Flunarizine in migraine prophylaxis: efficacy and tolerability of 5 mg and 10 mg dose levels
Vincenzo Centonze, Domenica Magrone, Marcello Vino, Paola Caporaletti, Ettore Attolini, Giancleto Campanale, Ottavio Albano
CEPHALALGIA Centonze V, Magrone D, Vino M, Caporaletti P, Attolini E, Campanale G, Albano O. Flunarizine in migraine prophylaxis: efficacy and tolerability of 5 mg and 10 mg dose levels. Cephalalgia 1990;10:17-24. Oslo. ISSN 0333-1024 The use of flunarizine, a drug which has proven its efficacy in migraine, is often associated with important side effects. The aim of this paper has been to check their incidence at different dose levels (5 mg vs 10 mg). Our data confirm the occurrence of important side effects (in particular weight gain); on the other hand, they emphasize the dose-dependency of the side effects. • Flunarizine, migraine prophylaxis, side effects Vincenzo Centonze, Domenica Magrone, MarcelIo Vino, Paola Caporaletti, Ettore Attolini, Giancleto Campanale, Ottavio Albano, Headache Unit, Department of Internal Medicine, University of Bari, Bari, Italy; Correspondence to Vincenzo Centonze, Clinica Medica I Universita' degli Studi di Bari, P. zza Giulio Cesare 70100 Bari Italy; Accepted 9 September 1989 The efficacy of Ca++ antagonists, and particularly of flunarizine, in the preventive therapy of migraine attacks is well established (1-5). This efficacy is nevertheless linked to side effects such as weight gain, tiredness, depression, as well as extra-pyramidal symptoms (6-9). Because of the increasingly important role played by this drug in the preventative therapy of migraine (10-16) and on the basis of our previous experience (17), it was deemed particularly useful to evaluate the efficacy as well as the tolerance of flunarizine administered in a single evening dose of 5 mg/day vs the "classical" dose of 10 mg/day. Material and methods
The study included 40 migraine patients, aged 20-50 years (32 F and 8 M) (Table 1), diagnosed according to the criteria of the Headache Classification Committee of the International Headache Society (18). None of them seemed to suffer from any other vascular pathology. The patients were divided into two groups. After a thirty-day "drug-free" period of observation, they were treated for a total Table 1. Demographic data. Patient material Total no. of patients 40 Females 32 Males 8 Migraine without aura 29 Migraine with aura 11 Mean age 35 Range 20-50 period of four months with an initial single evening dose of flunarizine of 5 mg (group A) and 10 mg (group B), respectively; this was then reversed in accordance with a cross-over randomized system (Fig. 1). Each of the treatment periods lasted 60 days. A special time table was used for evaluating the efficacy of the drug as well as its side effects on the basis of the usual parameters, i.e. Total Pain Index (duration in hours x severity), Migraine Index (frequency × severity), Frequency of Migraine (total number of attacks in one month), Total Hours of Headache (total number of hours of headache in one month), Severity of Migraine (very severe, severe, moderate, slight), Total Use of Analgesics, all assessed before and after the fixed treatment period.
We accepted only side effects which were present for an adequate period (more than three days), while side effects occurring in single cases, those that regressed spontaneously and those considered to be passing events, e.g. vertigo, nervous tension, asthenia, etc., were not taken into consideration. The statistical evaluation was performed using Student's t-test (two-tailed). Results
Flunarizine proved to be efficacious in 80% of the patients initially treated with the dose of 5 mg/day (group A) and in 90% of those with the dose of 10 mg/day (group B) . These patients were considered as "responders" because there was at least a 50% decrease in attack frequency when compared with the basal frequency (Fig. 2). The analytic evaluation of the headache parameters of the group initially treated with 10 mg of flunarizine showed a statistically significant decrease already at the end of the first course of treatment (60 days); the results did not change when the patients passed on to the following course of treatment in which they received 5 mg of flunarizine daily. As regards the group initially treated with 5 mg of flunarizine, the parameters evaluated showed a statistically significant decrease only for Frequency of Migraine, Migraine Index and Severity of Migraine in the first course of treatment; the following course, with flunarizine in the dose of 10 mg, caused a significant decrease for all the parameters considered (Figs. 3-8). A therapeutic latency of about 10-15 days was observed in group B, while it was of 25-30 days for group A. Only two patients from group B had to interrupt the treatment within the first two months, one case dropping out because of severe depression the other because of a marked gain in weight (8 kg). The side effects observed at the end of the total period of therapy (four months) were: weight gain, tiredness, depression, appetite gain, essential tremor (Table 2). Essential tremor occurred in only one patient from group B, with a negative family history of essential tremor. It was defined as essential because semeiologically it could not be attributed to extrapyramidal disorders since it was absent at rest and increased with voluntary movements. In group B the side effects were present at the end of the first period of treatment (two months) both as separate phenomena and in combinations; in particular, weight gain (3.5 kg on average), tiredness, appetite gain, depression were observed. The passage to treatment with 5 mg doses of flunarizine on the one hand gave rise to further weight gain (1.2 kg on average in addition to the first period of therapy) and on the other hand facilitated the reduction and/or the disappearance of tiredness and of appetite gain. In group A the only side effects at the end of the first treatment period (two months) were weight gain to a limited extent (1 kg on average) and slight tiredness which spontaneously disappeared after the first 20-30 days of therapy. The passage to doses of 10 mg/day caused a marked increase in weight gain (4 kg on average in addition to the first period of therapy), along with the manifestation of appetite gain and depression. Finally, when the efficacy of the drug was evaluated for the prodromes at the accompanying symptoms, present in a sub-group of patients suffering from ophthalmic migraine (n = 10) and migraine with neuro-
logical symptoms (n = 5), both at the end of the first treatment period (two months) and at the end of the total treatment period ( four months), the results confirmed our previous data (19): 1. Prodromes (flickering scotoma) disappeared in 73% of the cases and accompanying symptoms (paraesthesias) in 100% of the cases in group B; passage to the next treatment course with 5 mg/ day of flunarizine did not modify the situation for the prodromes significantly (disappearance in 71% of the cases); it did, however, lead to reappearance of the accompanying symptoms (paraesthesias) in 27% of the cases. 2. Prodromes disappeared in 58% of the
cases and accompanying symptoms in 75% of the cases in group A; passage to the following treatment period of 10 mg/ day of flunarizine led to the disappearance of both prodromes and accompanying symptoms in 100% of the cases. The three months follow-up after drug withdrawal showed remission of the side effects, except for a limited degree of weight gain (1 kg on average). During the same period, the clinical improvement attained at the end of the treatment was observed to continue: in all the patients (group A + group B)
Table 2. Side effects during four months of treatment with flunarizine, 5 rag/day and 10 rag/day. Side effects (after four months of therapy) Weight gain 70% Sleepiness 20% Depression 12.5% Appetite gain 15% Essential tremor 2.5%
the Frequency of Migraine did not show a statistically significant increase,
using Student's t-test (two-tailed).
Discussion
Our results confirm the therapeutic efficacy of flunarizine as a preventive drug treatment of migraine, used both at the "classical" dose level of 10 mg/day and at the less usual dose level of 5 mg/day. The drug seems to guarantee a more rapid and marked efficacy and a shorter therapeutic latency at the dose of 10 mg/day. Side effects, however, were enhanced and occurred more frequently during treatment with flunarizine at the dose of 10 mg/day. In our opinion, assessment of the efficacy of the drug and of its side effects, particularly weight gain, may further corroborate the suggestion that the drug has a central action. Flunarizine, a diphenylpiperazine molecule, thanks to its highly lipophilic nature, is able to pass the blood brain barrier easily and reach high blood levels in the central nervous system (CNS). Here, besides its well-known regulatory effects on vasal tone, the drug also seems to have a direct action on the calcium channels of neuronal cell membranes in many areas. The relation between calcium channels and the release of neurotransmitters is very complicated (20). In vitro experimental data have shown that flunarizine reduces the K+ induced release of dopamine and metenkephaline in corpus striatum. This action has been considered important for the elicitation of the extrapyramidal side effects of the drug. Flunarizine thus seems to interfere with mechanisms possibly involved in
migraine pathogenesis. Its direct protection on brain cells, inhibition of vasoconstriction, reduction of "spreading cortical depression" (in experimental conditions) and modulation of some neurotransmitter systems may be involved in the multifactorial genesis of migraine, thus accounting for its efficacy in the prophylaxis of this disease (21-30). Confirmation of the drug's greater efficacy on accompanying symptoms than on prodromes is an interesting observation. This is not easy to explain, considering the importance given to vasoconstriction in prodromes genesis. The greater efficacy on the accompanying symptoms, particularly the gastrointestinal symptoms, seems to suggest
a common basis for migraine and dyspeptic disorders. Some neurotransmitter and hormonal systems (catecholamines, gastrin, serotonin and dopamine systems, endogenous opioids) are involved in the pathophysiology of both syndromes. Flunarizine may possibly act on one or more of these systems, modifying migrainous pain and the dyspeptic symptoms. The lower incidence of side effects with doses of 5 mg/day may be due to a dose-dependent receptor stimulation. In conclusion, our data confirm the efficacy and tolerability of flunarizine at the dose of 5 mg/day in the preventive therapy of migraine and particularly for continuation therapy. Moreover, they suggest the possible immediate use of 5 mg/day of flunarizine when migraine is not too severe and when overweight or depression may contraindicate its use at the "classical" dose of 10 mg. References
1.
Amery WK, Wauquier A, Van Neuten JM, De Clerk F, Van Reempts JV, Janssen PAJ. The anti-migrainous pharmacology of flunarizine (R 14 950), a calcium antagonist. Drug Exptl Clin Res 1981;7:1-10
2.
Louis P. A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 1981;21:235-9
3.
Louis P, Spierings ELH. Comparison of flunarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double blind study. Cephalalgia 1982;2:197-203
4.
Diamond S, Shenbaum H. Flunarizine, a calcium channel blocker, in the prophylactic treatment of migraine. Headache 1983;23:39-42
5.
Peroutka SJ. The pharmacology of calcium channel antagonist: a novel class of anti-migraine agents? Headache 1983;23:278-83
6.
Centonze V, Tesauro P, Trizio T, Magrone D, Vino M, Macinagrossa G, Campanozzi F, Altomare E, Attolini E, Albano O. Efficacy and tolerability of flunarizine in the prophylaxis of migraine. Cephalalgia 1985;5:163-8
7.
Baldrati A, Albano F, de Carolis P, Sacquegna T. Essential tremor and flunarizine: description of a case. Cephalalgia 1987;7:285
8.
Chouza C, Scaramelli A, Caamano JL, De Medine O, Aljanati R, Romero S. Parkinsonism, tardive dyskinesia, akathisia and depression induced by flunarizine. Lancet 1986;1:1303-4
9.
Meyboom RHB, Ferrari MD, Dieleman BP. Parkinsonism, tardive dyskinesia, akathisia and depression induced by flunarizine. Lancet 1986;2:282
10.
Meyer SJ, Hardenberg J. Clinical effectiveness of calcium entry blockers in prophylactic treatment o migraine and cluster headache. Headache 1983 ;23:266-77
11.
Spierings ELH. Calcium entry blockers in treatment of migraine. In: Godfraind T, Vanhoutte PM, Govoni S, Paoletti S eds Calcium entry blockers and tissue protection. New York: Raven Press 1985:245-54
12.
Nattero G, Savi L, De Lorenzo C, Biale L, Torre E, Ancona M. Flunarizine in the treatment of headache. Cephalalgia 1985;5:534-5
13.
Bono G, Manzoni GC, Martucci N, Sacquegna T, Micieli G, Nappi G, Agnoli A. Flunarizine treatment in migraine syndrome: long-term follow up in common migraine and preliminary results in migraine with paroxysmal headache. Cephalalgia 1985;5:538-9
14.
Sorensen PS, Hansen K, Olesen J. Flunarizine in common migraine prophylaxis. A double-blind, cross-over study. Cephalalgia 1985;5:540-1
15.
Manna V, Agnoli A, Martucci N, Cerbo R. Protective effects of a calcium entry blocker, flunarizine on EEG pathological patterns in patients affected by common migraine. Cephalalgia 1987;7:408-9
16.
Canal P, Serinana JM, Arranz FJ. Multicentre study of preventive activity of flunarizine on migraine attacks. Cephalalgia 1987;7:418-19
17.
Centonze V, Attolini E, Macinagrossa G, Campanozzi F, Magrone D, Tessauro P, Loisy C, Albano O. 5 mg flunarizine in preventive therapy of migraine: efficacy and tolerance. Cephalalgia 1985;5:536-7
18.
Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgies and Facial Pain. Cephalalgia 1988; 8(suppl 7)
19.
Centonze V, Magrone D, Vino M, Campanozzi F, Macinagrossa G, Campanale G, Albano O. Flunarizina 10 mg vs flunarizina nella terapia preventiva della emicrania classica ed accompagnata. Farmaci 1987;1/2:11-17
20.
Govoni S, Trabucchi M, Magnoni MS, Pattaini F, Paoletti R. Abnormal neurotransmitter release and calcium entry blockers. In: Godfraind T, Vanhoutte PM, Govoni S, Paoletti Reds Calcium entry blockers and tissue protection. New York: Raven Press 1985: 151-62
21.
Marrannes R, Wauquier A. Influence of flunarizine on spreading depression. Cephalalgia 1985;5:208
22.
Marrannes R, Wauquier A, Reid K, Deprins E. Effects of drug on cortical spreading depression. In: Amery WK, Wauquier A eds The prelude to the migraine attack. Balliere Tindall 1986:158-73
23.
Manconi FM, Zuddas A, Piccardi MP, Del Zompo M, Corsini GU. Behavioural and biochemical effects of flunarizine on the dopaminergic system rodents. Cephalalgia 1987;7:420-1
24.
Godfraind T, Miller R, Wibo M. Calcium antagonist and calcium entry blockade. Pharmacol Rev 1986;38:321-416
25.
Cazalis MD, Nordmann JJ. Hormone release from isolated nerve endings of the rat neurohypophysis. J Physiol 1987;390:55-70
26.
Perney TM, Hirning LD, Leeman SE, Miller RJ. Multiple calcium channels mediate neurotransmitter release from peripheral neurons. Proc Natl Acad Sci 1986;83:6656-9
27.
Reynolds IJ, Wagner JA, Snyder SH, Thayer SA, Olivera BM, Miller RJM. Brain voltage sensitive calcium channel subtypes differentiated by omega-conotoxin fraction GVIA. Proc Natl Acad Sci 1986;83:8804-07
28.
Wei JW, Chiang DH. Effects of calcium antagonists on KCl evoked calcium reuptake by rat cortical synaptosomes. Jen Pharmacol 1986;17:261-5
29.
Amery WR. Migraine and cerebral hypoxia: hypothesis with pharmacotherapeutic implications. Cephalalgia 1985;5:131-3
30.
Govoni S, Battaini F, Magnoni MS, Trabucchi M. Non-vascular central nervous system effects of calcium entry blockers. Cephalalgia 1985;5:115-18
Vincenzo Centonze, Domenica Magrone, Marcello Vino, Paola Caporaletti, Ettore Attolini, Giancleto Campanale, Ottavio Albano
CEPHALALGIA Centonze V, Magrone D, Vino M, Caporaletti P, Attolini E, Campanale G, Albano O. Flunarizine in migraine prophylaxis: efficacy and tolerability of 5 mg and 10 mg dose levels. Cephalalgia 1990;10:17-24. Oslo. ISSN 0333-1024 The use of flunarizine, a drug which has proven its efficacy in migraine, is often associated with important side effects. The aim of this paper has been to check their incidence at different dose levels (5 mg vs 10 mg). Our data confirm the occurrence of important side effects (in particular weight gain); on the other hand, they emphasize the dose-dependency of the side effects. • Flunarizine, migraine prophylaxis, side effects Vincenzo Centonze, Domenica Magrone, MarcelIo Vino, Paola Caporaletti, Ettore Attolini, Giancleto Campanale, Ottavio Albano, Headache Unit, Department of Internal Medicine, University of Bari, Bari, Italy; Correspondence to Vincenzo Centonze, Clinica Medica I Universita' degli Studi di Bari, P. zza Giulio Cesare 70100 Bari Italy; Accepted 9 September 1989 The efficacy of Ca++ antagonists, and particularly of flunarizine, in the preventive therapy of migraine attacks is well established (1-5). This efficacy is nevertheless linked to side effects such as weight gain, tiredness, depression, as well as extra-pyramidal symptoms (6-9). Because of the increasingly important role played by this drug in the preventative therapy of migraine (10-16) and on the basis of our previous experience (17), it was deemed particularly useful to evaluate the efficacy as well as the tolerance of flunarizine administered in a single evening dose of 5 mg/day vs the "classical" dose of 10 mg/day. Material and methods
The study included 40 migraine patients, aged 20-50 years (32 F and 8 M) (Table 1), diagnosed according to the criteria of the Headache Classification Committee of the International Headache Society (18). None of them seemed to suffer from any other vascular pathology. The patients were divided into two groups. After a thirty-day "drug-free" period of observation, they were treated for a total Table 1. Demographic data. Patient material Total no. of patients 40 Females 32 Males 8 Migraine without aura 29 Migraine with aura 11 Mean age 35 Range 20-50 period of four months with an initial single evening dose of flunarizine of 5 mg (group A) and 10 mg (group B), respectively; this was then reversed in accordance with a cross-over randomized system (Fig. 1). Each of the treatment periods lasted 60 days. A special time table was used for evaluating the efficacy of the drug as well as its side effects on the basis of the usual parameters, i.e. Total Pain Index (duration in hours x severity), Migraine Index (frequency × severity), Frequency of Migraine (total number of attacks in one month), Total Hours of Headache (total number of hours of headache in one month), Severity of Migraine (very severe, severe, moderate, slight), Total Use of Analgesics, all assessed before and after the fixed treatment period.
We accepted only side effects which were present for an adequate period (more than three days), while side effects occurring in single cases, those that regressed spontaneously and those considered to be passing events, e.g. vertigo, nervous tension, asthenia, etc., were not taken into consideration. The statistical evaluation was performed using Student's t-test (two-tailed). Results
Flunarizine proved to be efficacious in 80% of the patients initially treated with the dose of 5 mg/day (group A) and in 90% of those with the dose of 10 mg/day (group B) . These patients were considered as "responders" because there was at least a 50% decrease in attack frequency when compared with the basal frequency (Fig. 2). The analytic evaluation of the headache parameters of the group initially treated with 10 mg of flunarizine showed a statistically significant decrease already at the end of the first course of treatment (60 days); the results did not change when the patients passed on to the following course of treatment in which they received 5 mg of flunarizine daily. As regards the group initially treated with 5 mg of flunarizine, the parameters evaluated showed a statistically significant decrease only for Frequency of Migraine, Migraine Index and Severity of Migraine in the first course of treatment; the following course, with flunarizine in the dose of 10 mg, caused a significant decrease for all the parameters considered (Figs. 3-8). A therapeutic latency of about 10-15 days was observed in group B, while it was of 25-30 days for group A. Only two patients from group B had to interrupt the treatment within the first two months, one case dropping out because of severe depression the other because of a marked gain in weight (8 kg). The side effects observed at the end of the total period of therapy (four months) were: weight gain, tiredness, depression, appetite gain, essential tremor (Table 2). Essential tremor occurred in only one patient from group B, with a negative family history of essential tremor. It was defined as essential because semeiologically it could not be attributed to extrapyramidal disorders since it was absent at rest and increased with voluntary movements. In group B the side effects were present at the end of the first period of treatment (two months) both as separate phenomena and in combinations; in particular, weight gain (3.5 kg on average), tiredness, appetite gain, depression were observed. The passage to treatment with 5 mg doses of flunarizine on the one hand gave rise to further weight gain (1.2 kg on average in addition to the first period of therapy) and on the other hand facilitated the reduction and/or the disappearance of tiredness and of appetite gain. In group A the only side effects at the end of the first treatment period (two months) were weight gain to a limited extent (1 kg on average) and slight tiredness which spontaneously disappeared after the first 20-30 days of therapy. The passage to doses of 10 mg/day caused a marked increase in weight gain (4 kg on average in addition to the first period of therapy), along with the manifestation of appetite gain and depression. Finally, when the efficacy of the drug was evaluated for the prodromes at the accompanying symptoms, present in a sub-group of patients suffering from ophthalmic migraine (n = 10) and migraine with neuro-
logical symptoms (n = 5), both at the end of the first treatment period (two months) and at the end of the total treatment period ( four months), the results confirmed our previous data (19): 1. Prodromes (flickering scotoma) disappeared in 73% of the cases and accompanying symptoms (paraesthesias) in 100% of the cases in group B; passage to the next treatment course with 5 mg/ day of flunarizine did not modify the situation for the prodromes significantly (disappearance in 71% of the cases); it did, however, lead to reappearance of the accompanying symptoms (paraesthesias) in 27% of the cases. 2. Prodromes disappeared in 58% of the
cases and accompanying symptoms in 75% of the cases in group A; passage to the following treatment period of 10 mg/ day of flunarizine led to the disappearance of both prodromes and accompanying symptoms in 100% of the cases. The three months follow-up after drug withdrawal showed remission of the side effects, except for a limited degree of weight gain (1 kg on average). During the same period, the clinical improvement attained at the end of the treatment was observed to continue: in all the patients (group A + group B)
Table 2. Side effects during four months of treatment with flunarizine, 5 rag/day and 10 rag/day. Side effects (after four months of therapy) Weight gain 70% Sleepiness 20% Depression 12.5% Appetite gain 15% Essential tremor 2.5%
the Frequency of Migraine did not show a statistically significant increase,
using Student's t-test (two-tailed).
Discussion
Our results confirm the therapeutic efficacy of flunarizine as a preventive drug treatment of migraine, used both at the "classical" dose level of 10 mg/day and at the less usual dose level of 5 mg/day. The drug seems to guarantee a more rapid and marked efficacy and a shorter therapeutic latency at the dose of 10 mg/day. Side effects, however, were enhanced and occurred more frequently during treatment with flunarizine at the dose of 10 mg/day. In our opinion, assessment of the efficacy of the drug and of its side effects, particularly weight gain, may further corroborate the suggestion that the drug has a central action. Flunarizine, a diphenylpiperazine molecule, thanks to its highly lipophilic nature, is able to pass the blood brain barrier easily and reach high blood levels in the central nervous system (CNS). Here, besides its well-known regulatory effects on vasal tone, the drug also seems to have a direct action on the calcium channels of neuronal cell membranes in many areas. The relation between calcium channels and the release of neurotransmitters is very complicated (20). In vitro experimental data have shown that flunarizine reduces the K+ induced release of dopamine and metenkephaline in corpus striatum. This action has been considered important for the elicitation of the extrapyramidal side effects of the drug. Flunarizine thus seems to interfere with mechanisms possibly involved in
migraine pathogenesis. Its direct protection on brain cells, inhibition of vasoconstriction, reduction of "spreading cortical depression" (in experimental conditions) and modulation of some neurotransmitter systems may be involved in the multifactorial genesis of migraine, thus accounting for its efficacy in the prophylaxis of this disease (21-30). Confirmation of the drug's greater efficacy on accompanying symptoms than on prodromes is an interesting observation. This is not easy to explain, considering the importance given to vasoconstriction in prodromes genesis. The greater efficacy on the accompanying symptoms, particularly the gastrointestinal symptoms, seems to suggest
a common basis for migraine and dyspeptic disorders. Some neurotransmitter and hormonal systems (catecholamines, gastrin, serotonin and dopamine systems, endogenous opioids) are involved in the pathophysiology of both syndromes. Flunarizine may possibly act on one or more of these systems, modifying migrainous pain and the dyspeptic symptoms. The lower incidence of side effects with doses of 5 mg/day may be due to a dose-dependent receptor stimulation. In conclusion, our data confirm the efficacy and tolerability of flunarizine at the dose of 5 mg/day in the preventive therapy of migraine and particularly for continuation therapy. Moreover, they suggest the possible immediate use of 5 mg/day of flunarizine when migraine is not too severe and when overweight or depression may contraindicate its use at the "classical" dose of 10 mg. References
1.
Amery WK, Wauquier A, Van Neuten JM, De Clerk F, Van Reempts JV, Janssen PAJ. The anti-migrainous pharmacology of flunarizine (R 14 950), a calcium antagonist. Drug Exptl Clin Res 1981;7:1-10
2.
Louis P. A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 1981;21:235-9
3.
Louis P, Spierings ELH. Comparison of flunarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double blind study. Cephalalgia 1982;2:197-203
4.
Diamond S, Shenbaum H. Flunarizine, a calcium channel blocker, in the prophylactic treatment of migraine. Headache 1983;23:39-42
5.
Peroutka SJ. The pharmacology of calcium channel antagonist: a novel class of anti-migraine agents? Headache 1983;23:278-83
6.
Centonze V, Tesauro P, Trizio T, Magrone D, Vino M, Macinagrossa G, Campanozzi F, Altomare E, Attolini E, Albano O. Efficacy and tolerability of flunarizine in the prophylaxis of migraine. Cephalalgia 1985;5:163-8
7.
Baldrati A, Albano F, de Carolis P, Sacquegna T. Essential tremor and flunarizine: description of a case. Cephalalgia 1987;7:285
8.
Chouza C, Scaramelli A, Caamano JL, De Medine O, Aljanati R, Romero S. Parkinsonism, tardive dyskinesia, akathisia and depression induced by flunarizine. Lancet 1986;1:1303-4
9.
Meyboom RHB, Ferrari MD, Dieleman BP. Parkinsonism, tardive dyskinesia, akathisia and depression induced by flunarizine. Lancet 1986;2:282
10.
Meyer SJ, Hardenberg J. Clinical effectiveness of calcium entry blockers in prophylactic treatment o migraine and cluster headache. Headache 1983 ;23:266-77
11.
Spierings ELH. Calcium entry blockers in treatment of migraine. In: Godfraind T, Vanhoutte PM, Govoni S, Paoletti S eds Calcium entry blockers and tissue protection. New York: Raven Press 1985:245-54
12.
Nattero G, Savi L, De Lorenzo C, Biale L, Torre E, Ancona M. Flunarizine in the treatment of headache. Cephalalgia 1985;5:534-5
13.
Bono G, Manzoni GC, Martucci N, Sacquegna T, Micieli G, Nappi G, Agnoli A. Flunarizine treatment in migraine syndrome: long-term follow up in common migraine and preliminary results in migraine with paroxysmal headache. Cephalalgia 1985;5:538-9
14.
Sorensen PS, Hansen K, Olesen J. Flunarizine in common migraine prophylaxis. A double-blind, cross-over study. Cephalalgia 1985;5:540-1
15.
Manna V, Agnoli A, Martucci N, Cerbo R. Protective effects of a calcium entry blocker, flunarizine on EEG pathological patterns in patients affected by common migraine. Cephalalgia 1987;7:408-9
16.
Canal P, Serinana JM, Arranz FJ. Multicentre study of preventive activity of flunarizine on migraine attacks. Cephalalgia 1987;7:418-19
17.
Centonze V, Attolini E, Macinagrossa G, Campanozzi F, Magrone D, Tessauro P, Loisy C, Albano O. 5 mg flunarizine in preventive therapy of migraine: efficacy and tolerance. Cephalalgia 1985;5:536-7
18.
Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgies and Facial Pain. Cephalalgia 1988; 8(suppl 7)
19.
Centonze V, Magrone D, Vino M, Campanozzi F, Macinagrossa G, Campanale G, Albano O. Flunarizina 10 mg vs flunarizina nella terapia preventiva della emicrania classica ed accompagnata. Farmaci 1987;1/2:11-17
20.
Govoni S, Trabucchi M, Magnoni MS, Pattaini F, Paoletti R. Abnormal neurotransmitter release and calcium entry blockers. In: Godfraind T, Vanhoutte PM, Govoni S, Paoletti Reds Calcium entry blockers and tissue protection. New York: Raven Press 1985: 151-62
21.
Marrannes R, Wauquier A. Influence of flunarizine on spreading depression. Cephalalgia 1985;5:208
22.
Marrannes R, Wauquier A, Reid K, Deprins E. Effects of drug on cortical spreading depression. In: Amery WK, Wauquier A eds The prelude to the migraine attack. Balliere Tindall 1986:158-73
23.
Manconi FM, Zuddas A, Piccardi MP, Del Zompo M, Corsini GU. Behavioural and biochemical effects of flunarizine on the dopaminergic system rodents. Cephalalgia 1987;7:420-1
24.
Godfraind T, Miller R, Wibo M. Calcium antagonist and calcium entry blockade. Pharmacol Rev 1986;38:321-416
25.
Cazalis MD, Nordmann JJ. Hormone release from isolated nerve endings of the rat neurohypophysis. J Physiol 1987;390:55-70
26.
Perney TM, Hirning LD, Leeman SE, Miller RJ. Multiple calcium channels mediate neurotransmitter release from peripheral neurons. Proc Natl Acad Sci 1986;83:6656-9
27.
Reynolds IJ, Wagner JA, Snyder SH, Thayer SA, Olivera BM, Miller RJM. Brain voltage sensitive calcium channel subtypes differentiated by omega-conotoxin fraction GVIA. Proc Natl Acad Sci 1986;83:8804-07
28.
Wei JW, Chiang DH. Effects of calcium antagonists on KCl evoked calcium reuptake by rat cortical synaptosomes. Jen Pharmacol 1986;17:261-5
29.
Amery WR. Migraine and cerebral hypoxia: hypothesis with pharmacotherapeutic implications. Cephalalgia 1985;5:131-3
30.
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