Flunarizine (10 and 20 mg) i.v. versus placebo in the treatment of acute migraine attacks: a multi-centre double-blind study

Volker Pfaffenrath, Wolfgang Oestreich, Wolfgang Haase

CEPHALALGIA Pfaffenrath V, Oestreich W, Haase W. Flunarizine (10 and 20 mg) i.v. versus placebo in the treatment of acute migraine attacks: a multi-centre double-blind study. Cephalalgia 1990;10:77-81. ISSN 0333-1024 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. • Acute migraine attacks, drug trial, flunarizine i.v., placebo Volker Pfaffenrath, Neurologist, Leopoldstr. 59/11, 8000 München 40, West Germany; Wolf-gang Oestreich, Medical-Development-Department, Janssen GmbH, Raiffeisenstr. 8, 4040 Neuss 21, West Germany; Wolfgang Haase, Institut für numerische Statistik, Ottostr. 1, 5000 Köln 40, West Germany; Correspondence to Dr. med. V. Pfaffenrath, Leopoldstr. 59/1I, 8000 München 40, West Germany; Accepted 12 December 1989 The efficacy of flunarizine in the prophylaxis of migraine has been confirmed by numerous controlled clinical trials. Quite recently Soyka et al. (1) found 20 mg flunarizine i.v. to be significantly effective in the treatment of acute migraine attacks compared to placebo. According to promising preliminary data (2) on its pharmacokinetics we tried to confirm the effect and tolerance of different dosages of flunarizine i.v. on migraine attacks with and/or without aura in a double-blind placebo controlled multi-centre trial. Methods

The study included 102 patients from seven West German Headache Centres. All patients had suffered from migraine for at least one year, with and/or without aura (3) and had an attack frequency ranging from 1 to 6 per month. The attack duration had to be between 4 and 72 h, the intensity of the pain limiting or prohibiting the capacity to work. Patients with ergotamine and/or analgesic abuse, regular users of psychotropic medications, those with psychiatric disorders, diabetes mellitus, disturbed orthostatic regulation, severe hepatic or renal dysfunction, other severe general diseases as well as pregnant and breast-feeding mothers or women of childbearing age without adequate contraception were excluded from the study. During the two months prior to the start of the trial, flunarizine was not allowed as a migraine prophylaxis; for other migraine prophylactics there were no limitations; this also applied to the use of pain-killers up to the time of the injection of the test substance, with the medication having to be documented regarding the type of substance, dosage and time of application. The headache history was recorded by means of a standardized questionnaire; informed consent of the patients was made according to the "Declaration of Helsinki". Migraine symptoms were recorded prior to the injection. The patients had to be in the phase of the acute attack, where no improvement had occurred in the intensity

of pain and the accompanying symptoms since the attack had started. Subsequently, the patients received 10 or 20 mg flunarizine or placebo (HP-beta-cydodextrine) intravenously. Placebo and treatment were similar in appearance. After injection of the drug the patients recorded the intensity of their pain at 5 min intervals on a visual analogue scale for at least 60 min. Accompanying symptoms were evaluated with respect to severity from 0 (no symptoms) to 3 (severe symptoms), prior to injection and after 60 and 120 min. Efficacy and tolerance of the drug were subject to an overall assessment of the attending physician. Blood pressure and pulse rate were measured prior to and again 5, 10, 30, 60 and 120 min after injection. Side effects were queried directly. Main response criterion was a minimum of 50% reduction of pain intensity on a visual analogue scale. The differences between the treatment groups were tested for significance using Fisher's exact 2 x 2 test with one-sided questions. The experiment related level of significance was set at a = 0.05 and was adjusted in line with the number of comparisons made according to Bonferroni (a = 0.025 equivalent to two comparisons). The efficacy of treatment was also evaluated regarding partial or complete attack interruption on the basis of the assessment by the physician using Fisher's exact test. In addition, descriptive methods were applied exclusively. Results

One hundred and three observations were available for assessment. One patient refused injection and was excluded from statistical evaluation. The inference statistical comparison of the groups treated was carried out on the basis of all available patient follow-ups (intent-to-treat assessment). The data of the intent-to-treat group compared with those of the patients who complied with the inclusion and exclusion criteria revealed no relevant differences. The characteristics of the 102 cases evaluated are given in Table 1. Thirty-three (32.4%) men and 69 (67.6%) women aged between 17 and 74 (X = 42) took part in the study. Details of the duration of the migraine disorder, the number of monthly attacks and the type of migraine at the time of the investigation are given in Table 1. Of the patients treated with 10 mg flunarizine 16.2 % were suffering from migraine with aura; the same was the case in 9.4% of the patients treated with 20 mg flunarizine and in 12.1% treated with placebo. The proportion of patients with severe attacks (incapacity to work) in the past was higher in the groups given active treatment (40.5% with 10 mg, 37.5% with 20 mg flunarizine) than in the placebo group (30.3%). In all three groups a one-sided pulsating headache dominated, which was worsened with head movement and changing of body posture. In 75.5% of patients severity of pain did not differ from those in the past. At the time of the trial, 15 patients (14.7%) were receiving a migraine prophylaxis, but none flunarizine. Prior to application of the trial substance, 24.3% (10 mg flunarizine), 18.8% (20 mg flunarizine) and 48.5% (placebo) of the patients treated had taken pain-killers, mainly analgesics. The period between the intake of the pain-killer and injection of the trial substance averaged 6 h in all three groups. The median values for the period between the beginning of the migraine attack and the application of the trial substance ranged (also centre specific) between 4.8 h (10 mg flunarizine), 4.1 h (20 mg flunarizine) and 3.7 h (placebo); however, there was only a slight mean difference between the three groups: with 10 mg flunarizine the average was 6.8 h, with 20 mg flunarizine 6.1 h and with placebo 6.5 h. The intensity of the headache on the visual analogue scale was 67 ± 20 in the group given active treatment, and 62 ± 23 in the placebo group, both at the beginning of the observation period. Sixty minutes after 20 mg flunarizine, the score was 33 ± 28 and 44 ± 33 in the placebo group. This equals a mean reduction in pain intensity of 50.7% in the active treatment group and 29% in the placebo group. A reduction in pain of at least 50% (see Table 2) was noted by 19 patients (59.4%) with 20 mg flunarizine and by 10 patients (30.3%)

Table 1. Characteristics of 102 cases. Flunarizine (10 mg)Flunarizine (20 mg) Placebo N = 37 N = 32 N = 33 Age (years) median 39 44 43 range 17-59 21-74 24-66 Sex male 11 (30%) 9 (28%) 13 (39%) female 26 (70%) 23 (72%) 20 (61%) Type of migraine* without aura with aura Duration (years) median range Frequency of monthly attacks median range * Type of migraine during the trial.

Total N = 102 41 17-74 33 (32%) 69 (68%)

33 (89%) 4 (11%)

27 (84%) 5 (16%)

28 (85%) 5 (15%)

88 (86%) 14 (14%)

15 2-44

20 1-37

l9 2-46

18.5 1-46

3 1-10

3 1-6

4 1-6

3 1 - 10

with placebo (see Table 2). This difference between active treatment and placebo was significant (p < 0.025). A summary of the assessment by the attending physician regarding the effect of 20 mg flunarizine compared with placebo is given in Table 3. Accordingly, complete attack interruption occurred in 12 patients (37.5%) on average 57± 28 min after the injection. In addition, 13 active treatment patients showed a partial attack interruption. All in all, a significant advantage for 20 mg flunarizine occurred (see Table 3). Table 4 shows that 60 min after injection, accompanying migraine symptoms in the active treatment group compared to placebo had either completely receded or had noticeably improved. The mean headache intensity on the visual analogue scale decreased with 10 mg flunarizine from 65 ± 23 to 47 ± 28 (mean reduction of 27.7%). A reduction of at least 50% was observed in nine patients (24.3%). There was no significant difference versus placebo (see Table 2). According to the physician's assessment the proportion of patients with complete attack interruption was lower under 10 mg flunarizine (10.8%) compared to placebo, while the proportion with partial interruption (48.6%) was higher Table 2. Intensity of pain (visual analogue scale) 60 min after injection of 10 and 20 mg flunarizine versus placebo, respectively. Flunarizine Flunarizine (10 mg) (20 mg) Placebo N = 37 N = 32 N = 33 abs. % abs. % abs. % At least 50% reduction of pain intensity 9 24.3 19 59.4 10 30.3 Less than 50% reduction of pain intensity 28 75.7 13 40.6 23 69.7 Flunarizine 20 mg versus placebo (p < 0.025). Flunarizine 10 mg versus placebo (p > 0.025).

Table 3. Overall assessment of the treatment success (physician's assessment). Flunarizine (10 mg) Flunarizine (20 mg) Placebo N = 37 N = 32 N = 33 Treatment success abs. % abs. % abs. % Complete 4 10.8 12 37.5 8 24.2 Partial 18 48.6 13 40.6 8 24.2 No 15 40.5 7 21.9 17 51.5 Flunarizine 20 mg versus placebo (p < 0.025). Flunarizine 10 mg versus placebo (p > 0.025). Table 4. Improvement of concomitant migraine symptoms (10 mg or 20 mg flunarizine versus placebo). Flunarizine (10 mg) Flunarizine (20 mg) Placebo Migraine Migraine symptoms CR * PR * * symptoms CR * PR * * Migraine CR * PR * * N (%) (%) Sickness 23 47.8 8.7 Nausea 17 52.9 5.9 Vomiting 6 83.3 0 Vertigo 13 46.2 7.7 Photophobia 17 58.8 11.8 Visual disturbance 6 50.0 0 Phonophobia 16 50.0 12.5 * CR = number of patients with complete remission. ** PR = number of patients with partial remission.

N 29 12 5 14 24 0 25

(%) 34.5 41.7 60.0 35.7 33.3 14.3 36.0

(%) 20.7 8.3 0 21.4 12.5 14.3 16.0

symptoms 22 14 2 14 18 6 16

(%) 31.8 21.4 0 28.6 38.9 50.0 37.5

(%) 18.2 7.1 0 14.3 11.1 0 0

Table 5. Centre specific results with 10 and 20 mg flunarizine versus placebo. At least 50% reduction in pain intensity/total number Pain intensity of patients No. of Still Flunarizine Flunarizine Centre patients Severe tolerable (10 mg) (20 mg) Placebo I 19 12 7 0/8 1/6 0/5 II 26 2 24 3/8 7/8 6/10 III 17 9 8 1/5 4/6 1/6 IV 15 8 7 1/6 0/4 0/5 V 18 4 14 2/6 6/6 2/6 VI 5 2 3 1/3 1/2 0/0 VII 2 0 2 1/1 0/0 1/1 Total 102 37 65 9/37 19/32 10/33 (see Table 3). With regard to migraine accompanying symptoms, the effect of 10 mg flunarizine was not significantly better than placebo (see Table 4). The treatment results obtained by the seven centres differed greatly (see Table 5). In Centres I and IV only one patient in each of the active treatment groups improved noticeably. There was no effect in the placebo group. All in all, both 10 mg and 20 mg flunarizine were well tolerated: 71.9% of patients with 20 mg flunarizine, 70.3% with 10 mg flunarizine and 69.7% with placebo did not

report any side effects. Unwanted side effects occurred in five patients (13.5%) with 10 mg flunarizine: tiredness in two cases and dizziness, nausea and heat sensation in one case each. Side effects also occurred in four placebo patients (12.1%). Of the 10 patients (31.3%) on 20 mg flunarizine, six described tiredness, two dryness of the mouth and one nausea, tongue and a general heat sensation. This last patient had an irregular pulse but otherwise the condition appeared normal. Blood pressure and pulse rate showed no major changes with 10 mg and 20 mg flunarizine during the 60 min observation period. Discussion

In the present study 20 mg flunarizine was significantly effective in migraine attacks with and/or without aura when compared with placebo. However, in this trial only 59.4% showed an improvement in the pain intensity exceeding 50%, which is noticeably less than in the trial by Soyka et al. (1) (74.2%). A probable explanation is given in Table 5, where it is indicated that two headache centres were unable to record any effect from 10 or 20 mg flunarizine or placebo. These patients may have suffered especially severe attacks for which a dosage of 20 mg flunarizine was insufficient. In addition, 10 mg flunarizine achieved no effects in pain intensity exceeding placebo. Based on these results, 20 mg flunarizine i.v. is probably within the lower gradient of the dose-effect curve. Accordingly, further trials are required with higher doses of flunarizine, which was characterized by excellent tolerance. References

1.

Soyka D, Taneri Z, Oestreich W, Schmidt R. Flunarizine i.v. in the acute treatment of common or classical migraine attacks - a placebo controlled double blind trial. Headache 1989;29:21-7

2.

De Rood M, Vandesteene R, Gasparini R, Van Peer A, Woestenborghs R, Heykants J, Geets T, De Beukelaar F. Preliminary study on intravenous pharmakokinetics of flunarizine (0.l mg/kg) in man. Janssen Data on file

3.

Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8 (suppl 7): 1-96

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 migraineu...
34KB Sizes 0 Downloads 0 Views