Flunarizine in Migraine: A Minireview
Massimo Leone, Licia Grazzi, Loredana La Mantia and Gennaro Bussone
Centro Cefalee, Istituto Neurologico "C. Besta", Via Celoria 11, 20133 Milano, Italy Reprint requests to: Gennaro Bussone, M.D., Istituto Neurologico "C. Besta", Via Celoria 11, 20133 Milano, Italy. Accepted for Publication: April 9, 1991. SYNOPSIS
Flunarizine is a non-selective calcium antagonist. It distributes preferentially in the adipose tissue and passes the blood brain barrier. Numerous controlled clinical studies have established that flunarizine is efficacious in migraine prophylaxis, including double-blind studies in which the drug was compared with placebo or other antimigraine drugs. To avoid side effects a special schedule or administration is necessary. Flunarizine has no myogenic effect on smooth muscle cells of the vessles. It is said to be the only calicum antagonist able to protect brain cells against hypoxic damage. In addition, the considerable body of information which shows flunarizine capable of directly influencing the central nervous system, suggests that the drug's anti-migraine action may depend on its ability to influence central phenomena. Key words: flunarizine, migraine, prophylaxis. (Headache 31:388-391, 1991) INTRODUCTION
Calcium ions preside over numerous cell, including nerve cell, functions. For executing these functions the ions are mobilised either from intracellular pools or enter from the exterior. Calcium enters cells via "slow" or "fast" channels. Fast, or receptor operated channels (ROC) are activated by the formation of a ligand-receptor complex at the external surface of the cell membrane. Slow or voltage operated channels (VOC) are activated by ad hoc changes in membrane potential. Calcium-antagonist drugs mainly exert their effects on VOC channels, at least three kinds of which have so far been identified: transient (T), long-lasting (L), and neuronal (N). L channels, with their prolonged opening period, seem particularly sensitive to calcium antagonists.1 When a certain potential difference exists across the neuronal membrane, the slow channels open to allow the ingress of calcium. The latter is responsible for the plateau phase of the action potential. Calcium antagonists act on these channels complex membrane proteins - by binding to specific sites on their exterior-facing surfaces. Such allosteric sites have been demonstrated for dihydropyridine (nimodipine), diphenylalkylamine (verapamil) and benzothiazepine (diltiazem).2 The presence of sites predisposed to bind specific molecules able to modulate the functional states of VOCs suggests the existence of endogenous ligands which perform that function physiologically.3 All three types of VOC appear to be present on a wide variety of cells, including neurons.4 Evidence has recently been presented that different tissues possess different forms (isoforms) of this calcium-channel protein.5 This would, at least in part, explain the differing affinities shown by the various calcium antagonists to various tissue types, as well as the multiple uses these drugs find in clinical medicine. Calcium antagonists are in fact a heterogeneous group of compounds and as noted above are employed in numerous clinical conditions. The World Health Organisation recently classified them into two main types:6 those selectively active on slow calcium channels and those active non-selectively on such channels. Each of these main groups is in turn subdivided on the basis of the clinical and detailed pharmacological properties of the individual compounds. Two groups of non-selective compounds are characterised by the fact that they are active on fast sodium channels at the same concentrations as they are active on slow calcium channels. The compound flunarizine is a non-selective calcium antagonist. A highly lipophilic, poorly water-soluble substance, it distributes preferentially in adipose tissue and binds tightly to plasma and tissue proteins. Blood levels of the drug are low and tissue levels are much higher. The compound is easily absorbed in the gastrointestinal tract and the liver probably exerts a "first passage" effect on it, which would explain the great variability in drug plasma levels among different subjects. Because it is lipophilic, flunarizine passes the blood-brain barrier and reaches the brain in significant quantities. Its half life in the body is 7-10 days, metabolic degradation apparently occurring principally via aromatic hydroxylation and oxidative dealkylation. RATIONALE FOR USE OF FLUNARIZINE IN MIGRAINE
Although the pathogenesis of migraine has still not been clarified, the vasomotor alterations which
accompany the attacks seem to play an important role in the genesis of migraine pain, whatever the ultimate origin of those alterations may be.7 It is known that the control smooth muscle cells exert on blood vessel diameter is regulated by calcium flux. It has been suggested that influx of calcium ions into those muscle cells may stabilise vasomotricity, thus avoiding or reducing pain. Initial data on the action of calcium antagonists, particularly flunarizine, in preventing migraine attacks were consistent with this suggestion. Continuing research showed that flunarizine possessed additional properties from which arose the prospect that other mechanisms might explain the drug's activity in migraine. It emerged that flunarizine had no myogenic effect on vessels and in fact caused neither vasodilation nor arterial pressure changes.8 It was also discovered that, of a series of calcium antagonists, only flunarizine was able to protect brain cells against hypoxic damage9 and, positing a neuronal genesis for migraine, this fact can be used to explain the anti-migraine action of flunarizine. But flunarizine exerts other effects on neurons. It is, for example, able to raise the excitability threshold in spreading depression and to reduce recovery time from that condition.10This is important because of the similarity between spreading depression and spreading oligoemia in migraine. Flunarizine can also influence the release of transmitters such as dopamine and met-enkephalin11 which could be involved in the pathogenesis of migraine. A further property of flunarizine is that of reducing epileptic neuronal activity and especially of inhibiting the propagation of that activity. The drug has been used clinically as an antiepileptic in association with basic therapy,12 as well as in patients affected with both migraine and epilepsy.13 Flunarizine is also known to induce changes in the hypothalamohypophyseal axis; at least in part these are mediated by a direct effect on the hypothalamus.14 A further effect of flunarizine is that of inducing behavioural changes; for example, after animal administration a reduction in conditioned behaviour is observed which is similar to that caused by haloperidol.14 Turning now to the side effects of treatment with flunarizine, extrapyramidal disturbances, somnolence, depression and the increased appetite observed during treatment, may all be explained by a direct action of the drug on the central nervous system. The considerable body of information on flunarizine, which shows it capable of directly influencing the CNS, naturally suggests that the drug's anti-migraine action depends on its ability to interfere with central phenomena. Several other important observations are consistent with this idea of a non-vascular mode of action for flunarizine in migraine prophylaxis, Consider the example of nimodipine, a calcium antagonist which is highly selective for cerebral blood vessels. Nimodipine is a thousand times more potent than flunarizine in inhibiting human temporal artery contractions,15 yet it is required at doses many times greater in order to achieve migraine prophylaxis, in fact seeming less effective than flunarizine in preventing attacks (see below). Note also that the vasomotor effects of flunarizine are slight and occur a few hours after administration of the drug - at the same time as the plasma concentration peaks. Migraine prophylaxis, on the other hand, commences after several days of treatment. This discrepancy could be explained by supposing that flunarizine acts (after concentration build-up in the CNS) by restoring correct functioning in the transmitter systems supposed to be involved in migraine. There are other possible explanations for flunarizine's anti-migraine activity. It could be mediated by inhibition of transmission along the trigemino-vascular system, although recent results16 indicate that flunarizine does not act at the level of the peripheral nervous system. Besides modifying intracellular calcium levels via its calcium antagonist effect, flunarizine could act directly on certain intracellular proteins which bind calcium - calmodulin for example. A particular form of calmodulin has been identified in the nucleus spinalis trigeminalis and the substantia gelatinosa Rolandi of man;17 both these CNS structures are involved in nociception. It appears that these calcium binding proteins are completely absent from the motor and epicritic (tactile and pro-prioreceptive) systems. EFFECTIVENESS AND SAFETY OF FLUNARIZINE IN MIGRAINE THERAPY
Numerous controlled clinical studies have established that flunarizine is efficacious in migraine prophylaxis, including double-blind studies in which the drug was compared with placebo18 and the anti-migraine drugs pizotifen,19 ß-blockers20 and nimodipine.21 Our group conducted the latter study, a multicentre double-blind trial with parallel groups in which flunarizine at 10 mg/day was compared with nimodipine at 120 mg/day; the study conclusion was that flunarizine was efficacious in migraine prophylaxis. The studies cited above all used flunarize at 10 mg/day. The parameter most sensitive to the treatment is headache frequency, a reduction of which is evident after one month,22 as occurs with other anti-migraine therapies. In these studies it appeared that the number of responders (subjects with pain index improvement of >50%) tends to increase as long-term therapy continues. The time required for the drug to begin having an effect corresponds well with the approximately 4-5 weeks required for it to reach a steady state concentration. After establishing the drug's efficacy, the effects of long-term use remained to be investigated. Specifically the incidence of unpleasant side effects and their dose dependence had to be determined, as
well as whether tolerance developed or the clinical advantage persisted after the suspension of therapy. It was also necessary to optimise treatment duration and find a dose having the best benefit/side effects ratio. The first open multicentred long-term study envisaged the administration of flunarizine to 120 migraine patients for 2 years at 10 mg/day23 Only 44 remained at the final check-up after 2 years of therapy. Interestingly those who took the drug for that period did not develop tolerance. After three months 54% of the 110 patients checked were responders; at the 9th month 72% of the 93 checked were responders. The side effects which developed over the 2 year period constituted the main limitation to the therapy: weight gain (mean 8 Kg) in 54%, somnolence in 42% particularly in the first month, and depression - the most frequent reason for dropping out. Given the high frequency of side effects it became necessary to review the way in which the drug was administered over the long-term. A second multicentred study addressed this problem,24 evaluating efficacy and side effects over one year during which the novel regime of six month's prophylaxis with flunarizine followed by 6 months with no treatment was applied. In the first month flunarizine was given at 10 mg/day and for the following 5 months it was administered for only 3 weeks per month. Of the 100 patients enrolled, 92 completed the first phase; of those dropping out 2 received no benefit from the treatment, 3 stopped because of side effects (2 for an average 2 Kg weight increase, 1 for depression) and the last patient was not compliant. There were 60 (70.6%) responders at the end of this first treatment period. Seventy-nine patients completed the 2nd six months of observation without therapy. Of the 60 responders observed at the end of therapy, 32 (53.4%) derived benefit from it during the following six months of non-therapy. The side effects observed were: somnolence (N=20), transitory in nearly all cases; depression (N=3); and modest weight increase (2.3 ± 1.5 Kg) (N=30); there were no extrapyramidal disturbances. The mode of flunarizine administration tested in this study resulted in a marked reduction in the frequency and severity of side effects while retaining the therapeutic benefit, in many cases, for six months after treatment suspension. With the aim of further optimising flunarizine administration Centonze et al25 recruited a group of 40 migraine patients (11 with aura and 29 without) to a crossover study (each treatment period lasting 60 days) in which the result of administering flunarizine at 5 mg/day was compared with the more usual 10 mg/day dosage. The clinical protocol suggested by the results is that of employing flunarizine at 10 mg/day during the first 15-20 days, thus keeping the latency period short, and then passing to a 5 mg/day maintenance regime to keep side effects to a minimum. It was observed in fact that patients who took flunarizine at 10 mg/day in the initial phase maintained their clinical improvement when they took the drug at 5 mg/day. Flunarizine has also been successfully employed to treat migraine attacks. In a double blind study, the efficacy of 20 mg of flunarizine administered intravenously in 31 patients with migraine headache (7 with and 23 without aura) was compared with similarly administered placebo in 29 subjects (10 with and 19 without aura)26 After the first hour's observation 74.2% of those found to have taken flunarizine were responders, while only 27.6% of those given placebo were responders. Similar results were obtained for the phenomena accompanying migraine. Pulse and arterial pressure did not change significantly and 11 patients were somnolent. Notwithstanding these encouraging results it will be necessary to perform further studies, employing rigorous methodology and large groups of patients, to compare the now established efficacy of flunarizine with other symptomatic treatments for migraine. Migraine is not a condition which only affects adults, and the problem of treating the considerable number of pediatric cases arises. Seventy child sufferers of common migraine (ages between 6 and 11) were recently involved in a trial to evaluate the efficacy of flunarizine in this field.27 The study employed a double blind crossover protocol against placebo, and lasted eight months. A significant reduction in the frequency and duration of migraine attacks, beginning from the 2nd month of treatment, was observed in those who received flunarizine in the first phase. The reductions were maintained until the end of the study. Those who received the drug in the second phase of the trial only experienced a clinical advantage a month after the crossover, ie after a month of flunarizine administration. The most frequent side effects were weight increase in 14 (22.2%) (mean increase not reported) and somnolence in 6 (9.5%). Apart from the fact that flunarizine was efficacious, the most interesting thing to emerge was that the clinical benefit persisted long after the drug was suspended, a similar result to that obtained by us in our adult study.24 It is concluded that flunarizine can be regarded as one of the more important prophylactic therapies for migraine. The unpleasant side effects which emerge on long-term treatment can be very effectively reduced by the application of a specific treatment regime. The compound has also been shown to be useful in pediatric patients both prophylactically and for treating migraine attacks, although further studies will be necessary to confirm these initial findings. It is noted, finally, that the drug is very probably centrally acting and this is consistent with current views on the pathogenesis of migraine.
REFERENCES
1.
Braunwald E: Mechanism of action of calcium channel-blocking agents. NEJM 307:1616-1627, 1982.
2.
Govoni S: In: Intrammed Comm. Ed. II calcio nella fisiopatologia del sistema nervoso centrale. Milano: 27-26, 1988.
3.
Thayer SA, Stein L, Fairhurst AS: Endogenous modulator of calcium channels. IUPHAR 9th International Congress of Pharmacology (Abstr), 1989.
4.
Dolphin AC, Scott RH: Pharmacologycal analysis of neuronal calcium channels: interaction with G proteins. 4th International Symposium on Calcium Antagonists. Florence: 98-99 (Abstr), 1989.
5.
Koch WJ, Hui A, Engle D el al: Calcium antagonists: from molecular pharmacology to the patients. 4th International Symposium on Calcium Antagonists. Florence:40-41 (Abstr), 1989.
6.
Agnoli A: The classification of calcium antagonists by the WHO expert committee: relevance in neurology. Cephalalgia 8, suppl 8:7-10, 1988.
7.
Moskowitz MA: The neurobiology of vascular head pain. Ann Neurol 16:157-168, 1984.
8.
Vanhoutee PM: Calcium entry blockers, vascular smooth muscle and systemic hypertension. Am J Cardiol 55:17B-23B, 1985.
9.
Wauquier A, Ashton D, Clincke G, Frasen Y: Calcium entry blockers as cerebral protecting agents: comparative activity in tests of hypoxia and hyperexcitability. Jap J Pharmacol 38:1-7, 1985.
10.
Marranes S, Wauquier A, Reid K, De Prins E: Effect of drugs on cortical spreading depression. In: Amery WK and Wauquier A eds. The prelude to the Migraine Attack. London, Bailliere Tindall: 158-173, 1986.
11.
Govoni S, Battaini F, Magnoni MS, Trabucchi M: Non-vascular central nervous system effects of caIcium entry blockers. Cehalalgia 5, suppl 2:115-118, 1985.
12.
Overweg J, Binnie CD, Meijer JWA et al: Double-blind placebo controlled trial of flunarizine as add-on therapy in epilepsy. Epilepsia 25:217-222, 1984.
13.
Narbone MC, D'Amico D, Di Perri R: Classic Migraine and intercalated seizures in a young woman: efficacy of flunarizine. Headache 28:209-211, 1988.
14.
Drago F, Continella G, Mangano O et al: Neuroendocrine and behavioral effects of flunarizine in young and old rats. Cephalalgia 5, suppl 2:125-129, 1985.
15.
Jansen I, Edvinsson L: Effects of extracellular calcium and the calcium entry blockers flunarizine and nimodipine on contractile responses in human temporal arteries. Cephalalgia 6:235-240, 1986.
16.
Schneider J, Fruh C, Wilffert B, Peters T: Absence of blocking properties of flunarizine respect to cardiac, vascular and peripheral neuronal calcium channel in the pithed rat. 4th International Symposium on Calcium Antagonists. Florence: 70 (Abstr), 1989.
17.
Fournet N, Garcia-Segura LM, Norman AW, Orci L: Selective localization of calcium-binding protein in human brainstem, cerebellum spinal cord. Brain Res 399:310-316, 1986.
18.
Louis P: A double-blind placebo controlled prophylcatic study of flunarizine (sibelium) in migraine. Headache 21:235-239, 1981.
19.
Cerbo R, Casacchia M, Formisano R et al: Flunarizine-pizotifen single dose, double blind cross over trial in migraine prophylaxis. Cephalalgia 6:15-18, 1986.
20.
Lucking HC, Oestreich W, Schmidt R, Soyka D: Flunarizine vs propranolol in the prophylaxis of migraine: two double-blind comparative studies in more than 400 patients. Cephalalgia 8, suppl 8:21-26, 1988.
21.
Bussone G, Baldini S, D'Andrea G et al: Nimodipine vs flunarizine in common migraine: a controlled pilot trial. Headache 27:76-79, 1987.
22.
Amery AK: Onset of action of various migraine prophylactics. Cephalalgia 8, suppl 8:11-13, 1988.
23.
Bono G, Manzoni GC, Martucci N et al: Flunarizine treatment in migraine syndrome: long term follow-up in common migraine and preliminary results in migraine with paroxismal headache. Cephalalgia 5:538-539, 1985.
24.
Manzoni GC, Bussone G, Granella F et al: Long-term efficacy and safety of flunarizine in the prophylaxis of migraine without aura. Cephalalgia 9, suppl 10:426-427, 1989.
25.
Centonze V, Magrone D, Vino M et al: Flunarizine in migraine prophylaxis: efficay and tolerability of 5 mg and 10 mg dose levels. Cephalalgia 10:17-24, 1990.
26.
Soyka D, Taneri Z, Oestreich W, Schmidt R: Flunarizine iv in the acute treatment of the migraine attack. A double blind placebo controlled study. Cephalalgia 8, suppl 8:35-40, 1988.
27.
Sorge F, De Simone R, Marano R et al: Flunarizine in prophylaxis of childhood migraine. Cephalalgia 8:1-6, 1988.
Massimo Leone, Licia Grazzi, Loredana La Mantia and Gennaro Bussone
Centro Cefalee, Istituto Neurologico "C. Besta", Via Celoria 11, 20133 Milano, Italy Reprint requests to: Gennaro Bussone, M.D., Istituto Neurologico "C. Besta", Via Celoria 11, 20133 Milano, Italy. Accepted for Publication: April 9, 1991. SYNOPSIS
Flunarizine is a non-selective calcium antagonist. It distributes preferentially in the adipose tissue and passes the blood brain barrier. Numerous controlled clinical studies have established that flunarizine is efficacious in migraine prophylaxis, including double-blind studies in which the drug was compared with placebo or other antimigraine drugs. To avoid side effects a special schedule or administration is necessary. Flunarizine has no myogenic effect on smooth muscle cells of the vessles. It is said to be the only calicum antagonist able to protect brain cells against hypoxic damage. In addition, the considerable body of information which shows flunarizine capable of directly influencing the central nervous system, suggests that the drug's anti-migraine action may depend on its ability to influence central phenomena. Key words: flunarizine, migraine, prophylaxis. (Headache 31:388-391, 1991) INTRODUCTION
Calcium ions preside over numerous cell, including nerve cell, functions. For executing these functions the ions are mobilised either from intracellular pools or enter from the exterior. Calcium enters cells via "slow" or "fast" channels. Fast, or receptor operated channels (ROC) are activated by the formation of a ligand-receptor complex at the external surface of the cell membrane. Slow or voltage operated channels (VOC) are activated by ad hoc changes in membrane potential. Calcium-antagonist drugs mainly exert their effects on VOC channels, at least three kinds of which have so far been identified: transient (T), long-lasting (L), and neuronal (N). L channels, with their prolonged opening period, seem particularly sensitive to calcium antagonists.1 When a certain potential difference exists across the neuronal membrane, the slow channels open to allow the ingress of calcium. The latter is responsible for the plateau phase of the action potential. Calcium antagonists act on these channels complex membrane proteins - by binding to specific sites on their exterior-facing surfaces. Such allosteric sites have been demonstrated for dihydropyridine (nimodipine), diphenylalkylamine (verapamil) and benzothiazepine (diltiazem).2 The presence of sites predisposed to bind specific molecules able to modulate the functional states of VOCs suggests the existence of endogenous ligands which perform that function physiologically.3 All three types of VOC appear to be present on a wide variety of cells, including neurons.4 Evidence has recently been presented that different tissues possess different forms (isoforms) of this calcium-channel protein.5 This would, at least in part, explain the differing affinities shown by the various calcium antagonists to various tissue types, as well as the multiple uses these drugs find in clinical medicine. Calcium antagonists are in fact a heterogeneous group of compounds and as noted above are employed in numerous clinical conditions. The World Health Organisation recently classified them into two main types:6 those selectively active on slow calcium channels and those active non-selectively on such channels. Each of these main groups is in turn subdivided on the basis of the clinical and detailed pharmacological properties of the individual compounds. Two groups of non-selective compounds are characterised by the fact that they are active on fast sodium channels at the same concentrations as they are active on slow calcium channels. The compound flunarizine is a non-selective calcium antagonist. A highly lipophilic, poorly water-soluble substance, it distributes preferentially in adipose tissue and binds tightly to plasma and tissue proteins. Blood levels of the drug are low and tissue levels are much higher. The compound is easily absorbed in the gastrointestinal tract and the liver probably exerts a "first passage" effect on it, which would explain the great variability in drug plasma levels among different subjects. Because it is lipophilic, flunarizine passes the blood-brain barrier and reaches the brain in significant quantities. Its half life in the body is 7-10 days, metabolic degradation apparently occurring principally via aromatic hydroxylation and oxidative dealkylation. RATIONALE FOR USE OF FLUNARIZINE IN MIGRAINE
Although the pathogenesis of migraine has still not been clarified, the vasomotor alterations which
accompany the attacks seem to play an important role in the genesis of migraine pain, whatever the ultimate origin of those alterations may be.7 It is known that the control smooth muscle cells exert on blood vessel diameter is regulated by calcium flux. It has been suggested that influx of calcium ions into those muscle cells may stabilise vasomotricity, thus avoiding or reducing pain. Initial data on the action of calcium antagonists, particularly flunarizine, in preventing migraine attacks were consistent with this suggestion. Continuing research showed that flunarizine possessed additional properties from which arose the prospect that other mechanisms might explain the drug's activity in migraine. It emerged that flunarizine had no myogenic effect on vessels and in fact caused neither vasodilation nor arterial pressure changes.8 It was also discovered that, of a series of calcium antagonists, only flunarizine was able to protect brain cells against hypoxic damage9 and, positing a neuronal genesis for migraine, this fact can be used to explain the anti-migraine action of flunarizine. But flunarizine exerts other effects on neurons. It is, for example, able to raise the excitability threshold in spreading depression and to reduce recovery time from that condition.10This is important because of the similarity between spreading depression and spreading oligoemia in migraine. Flunarizine can also influence the release of transmitters such as dopamine and met-enkephalin11 which could be involved in the pathogenesis of migraine. A further property of flunarizine is that of reducing epileptic neuronal activity and especially of inhibiting the propagation of that activity. The drug has been used clinically as an antiepileptic in association with basic therapy,12 as well as in patients affected with both migraine and epilepsy.13 Flunarizine is also known to induce changes in the hypothalamohypophyseal axis; at least in part these are mediated by a direct effect on the hypothalamus.14 A further effect of flunarizine is that of inducing behavioural changes; for example, after animal administration a reduction in conditioned behaviour is observed which is similar to that caused by haloperidol.14 Turning now to the side effects of treatment with flunarizine, extrapyramidal disturbances, somnolence, depression and the increased appetite observed during treatment, may all be explained by a direct action of the drug on the central nervous system. The considerable body of information on flunarizine, which shows it capable of directly influencing the CNS, naturally suggests that the drug's anti-migraine action depends on its ability to interfere with central phenomena. Several other important observations are consistent with this idea of a non-vascular mode of action for flunarizine in migraine prophylaxis, Consider the example of nimodipine, a calcium antagonist which is highly selective for cerebral blood vessels. Nimodipine is a thousand times more potent than flunarizine in inhibiting human temporal artery contractions,15 yet it is required at doses many times greater in order to achieve migraine prophylaxis, in fact seeming less effective than flunarizine in preventing attacks (see below). Note also that the vasomotor effects of flunarizine are slight and occur a few hours after administration of the drug - at the same time as the plasma concentration peaks. Migraine prophylaxis, on the other hand, commences after several days of treatment. This discrepancy could be explained by supposing that flunarizine acts (after concentration build-up in the CNS) by restoring correct functioning in the transmitter systems supposed to be involved in migraine. There are other possible explanations for flunarizine's anti-migraine activity. It could be mediated by inhibition of transmission along the trigemino-vascular system, although recent results16 indicate that flunarizine does not act at the level of the peripheral nervous system. Besides modifying intracellular calcium levels via its calcium antagonist effect, flunarizine could act directly on certain intracellular proteins which bind calcium - calmodulin for example. A particular form of calmodulin has been identified in the nucleus spinalis trigeminalis and the substantia gelatinosa Rolandi of man;17 both these CNS structures are involved in nociception. It appears that these calcium binding proteins are completely absent from the motor and epicritic (tactile and pro-prioreceptive) systems. EFFECTIVENESS AND SAFETY OF FLUNARIZINE IN MIGRAINE THERAPY
Numerous controlled clinical studies have established that flunarizine is efficacious in migraine prophylaxis, including double-blind studies in which the drug was compared with placebo18 and the anti-migraine drugs pizotifen,19 ß-blockers20 and nimodipine.21 Our group conducted the latter study, a multicentre double-blind trial with parallel groups in which flunarizine at 10 mg/day was compared with nimodipine at 120 mg/day; the study conclusion was that flunarizine was efficacious in migraine prophylaxis. The studies cited above all used flunarize at 10 mg/day. The parameter most sensitive to the treatment is headache frequency, a reduction of which is evident after one month,22 as occurs with other anti-migraine therapies. In these studies it appeared that the number of responders (subjects with pain index improvement of >50%) tends to increase as long-term therapy continues. The time required for the drug to begin having an effect corresponds well with the approximately 4-5 weeks required for it to reach a steady state concentration. After establishing the drug's efficacy, the effects of long-term use remained to be investigated. Specifically the incidence of unpleasant side effects and their dose dependence had to be determined, as
well as whether tolerance developed or the clinical advantage persisted after the suspension of therapy. It was also necessary to optimise treatment duration and find a dose having the best benefit/side effects ratio. The first open multicentred long-term study envisaged the administration of flunarizine to 120 migraine patients for 2 years at 10 mg/day23 Only 44 remained at the final check-up after 2 years of therapy. Interestingly those who took the drug for that period did not develop tolerance. After three months 54% of the 110 patients checked were responders; at the 9th month 72% of the 93 checked were responders. The side effects which developed over the 2 year period constituted the main limitation to the therapy: weight gain (mean 8 Kg) in 54%, somnolence in 42% particularly in the first month, and depression - the most frequent reason for dropping out. Given the high frequency of side effects it became necessary to review the way in which the drug was administered over the long-term. A second multicentred study addressed this problem,24 evaluating efficacy and side effects over one year during which the novel regime of six month's prophylaxis with flunarizine followed by 6 months with no treatment was applied. In the first month flunarizine was given at 10 mg/day and for the following 5 months it was administered for only 3 weeks per month. Of the 100 patients enrolled, 92 completed the first phase; of those dropping out 2 received no benefit from the treatment, 3 stopped because of side effects (2 for an average 2 Kg weight increase, 1 for depression) and the last patient was not compliant. There were 60 (70.6%) responders at the end of this first treatment period. Seventy-nine patients completed the 2nd six months of observation without therapy. Of the 60 responders observed at the end of therapy, 32 (53.4%) derived benefit from it during the following six months of non-therapy. The side effects observed were: somnolence (N=20), transitory in nearly all cases; depression (N=3); and modest weight increase (2.3 ± 1.5 Kg) (N=30); there were no extrapyramidal disturbances. The mode of flunarizine administration tested in this study resulted in a marked reduction in the frequency and severity of side effects while retaining the therapeutic benefit, in many cases, for six months after treatment suspension. With the aim of further optimising flunarizine administration Centonze et al25 recruited a group of 40 migraine patients (11 with aura and 29 without) to a crossover study (each treatment period lasting 60 days) in which the result of administering flunarizine at 5 mg/day was compared with the more usual 10 mg/day dosage. The clinical protocol suggested by the results is that of employing flunarizine at 10 mg/day during the first 15-20 days, thus keeping the latency period short, and then passing to a 5 mg/day maintenance regime to keep side effects to a minimum. It was observed in fact that patients who took flunarizine at 10 mg/day in the initial phase maintained their clinical improvement when they took the drug at 5 mg/day. Flunarizine has also been successfully employed to treat migraine attacks. In a double blind study, the efficacy of 20 mg of flunarizine administered intravenously in 31 patients with migraine headache (7 with and 23 without aura) was compared with similarly administered placebo in 29 subjects (10 with and 19 without aura)26 After the first hour's observation 74.2% of those found to have taken flunarizine were responders, while only 27.6% of those given placebo were responders. Similar results were obtained for the phenomena accompanying migraine. Pulse and arterial pressure did not change significantly and 11 patients were somnolent. Notwithstanding these encouraging results it will be necessary to perform further studies, employing rigorous methodology and large groups of patients, to compare the now established efficacy of flunarizine with other symptomatic treatments for migraine. Migraine is not a condition which only affects adults, and the problem of treating the considerable number of pediatric cases arises. Seventy child sufferers of common migraine (ages between 6 and 11) were recently involved in a trial to evaluate the efficacy of flunarizine in this field.27 The study employed a double blind crossover protocol against placebo, and lasted eight months. A significant reduction in the frequency and duration of migraine attacks, beginning from the 2nd month of treatment, was observed in those who received flunarizine in the first phase. The reductions were maintained until the end of the study. Those who received the drug in the second phase of the trial only experienced a clinical advantage a month after the crossover, ie after a month of flunarizine administration. The most frequent side effects were weight increase in 14 (22.2%) (mean increase not reported) and somnolence in 6 (9.5%). Apart from the fact that flunarizine was efficacious, the most interesting thing to emerge was that the clinical benefit persisted long after the drug was suspended, a similar result to that obtained by us in our adult study.24 It is concluded that flunarizine can be regarded as one of the more important prophylactic therapies for migraine. The unpleasant side effects which emerge on long-term treatment can be very effectively reduced by the application of a specific treatment regime. The compound has also been shown to be useful in pediatric patients both prophylactically and for treating migraine attacks, although further studies will be necessary to confirm these initial findings. It is noted, finally, that the drug is very probably centrally acting and this is consistent with current views on the pathogenesis of migraine.
REFERENCES
1.
Braunwald E: Mechanism of action of calcium channel-blocking agents. NEJM 307:1616-1627, 1982.
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