Flunarizine in Migraine: A Double-blind Placebo-controlled Study (in a Saudi Population)
S. M. AI Deeb, M.D., N. Biary, M.D., Y. Bahou, M.D., M. AI Jaberi, M.D. and W. Khoja, M.D.,
Reprints requests to: Dr Saleh M AI Deeb, Department of Clinical Neurosciences, Riyadh Armed Forces Hospital, PC Box 7897, Riyadh 11159, Kingdom of Saudi Arabia Accepted for publication July 5, 1992 SYNOPSIS
We evaluated the effect of flunarizine (Fz) (10 mg/d) on migraine in e double-blind placebo-controlled design. The attacks' frequency, duration, severity and associated symptoms were compared before and after treatment. Forty-two patients completed a three-month trial period; 21 patients received Fz and 21 placebo, Statistical analysis showed no significant difference between Fz and placebo (p>0.051. In this study Fz was not more efficient than placebo in migraine. Key words: Flunarizine, migraine, headache. Abbreviations: Fz Flunarizine, GI gastro-intestinal, IHS International Headache Society, SD standard deviation. (Headache 32: 461-462) INTRODUCTION
After a series of reports had appeared, mainly from Western hemisphere countries, indicating a beneficial effect of flunarizine (Fz) on migraine,1-4 it was decided to carry out a prospective study to detect whether such an effect could be confirmed in a Mid-Eastern population. A placebo-controlled double-blind schedule, not including a wash-out interval/cross-over modulus, was considered to be the optimal method, given the prevailing social habits as well as the geographically wide referral-area of the population to be addressed. METHODS AND SUBJECTS The protocol was aimed at verification of effects of Fz on the frequency and duration of migraine-attacks, while any effect of the drug on the severity of attacks was measured by scoring (a) the intensity of pain (4 point scale); (b) associated symptoms: photophobia (1 point), gastro-intestinal (GI) symptoms such as anorexia, nausea and vomiting (3 point scale), associated neurological symptoms such as scintillating scotoma, hemianopsia, paraesthesias or motor deficit (1 point), and mental changes such as depression, apathy, hyperactivity, amnestic syndrome, confusion, or hallucinations (1 point). The total sum of points for intensity and associated symptoms could therefore not exceed ten. Classic and common migraine were defined according to the 1988 IHS5 classification, which served as inclusion criteria. Excluded were patients with dementing illness, systemic disease, hepatic, gastrointestinal, renal disease, or pregnancy and those who were using Fz already. In order to provide the study the handicap inherent to any long-term pharmacotherapy of chronic disease, it was decided not to exclude patients because of age, duration of disease, or number of different ineffective medications previously used; demonstrating any beneficial effect from Fz in such a "realistic" group would only be the more significant. A baseline value of attack frequency was obtained by having the patients (while not on either Fz or placebo) record the number of attacks over 6 months, and dividing this by two, yielding the number of attacks over a three-month period. To ensure reliability of these data, monthly follow-up visits were arranged over that six-month period. In a similar fashion the average duration and severity of attacks was obtained at the end of the six-month period, to serve for statistical comparison with the scores obtained at the end of the three month drug-trial period. During the trial period, migraine calendars kept by the patients were checked at two two-week and two one-month follow-up visits at which routine neurological examination and inquiries as to side-effects were made and recorded. Over a period of one year, out-patients meeting the diagnostic criteria outlined above were consecutively enrolled in the study, after having been advised of the aim of the study, the possible side-effects of the drug, the lack of awareness by both patient and physician as to the nature of the tablets (placebo or drug) dispensed; their liberty to discontinue participation at any time without any consequences for them as well as their freedom to continue any analgesic medication they usually employed in addition to the "new" tablets; not allowing however any concurrent migraine prophylactic drugs, such as pizotifen, or methysergide. The protocol was approved by the Hospital Medical Ethical Committee. The trial code was broken after the last of 42 patients had completed the trial. Fifty patients were enrolled. Eight were eventually excluded: four because of mild side-effects, such as tiredness or weight-gain, depression or giddiness, four because they were lost to follow-up. RESULTS
As shown in Table 1, neither the number, nor the sex-ratio, nor the age-ranges or duration of disease of the patients differed materially between both groups. However, the medians and arithmetic means of the age differed substantially between both groups. Also, after breaking the code, the Fz group proved to contain seven patients with migraine with aura (classic) and 14 patients with migraine without aura (common), whereas these figures in the placebo group were one and 20 respectively. Also, the Fz group proved to include
nine (and the placebo group six) patients with migraine-onset at age 25 or over. These data actually made the Fz group the most unfavorable of the two for expecting beneficial results from yet another drug. Frequency of attacks. In the Fz group the frequency of migraine-attacks dropped from a mean of 13.75 (SD 7.7) at the beginning to 9.9 (SD 5.3) at the end of the three-month period. For the placebo group the corresponding figures were 9.83 (SD 5) and 7.86 (SD 5.9) respectively. Three patients in the Fz and seven patients in the placebo-group had more attacks at the close of the three-month trial. Student's t-test comparing the attack-frequency reduction in both groups yielded a non-significant value (p=0.08). Severity of attacks. With respect to this predominantly subjective parameter, the scoring values obtained were so close to each other as to preclude any significant statistical difference between both groups. On classifying the reported results as a) no improvement; b) 25-49% improvement; and c) 50-100% improvement, in both groups there were ten patients in the "a" - category, while the "b" - category included five of the Fz and six of the placebo group, the "c" - category included six of the Fz and five of the placebo group. Duration of attack. With respect to this para meter, no curtailment was observed in 12 Fz - and 11 placebo-group patients. Curiously, seven patients in each group showed a reduction of 85-100% in attack-duration, with a 30-50% reduction in two and three patients respectively. There was a wide variation in attack-duration in both groups: in the Fz group, before the trial started, between one and 72 hours, and after three months, between 0.5 and 24 hours; in the placebo group between two and 72 hours, and one and 72 hours respectively. Associated Symptoms. The placebo group fared better than the Fz group on this parameter, the beginning and end score values being 81 over 43 (placebo) versus 76 over 52 (Fz). Even if one adds the scores of associated symptoms to those of severity (maximum ten points), the Fz group shows a 146 to 101 points drop over three months, while the placebo-group shows a 146 to 86 points reduction. DISCUSSION
The results of the present trial can be summarized as follows: Fz tended to reduce the frequency of attacks without reaching the significance level of 0.05; it showed the same number of non-responders (as well as of dramatically improving responders) as the placebo-treated patients with respect to severity and duration of attacks, whereas the placebo-group came out better than the Fz group in reduction of scored associated symptoms or the sum of associated symptoms and severity. Given the higher mean-age, the higher number of attacks at baseline, and the much greater number of classic migraineurs in the Fz group, one might infer that Fz exerts a beneficial effect in reducing the frequency of attacks. The most simplistic inference to be drawn from the present study would be that the drug apparently offers no advantage over placebo in Saudi-Arabian patients. In which case, intriguing questions remain unanswered, viz. how to explain the substantial portion of patients who unequivocally and dramatically responded either to placebo or to Fz. The design of the study made a skewed distribution over both treatment-schedules as well as over diagnostic categories statistically most improbable, as is borne out by the figures (Table 1). The sample-sizes (n=21) may still have been too limited, the more-than-routine attention to detail and intensive guiding by the physicians during the trial may have obscured any discriminatory effect, or - the least popular but perhaps the most truthful explanation - the patients who participated either consistently volunteered induced information, or suffered from unusually marked suggestibility.
N Sex:
Table 1 Flunarizine Placebo 12 21 Male 4 6 Female 17 15 16-65 13 Median: 37 32 36.29 (SD9.92) 32.33(SD 11)
Age: (Yr) Arith Mean: Duration of disease (yrs): 11.55 (SD 6.5) Migraine type: Without aura (Common) 14 With aura (Classic) 7
-65
11.7(SD 7.1) 20 1
Acknowledgement: This study was supported by Janssen Research Council of Janssen Pharmaceutica, Riyadh. We would also like to thank Professor George Bruyn, Professor and Chairman of the Department of Neurology, University Hospital Leyden, The Netherlands, for his guidance and help in preparing this paper. REFERENCES
1.
Louis P. A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 1981; 21:235-239.
2.
Diamond S, Schenbaum H. Flunarizine, a calcium channel blocker, in the prophylactic treatment of migraine. Headache 1983; 23:39-42.
3.
Amery WK. Flunarizine, a calcium channel blocker: a new prophylactic drug in migraine. Headache 1983; 23:70-74.
4.
Leone M, Grazzi L, La Mantia L, Bussone G. Flunarizine in migraine: a mini review. Headache 1991; 31:388-391.
5.
Headache Classification Committee of IHS. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):19-28.
S. M. AI Deeb, M.D., N. Biary, M.D., Y. Bahou, M.D., M. AI Jaberi, M.D. and W. Khoja, M.D.,
Reprints requests to: Dr Saleh M AI Deeb, Department of Clinical Neurosciences, Riyadh Armed Forces Hospital, PC Box 7897, Riyadh 11159, Kingdom of Saudi Arabia Accepted for publication July 5, 1992 SYNOPSIS
We evaluated the effect of flunarizine (Fz) (10 mg/d) on migraine in e double-blind placebo-controlled design. The attacks' frequency, duration, severity and associated symptoms were compared before and after treatment. Forty-two patients completed a three-month trial period; 21 patients received Fz and 21 placebo, Statistical analysis showed no significant difference between Fz and placebo (p>0.051. In this study Fz was not more efficient than placebo in migraine. Key words: Flunarizine, migraine, headache. Abbreviations: Fz Flunarizine, GI gastro-intestinal, IHS International Headache Society, SD standard deviation. (Headache 32: 461-462) INTRODUCTION
After a series of reports had appeared, mainly from Western hemisphere countries, indicating a beneficial effect of flunarizine (Fz) on migraine,1-4 it was decided to carry out a prospective study to detect whether such an effect could be confirmed in a Mid-Eastern population. A placebo-controlled double-blind schedule, not including a wash-out interval/cross-over modulus, was considered to be the optimal method, given the prevailing social habits as well as the geographically wide referral-area of the population to be addressed. METHODS AND SUBJECTS The protocol was aimed at verification of effects of Fz on the frequency and duration of migraine-attacks, while any effect of the drug on the severity of attacks was measured by scoring (a) the intensity of pain (4 point scale); (b) associated symptoms: photophobia (1 point), gastro-intestinal (GI) symptoms such as anorexia, nausea and vomiting (3 point scale), associated neurological symptoms such as scintillating scotoma, hemianopsia, paraesthesias or motor deficit (1 point), and mental changes such as depression, apathy, hyperactivity, amnestic syndrome, confusion, or hallucinations (1 point). The total sum of points for intensity and associated symptoms could therefore not exceed ten. Classic and common migraine were defined according to the 1988 IHS5 classification, which served as inclusion criteria. Excluded were patients with dementing illness, systemic disease, hepatic, gastrointestinal, renal disease, or pregnancy and those who were using Fz already. In order to provide the study the handicap inherent to any long-term pharmacotherapy of chronic disease, it was decided not to exclude patients because of age, duration of disease, or number of different ineffective medications previously used; demonstrating any beneficial effect from Fz in such a "realistic" group would only be the more significant. A baseline value of attack frequency was obtained by having the patients (while not on either Fz or placebo) record the number of attacks over 6 months, and dividing this by two, yielding the number of attacks over a three-month period. To ensure reliability of these data, monthly follow-up visits were arranged over that six-month period. In a similar fashion the average duration and severity of attacks was obtained at the end of the six-month period, to serve for statistical comparison with the scores obtained at the end of the three month drug-trial period. During the trial period, migraine calendars kept by the patients were checked at two two-week and two one-month follow-up visits at which routine neurological examination and inquiries as to side-effects were made and recorded. Over a period of one year, out-patients meeting the diagnostic criteria outlined above were consecutively enrolled in the study, after having been advised of the aim of the study, the possible side-effects of the drug, the lack of awareness by both patient and physician as to the nature of the tablets (placebo or drug) dispensed; their liberty to discontinue participation at any time without any consequences for them as well as their freedom to continue any analgesic medication they usually employed in addition to the "new" tablets; not allowing however any concurrent migraine prophylactic drugs, such as pizotifen, or methysergide. The protocol was approved by the Hospital Medical Ethical Committee. The trial code was broken after the last of 42 patients had completed the trial. Fifty patients were enrolled. Eight were eventually excluded: four because of mild side-effects, such as tiredness or weight-gain, depression or giddiness, four because they were lost to follow-up. RESULTS
As shown in Table 1, neither the number, nor the sex-ratio, nor the age-ranges or duration of disease of the patients differed materially between both groups. However, the medians and arithmetic means of the age differed substantially between both groups. Also, after breaking the code, the Fz group proved to contain seven patients with migraine with aura (classic) and 14 patients with migraine without aura (common), whereas these figures in the placebo group were one and 20 respectively. Also, the Fz group proved to include
nine (and the placebo group six) patients with migraine-onset at age 25 or over. These data actually made the Fz group the most unfavorable of the two for expecting beneficial results from yet another drug. Frequency of attacks. In the Fz group the frequency of migraine-attacks dropped from a mean of 13.75 (SD 7.7) at the beginning to 9.9 (SD 5.3) at the end of the three-month period. For the placebo group the corresponding figures were 9.83 (SD 5) and 7.86 (SD 5.9) respectively. Three patients in the Fz and seven patients in the placebo-group had more attacks at the close of the three-month trial. Student's t-test comparing the attack-frequency reduction in both groups yielded a non-significant value (p=0.08). Severity of attacks. With respect to this predominantly subjective parameter, the scoring values obtained were so close to each other as to preclude any significant statistical difference between both groups. On classifying the reported results as a) no improvement; b) 25-49% improvement; and c) 50-100% improvement, in both groups there were ten patients in the "a" - category, while the "b" - category included five of the Fz and six of the placebo group, the "c" - category included six of the Fz and five of the placebo group. Duration of attack. With respect to this para meter, no curtailment was observed in 12 Fz - and 11 placebo-group patients. Curiously, seven patients in each group showed a reduction of 85-100% in attack-duration, with a 30-50% reduction in two and three patients respectively. There was a wide variation in attack-duration in both groups: in the Fz group, before the trial started, between one and 72 hours, and after three months, between 0.5 and 24 hours; in the placebo group between two and 72 hours, and one and 72 hours respectively. Associated Symptoms. The placebo group fared better than the Fz group on this parameter, the beginning and end score values being 81 over 43 (placebo) versus 76 over 52 (Fz). Even if one adds the scores of associated symptoms to those of severity (maximum ten points), the Fz group shows a 146 to 101 points drop over three months, while the placebo-group shows a 146 to 86 points reduction. DISCUSSION
The results of the present trial can be summarized as follows: Fz tended to reduce the frequency of attacks without reaching the significance level of 0.05; it showed the same number of non-responders (as well as of dramatically improving responders) as the placebo-treated patients with respect to severity and duration of attacks, whereas the placebo-group came out better than the Fz group in reduction of scored associated symptoms or the sum of associated symptoms and severity. Given the higher mean-age, the higher number of attacks at baseline, and the much greater number of classic migraineurs in the Fz group, one might infer that Fz exerts a beneficial effect in reducing the frequency of attacks. The most simplistic inference to be drawn from the present study would be that the drug apparently offers no advantage over placebo in Saudi-Arabian patients. In which case, intriguing questions remain unanswered, viz. how to explain the substantial portion of patients who unequivocally and dramatically responded either to placebo or to Fz. The design of the study made a skewed distribution over both treatment-schedules as well as over diagnostic categories statistically most improbable, as is borne out by the figures (Table 1). The sample-sizes (n=21) may still have been too limited, the more-than-routine attention to detail and intensive guiding by the physicians during the trial may have obscured any discriminatory effect, or - the least popular but perhaps the most truthful explanation - the patients who participated either consistently volunteered induced information, or suffered from unusually marked suggestibility.
N Sex:
Table 1 Flunarizine Placebo 12 21 Male 4 6 Female 17 15 16-65 13 Median: 37 32 36.29 (SD9.92) 32.33(SD 11)
Age: (Yr) Arith Mean: Duration of disease (yrs): 11.55 (SD 6.5) Migraine type: Without aura (Common) 14 With aura (Classic) 7
-65
11.7(SD 7.1) 20 1
Acknowledgement: This study was supported by Janssen Research Council of Janssen Pharmaceutica, Riyadh. We would also like to thank Professor George Bruyn, Professor and Chairman of the Department of Neurology, University Hospital Leyden, The Netherlands, for his guidance and help in preparing this paper. REFERENCES
1.
Louis P. A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 1981; 21:235-239.
2.
Diamond S, Schenbaum H. Flunarizine, a calcium channel blocker, in the prophylactic treatment of migraine. Headache 1983; 23:39-42.
3.
Amery WK. Flunarizine, a calcium channel blocker: a new prophylactic drug in migraine. Headache 1983; 23:70-74.
4.
Leone M, Grazzi L, La Mantia L, Bussone G. Flunarizine in migraine: a mini review. Headache 1991; 31:388-391.
5.
Headache Classification Committee of IHS. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7):19-28.
