NS (NS) NS (NS) 0.03 (0.02)

*Mann-Whitney U-test (two-tailed).†See text.NS: No significance.

the last four weeks of placebo treatment is given in Table 3.

Discussion

Methodological considerations

A significant periodical/time-effect has been demonstrated in the present and in previous studies of migraineprophylaxis (10, 13). The periodical effect might be due to medical attention or prolonged placebo action(10). In the present study, however, the periodical effect only seems to be present for about the first fourmonths of the trial. The existence of a periodical/time-effect emphasizes the importance of including placebocontrol in a trial instead of comparing two active drugs. Because of lack of statistical power and presence of asignificant time-effect, the misleading conclusion in trials comparing two drugs will often be that both drugsdecreased migraine attacks when compared to the baseline period, and that the two drugs were thereforeequally effective.

No effect on the occurrence of interval headache could be demonstrated during flunarizine treatment,possibly because only little interval headache was reported by the patients. Hence, the present study doesnot help in clarifying whether interval headache and common migraine respond in a similar way toprophylactic treatment.

In one of our previous studies where both treatments were inactive (10), reduction of migraine parameterswas independent of the severity of migraine. The present trial, where an active drug was employed, revealedgreater effect in patients with high attack frequency. Therefore per cent reduction of migraine parametersshould be preferred over absolute values in the statistical calculations. In addition we also calculatedsignificance for a number of parameters using analysis of variance and absolute values. This was in order tocompare the statistical power of different parameters. It appeared that the power was largely equal fornumber of migraine attacks, migraine index, severity of migraine and hours with migraine. Flunarizine,however, seemed to affect only number of migraine attacks, not severity of attacks. The significant effect onmigraine indices and hours with migraine could largely be ascribed to the reduction in number of attacks,average duration of attacks remaining unaltered. Drug consumption was reduced by flunarizine, but seems tobe a relatively insensitive parameter. Since the distribution of data was not normal, nonparametric statisticswere preferred; these gave more significant results.

Previous studies and present results

The results of the present study demonstrate that flunarizine is an effective prophylactic drug in commonmigraine. Flunarizine reduces the frequency of migraine attacks significantly, whereas severity and durationof single attacks are not significantly influenced. These findings are in accordance with the observation madein another placebo-controlled study of flunarizine in migraine prophylaxis (3). However, in two other studies,which did not include a placebo control group, flunarizine was reported to reduce both frequency and severityof headache attacks (4, 6). Previous studies have included both classic and common migraine, but thenumbers of patients with classic migraine were too small for separate statistical evaluation (3-6). In thepresent study of common migraine, flunarizine reduced the number of migraine attacks by 39%, which is anefficacy similar to that reported from treatment with well established prophylactic drugs like beta-adrenergicblockers (14, 15) and pizotifen (16, 17). This is remarkably good since the patient material in the presentstudy, owing to recruitment procedures, represents the rather heavily afflicted part of the spectrum ofmigraine sufferers with a long history of severe migraine attacks and often previous unsuccessful preventivetreatment.

The onset of effect of flunarizine seems to be very slow, the maximum effect being attained only afterthree months of treatment. This may partly be due to the pharmacokinetics of flunarizine. During chronicadministration of flunarizine, 5-30 mg daily in healthy volunteers, the plasma concentration graduallyincreased, reaching steady-state 5-6 weeks after the start of treatment (18). The mean plasma elimination

half-life was about 18 days (18). Because of the very long elimination half-life of the drug, it was decided to use a relativelylong placebo wash-out period of four weeks and to disregard the first four weeks in each treatment period when calculatingthe treatment effect.

Furthermore, it must be emphasized that no statistically significant carry-over effect was found in the present study and anysuch effect would be in disfavour of flunarizine treatment effect.

It is not yet known by which mechanism flunarizine exerts its prophylactic effect in common migraine. Flunarizine hasstrong anti-vasoconstrictive properties. The drug selectively inhibits vasoconstriction by decreasing the cell membranepermeability for calcium ions in the vascular smooth muscle cells without modifying the inherent myogenic activity, and,therefore, without interfering with physiological autoregulation processes (19). Reduced cerebral blood flow (7, 8, 20) hasbeen implicated in the pathophysiology of classic migraine, but is less likely to play a role in common migraine (9). Flunarizineinhibits activation of platelets induced by calcium ions and possesses classic antihistaminic effects as a pure histamineH1-receptor antagonist (19). However, none of these effects satisfactorily explain the mode of action in common migraineprophylaxis.

The only side-effect of flunarizine reported by a few patients in the present study was mild day-time sedation. This is inaccordance with the experiences in previous trials (3, 4). Weight gain has been reported in a single study (6) but did not occurin the present study. Owing to the negligible side-effects of flunarizine, blindness was preserved during the entire cross-overtrial.

It is concluded that flunarizine is a valuable new drug for common migraine prophylaxis with few and mild side-effects.

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