A Placebo-Controlled Crossover Trial of Nimodipine in Pediatric Migraine
P.A. Battistella, R. Ruffilli, R. Moro, M. Fabiani, S. Bertoli, A. Antolini and F. Zacchello Department of Pediatrics, University of Padua, Italy. Reprint requests to: P.A. Battistella, M.D., Department of Pediatrics, University of Padua, via Glustiniani 3, 35128 Padova, Italy.
Accepted for Publication: December 9, 1989. SYNOPSIS
An 8-month, double-blind, placebo-controlled crossover trial was carried out on the use of nimodipine in migraine prophylaxis in 37 patients aged 7 to 18 years old. After a 4-week medication-free run-in period, 19 subjects (Group 1) received a placebo while 18 (Group 2) received nimodipine (10-20 mg t.i.d., according to body weight), for 12 weeks. After a 4-week wash-out period, the groups switched therapy for a further 12 weeks. 30 patients completed the trial and the number of dropouts was comparable in the 2 groups. The only side-effect during nimodipine treatment was mild abdominal discomfort (3 cases). The treatments were evaluated on the basis of frequency and duration of attacks. There was a significant reduction in both parameters during the first period of treatment. During the second period of treatment, nimodipine proved to have a significantly greater effect than the placebo with regard to frequency, whereas the response was similar with the placebo as regards duration of attacks. The latter parameter shows a significant decrease during the treatment periods, regardless of type of therapy. (Headache 30:264-268, 1990) INTRODUCTION
Nimodipine is a selective calcium entry blocker for the slow calcium channels, belonging to Class II (Nifedipine-like):1 it is a 1.4-dihydropyridine derivative with a selective action on the cerebral vessels2 and no significant effect on peripheral vasculature.3 Recent studies have also suggested an inhibitory effect on neurotransmitter release.4 Though few controlled studies have been published to date, its use in migraine prophylaxis is promising because of its considerable effectiveness reported in adults, with scarce side-effects,5,8 even if a recent study reported no significant differences versus the placebo.9 Levels of response are dose-dependent - the higher the dose, the greater the effect.6,10 In common migraine, the effectiveness of nimodipine in comparison with other calcium entry blockers is comparable with that of flunarizine but with a shorter latency.11 Versus other calcium entry blockers, nimodipine is more effective in controlling migraine headache, with a lower incidence of tolerance and side-effects.6,12 It is also as effective as pizotifen, here again with a shorter latency and fewer side effects.10,13 Results of various prophylactic drug trials on migrainous children still seem contradictory, especially with regard to propranolol,14,15 clonidine,16,17 L-5-hydroxytryptophan18,19 and pizotifen;20,21 but timolol proved equivalent to the placebo in the only controlled study performed so far.22 Other drugs such as amitriptyline,23 papaverine24 and lisuride maleate25 have been successfully used as prophylactic agents but need further confirmation. Calcium entry blockers have recently been used: in controlled studies, flunarizine proved more effective than the placebo,26 like acetylsalicylic acid,27 especially with regard to frequency of attacks; this confirmed other open trials.28,29 As for nimodipine, the only crossover trial versus flunarizine showed a similar effect and tolerability for the two calcium entry blockers with a shorter latency for nimodipine,30 confirming results observed in adults.10 In this study, nimodipine was tested in a double-blind crossover trial versus a placebo with 37 young migraine out-patients. MATERIALS AND METHODS
A total of 37 eligible patients (18 males and 19 females) began the trial: 7 patients dropped out for reasons unrelated to any side effects of the treatment. Of the remaining 30 patients, there were 16 males and 14 females, aged 7 to 18 years (mean ± SD: 12.2 ± 3.3 yrs). Of these patients, 21 had migraine without aura (or the "common" form), whereas 9 had migraine with aura ("classic" form), according to the criteria of Ad Hoc Committee of the International Headache Society.31 The patients' clinical features are listed in Table 1. For six months preceding the trial, the patients had been suffering from at least one attack a month. They were asked to fill in a standard card with number, duration and severity of attacks: the trial only considered moderate attacks (headache reducing activity, i.e. could not study or play) or severe attacks (headache requiring rest in bed), as children's reports are often unreliable
Table 1 Patients' clinical data Patients (No.)
Age (yrs) Mean ± SD Range
Migraine without aura - Males - Females Total
12 9 21
13.1 ± 2.9 12.2 ± 4.0 12.7 ± 3.4
11-18 7-18 7-18
Migraine with aura - Males - Females Total
4 5 9
10.5 ± 3.0 11.4 ± 2.4 11.0 ± 2.7
7-14 8-14 7-14
with regard to intensity. The efficacy of treatment was evaluated according to headache frequency (attacks per month) and duration (hours per attack). Prophylactic treatment was stopped for three months prior to the trial; acetaminophen (15 mg/kg) was allowed as a symptomatic escape. All patients underwent a full neurological examination and physical assessment, including blood pressure, heart-rate and weight measurements. Routine laboratory investigations were carried out at visits before and after each stage of treatment. The patients were divided at random into two groups (Fig. 1). The trial involved four stages (total observation period 32 weeks): stage 1 (4 wks): medication-free, run-in observation period; stage 2 (12 wks): 1st treatment with Group 1 taking a placebo while Group 2 took nimodipine (NimotopR Bayer); stage 3 (4 wks): wash-out period with no treatment; stage 4 (12 wks): 2nd treatment with Group 1 taking nimodipine and Group 2 taking placebo.
Group 1 consisted of 19 subjects with a mean age (± SD) of 12.4 ± 3.3 yrs (range 7-18), of which 10 were females (12.4 ± 3.6 yrs) and 9 were males (12.4 ± 2.9 yrs): 14 were affected with migraine without aura and 5 with aura. Group 2 included 18 subjects with a mean age (± SD) of 12.0 ± 3.4 yrs (range 7-18), 9 of which were females (11.3 ± 3.4 yrs) and 9 males (12.4 ± 3.3 yrs): 14 had migraine without aura and 4 with aura. The groups were comparable with regard to duration of the illness and frequency and duration of the headache attacks. Four patients dropped out from Group 1 and 3 from Group 2, all of whom suffered from migraine without aura. The dosage of nimodipine was 10 to 20 mg three times daily (i.e. 50 kg: 20 mg = 10 drops t.i.d.); equivalent amounts of placebo were administered t.i.d. according to body weight. The nimodipine and placebo were identical in col-our. Both patients and physicians were blinded as to which compound was being administered. Reports of side effects were carefully collected and the efficacy of the treatment was assessed by statistical analysis on unpaired data (Mann-Whitney "U" test) to compare the two groups and on paired data (Wilcoxon) to compare frequency and duration of attacks within each group, during run-in, the third month of each treatment stage and wash-out. Test values with a p
P.A. Battistella, R. Ruffilli, R. Moro, M. Fabiani, S. Bertoli, A. Antolini and F. Zacchello Department of Pediatrics, University of Padua, Italy. Reprint requests to: P.A. Battistella, M.D., Department of Pediatrics, University of Padua, via Glustiniani 3, 35128 Padova, Italy.
Accepted for Publication: December 9, 1989. SYNOPSIS
An 8-month, double-blind, placebo-controlled crossover trial was carried out on the use of nimodipine in migraine prophylaxis in 37 patients aged 7 to 18 years old. After a 4-week medication-free run-in period, 19 subjects (Group 1) received a placebo while 18 (Group 2) received nimodipine (10-20 mg t.i.d., according to body weight), for 12 weeks. After a 4-week wash-out period, the groups switched therapy for a further 12 weeks. 30 patients completed the trial and the number of dropouts was comparable in the 2 groups. The only side-effect during nimodipine treatment was mild abdominal discomfort (3 cases). The treatments were evaluated on the basis of frequency and duration of attacks. There was a significant reduction in both parameters during the first period of treatment. During the second period of treatment, nimodipine proved to have a significantly greater effect than the placebo with regard to frequency, whereas the response was similar with the placebo as regards duration of attacks. The latter parameter shows a significant decrease during the treatment periods, regardless of type of therapy. (Headache 30:264-268, 1990) INTRODUCTION
Nimodipine is a selective calcium entry blocker for the slow calcium channels, belonging to Class II (Nifedipine-like):1 it is a 1.4-dihydropyridine derivative with a selective action on the cerebral vessels2 and no significant effect on peripheral vasculature.3 Recent studies have also suggested an inhibitory effect on neurotransmitter release.4 Though few controlled studies have been published to date, its use in migraine prophylaxis is promising because of its considerable effectiveness reported in adults, with scarce side-effects,5,8 even if a recent study reported no significant differences versus the placebo.9 Levels of response are dose-dependent - the higher the dose, the greater the effect.6,10 In common migraine, the effectiveness of nimodipine in comparison with other calcium entry blockers is comparable with that of flunarizine but with a shorter latency.11 Versus other calcium entry blockers, nimodipine is more effective in controlling migraine headache, with a lower incidence of tolerance and side-effects.6,12 It is also as effective as pizotifen, here again with a shorter latency and fewer side effects.10,13 Results of various prophylactic drug trials on migrainous children still seem contradictory, especially with regard to propranolol,14,15 clonidine,16,17 L-5-hydroxytryptophan18,19 and pizotifen;20,21 but timolol proved equivalent to the placebo in the only controlled study performed so far.22 Other drugs such as amitriptyline,23 papaverine24 and lisuride maleate25 have been successfully used as prophylactic agents but need further confirmation. Calcium entry blockers have recently been used: in controlled studies, flunarizine proved more effective than the placebo,26 like acetylsalicylic acid,27 especially with regard to frequency of attacks; this confirmed other open trials.28,29 As for nimodipine, the only crossover trial versus flunarizine showed a similar effect and tolerability for the two calcium entry blockers with a shorter latency for nimodipine,30 confirming results observed in adults.10 In this study, nimodipine was tested in a double-blind crossover trial versus a placebo with 37 young migraine out-patients. MATERIALS AND METHODS
A total of 37 eligible patients (18 males and 19 females) began the trial: 7 patients dropped out for reasons unrelated to any side effects of the treatment. Of the remaining 30 patients, there were 16 males and 14 females, aged 7 to 18 years (mean ± SD: 12.2 ± 3.3 yrs). Of these patients, 21 had migraine without aura (or the "common" form), whereas 9 had migraine with aura ("classic" form), according to the criteria of Ad Hoc Committee of the International Headache Society.31 The patients' clinical features are listed in Table 1. For six months preceding the trial, the patients had been suffering from at least one attack a month. They were asked to fill in a standard card with number, duration and severity of attacks: the trial only considered moderate attacks (headache reducing activity, i.e. could not study or play) or severe attacks (headache requiring rest in bed), as children's reports are often unreliable
Table 1 Patients' clinical data Patients (No.)
Age (yrs) Mean ± SD Range
Migraine without aura - Males - Females Total
12 9 21
13.1 ± 2.9 12.2 ± 4.0 12.7 ± 3.4
11-18 7-18 7-18
Migraine with aura - Males - Females Total
4 5 9
10.5 ± 3.0 11.4 ± 2.4 11.0 ± 2.7
7-14 8-14 7-14
with regard to intensity. The efficacy of treatment was evaluated according to headache frequency (attacks per month) and duration (hours per attack). Prophylactic treatment was stopped for three months prior to the trial; acetaminophen (15 mg/kg) was allowed as a symptomatic escape. All patients underwent a full neurological examination and physical assessment, including blood pressure, heart-rate and weight measurements. Routine laboratory investigations were carried out at visits before and after each stage of treatment. The patients were divided at random into two groups (Fig. 1). The trial involved four stages (total observation period 32 weeks): stage 1 (4 wks): medication-free, run-in observation period; stage 2 (12 wks): 1st treatment with Group 1 taking a placebo while Group 2 took nimodipine (NimotopR Bayer); stage 3 (4 wks): wash-out period with no treatment; stage 4 (12 wks): 2nd treatment with Group 1 taking nimodipine and Group 2 taking placebo.
Group 1 consisted of 19 subjects with a mean age (± SD) of 12.4 ± 3.3 yrs (range 7-18), of which 10 were females (12.4 ± 3.6 yrs) and 9 were males (12.4 ± 2.9 yrs): 14 were affected with migraine without aura and 5 with aura. Group 2 included 18 subjects with a mean age (± SD) of 12.0 ± 3.4 yrs (range 7-18), 9 of which were females (11.3 ± 3.4 yrs) and 9 males (12.4 ± 3.3 yrs): 14 had migraine without aura and 4 with aura. The groups were comparable with regard to duration of the illness and frequency and duration of the headache attacks. Four patients dropped out from Group 1 and 3 from Group 2, all of whom suffered from migraine without aura. The dosage of nimodipine was 10 to 20 mg three times daily (i.e. 50 kg: 20 mg = 10 drops t.i.d.); equivalent amounts of placebo were administered t.i.d. according to body weight. The nimodipine and placebo were identical in col-our. Both patients and physicians were blinded as to which compound was being administered. Reports of side effects were carefully collected and the efficacy of the treatment was assessed by statistical analysis on unpaired data (Mann-Whitney "U" test) to compare the two groups and on paired data (Wilcoxon) to compare frequency and duration of attacks within each group, during run-in, the third month of each treatment stage and wash-out. Test values with a p
