Flunarizine in Migraine Prophylaxis: An Indian Trial
M. Thomas, M. Behari and GK Ahuja
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India. Reprint requests to: Dr. G. K. Ahuja, Professor, Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029, India. Accepted for Publication: August 22, 1991. SYNOPSIS
Flunarizine, a calcium channel blocker is considered useful in migraine prophylaxis. We report the first Indian trial with this drug. Fifteen patients with migraine were studied in a 6 months double-blind, placebo-controlled crossover trial. Flunarizine was superior to placebo in reducing the severity and duration of the individual attacks though there was no statistically significant effect on frequency of migraine attacks. The side effects most frequently caused by flunarizine were weight gain and daytime sleepiness. Key words: flunarizine, migraine. (Headache 31:613-615, 1991) INTRODUCTION
Migraine is a condition that inconveniences, even incapacitates its sufferers, and therefore demands relief. Several drugs are already in use for prophylaxis, but the search for an ideal drug is not yet over. Antimigrainous drugs have come into use as various hypotheses for the causes of migraine have gained acceptance. Presently vying for dominance are the vascular and hypoxic theories of migraine. Flunarizine has the advantage of possessing both anti-vasoconstrictive and antihypoxic properties, which form a sound theoretical basis for its usefulness.1,2,3 METHODS
Between June 1988 and August 1989, fifteen adults with migraine (as per Ad Hoc committee definition)4 were studied to evaluate the efficacy and safety of flunarizine in the prophylaxis of migraine. All of them had experienced headaches for more than 2 years and had at least 3 headaches per month in the previous 3 months, Patients with daily attacks of tension-type headache, with a physical cause for headache, with severe systemic illness, or pregnancy, were excluded. Experimental design. The study was a double blind crossover trial with flunarizine (10mg) and placebo. Patients were included in the study after informed consent and were fully aware of their right to drop out whenever they wished to do so, Every patient underwent a complete physical and neurological assessment. Haematological and biochemical parameters including hepatic and renal functions were done before starting the trial and subsequently after the placebo and drug. The drug and placebo were administered as identical-looking white tablets in identical packets. The patients were instructed to take a single tablet at bed time which could be flunarizine (10mg) or an identical tablet of placebo for a period of 12 weeks. They were asked to maintain a diary regarding the number, severity, duration of attacks, associated symptoms, analgesic consumption and side effects. Patients were seen at 4 week intervals and were crossed over from drug to placebo or vice-versa after a two week washout period. Evaluation of Efficacy. The efficacy of flunarizine as compared with placebo, was assessed by means of four indices and was considered significant if the reduction was half or more of the baseline indices. Headache Unit Index (HUI) = Number of headaches Number of days in visit period Corrected Headache Unit Index (HUIc) = Severity of attacks x duration of attacks. Number of days in visit period Headache Index (HI)
= Number of headaches x severity No. of days in visit period
Relief Medication Index (RMI) = Number of doses taken x strength Number of days in visit period The severity of headache was graded as follows: 1. Mild (able to continue working) 2. Moderate (unable to continue working) 3. Severe (confined to bed). The duration was arbitrarily graded as follows: 1. 2-8 hours; 8-12 hours; 3. More than 12 hours. Statistical analysis. McNamara's chi-square test was used to assess the significance of reduction of individual baseline indices by flunarizine versus placebo. Also, median values of these indices for the patients as a group were calculated during the baseline flunarizine and placebo time periods. The statistical significance of this was tested by Friedman's two-way analysis of variance.
RESULTS
All 15 patients had common migraine. There were 13 women and 2 men; their ages ranged from 20-43 years (mean 30.46 years). These were the patients who completed both phases of the trial. Eight patients followed a placebo-flunarizine sequence while the other seven followed a flunarizine-placebo sequence. There were 14 dropouts from among the 29 patients who were started on the trial. Ten of these patients dropped out while on placebo while the other 4 patients did so while on flunarizine. One 24 year old patient was asked to discontinue within 2 weeks of starting the trial as she became pregnant. A 40 year old female patient developed galactorrhea, after being on flunarizine for 2 months-she was asked to stop the drug, and to undergo investigation as to the cause of galactorrhea, but she did not return for follow up. The other 12 patients dropped out during varying phases of the trial without giving any specific reason for doing so. They did not report back to the hospital or respond to letters sent out to them. EFFICACY OF TREATMENT
The number of individual patients with a beneficial reduction of the various indices was not statistically significant, although the trend was in favour of flunarizine rather than placebo (Table 1). When the
Parameters
Flunarizine
HUI HI HUIc RMI Global appreciation
Table 1 Placebo Overlap
Unchanged
X2Valuee
5 8 8 5
2 2 2 2
3 4 3 0
5 1 2 8
0.58(N.S.) 2.5(N.S.) 2.5(N.S.) 0.58(N.S.)
10
3
0
2
2.8(N.S.)
median values of indices for the group as a whole were considered, flunarizine brought about a statistically significant reduction as compared to placebo (Table 2). Headache Unit Index (HUI) was reduced by half or more in 5 patients with flunarizine and in 2 patients with placebo. There was an overlap of benefit with flunarizine and placebo in 3 patients. In 5 patients, the reduction was less than half with both flunarizine and placebo, and was considered as 'No benefit' when assessing efficacy. The chi-square value of 0.25 was not significant, suggesting that flunarizine showed no advantage over placebo in reducing the number of migraine attacks per visit period (Table 3). Index
Baseline
Flunarizine
HUI HI HUIc
4.0 6.7 4.0
3.0 3.0 1.0
Table 2 Placebo 3.3 6.0 4.0
Flunarizine Vs. Baseline P
M. Thomas, M. Behari and GK Ahuja
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India. Reprint requests to: Dr. G. K. Ahuja, Professor, Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029, India. Accepted for Publication: August 22, 1991. SYNOPSIS
Flunarizine, a calcium channel blocker is considered useful in migraine prophylaxis. We report the first Indian trial with this drug. Fifteen patients with migraine were studied in a 6 months double-blind, placebo-controlled crossover trial. Flunarizine was superior to placebo in reducing the severity and duration of the individual attacks though there was no statistically significant effect on frequency of migraine attacks. The side effects most frequently caused by flunarizine were weight gain and daytime sleepiness. Key words: flunarizine, migraine. (Headache 31:613-615, 1991) INTRODUCTION
Migraine is a condition that inconveniences, even incapacitates its sufferers, and therefore demands relief. Several drugs are already in use for prophylaxis, but the search for an ideal drug is not yet over. Antimigrainous drugs have come into use as various hypotheses for the causes of migraine have gained acceptance. Presently vying for dominance are the vascular and hypoxic theories of migraine. Flunarizine has the advantage of possessing both anti-vasoconstrictive and antihypoxic properties, which form a sound theoretical basis for its usefulness.1,2,3 METHODS
Between June 1988 and August 1989, fifteen adults with migraine (as per Ad Hoc committee definition)4 were studied to evaluate the efficacy and safety of flunarizine in the prophylaxis of migraine. All of them had experienced headaches for more than 2 years and had at least 3 headaches per month in the previous 3 months, Patients with daily attacks of tension-type headache, with a physical cause for headache, with severe systemic illness, or pregnancy, were excluded. Experimental design. The study was a double blind crossover trial with flunarizine (10mg) and placebo. Patients were included in the study after informed consent and were fully aware of their right to drop out whenever they wished to do so, Every patient underwent a complete physical and neurological assessment. Haematological and biochemical parameters including hepatic and renal functions were done before starting the trial and subsequently after the placebo and drug. The drug and placebo were administered as identical-looking white tablets in identical packets. The patients were instructed to take a single tablet at bed time which could be flunarizine (10mg) or an identical tablet of placebo for a period of 12 weeks. They were asked to maintain a diary regarding the number, severity, duration of attacks, associated symptoms, analgesic consumption and side effects. Patients were seen at 4 week intervals and were crossed over from drug to placebo or vice-versa after a two week washout period. Evaluation of Efficacy. The efficacy of flunarizine as compared with placebo, was assessed by means of four indices and was considered significant if the reduction was half or more of the baseline indices. Headache Unit Index (HUI) = Number of headaches Number of days in visit period Corrected Headache Unit Index (HUIc) = Severity of attacks x duration of attacks. Number of days in visit period Headache Index (HI)
= Number of headaches x severity No. of days in visit period
Relief Medication Index (RMI) = Number of doses taken x strength Number of days in visit period The severity of headache was graded as follows: 1. Mild (able to continue working) 2. Moderate (unable to continue working) 3. Severe (confined to bed). The duration was arbitrarily graded as follows: 1. 2-8 hours; 8-12 hours; 3. More than 12 hours. Statistical analysis. McNamara's chi-square test was used to assess the significance of reduction of individual baseline indices by flunarizine versus placebo. Also, median values of these indices for the patients as a group were calculated during the baseline flunarizine and placebo time periods. The statistical significance of this was tested by Friedman's two-way analysis of variance.
RESULTS
All 15 patients had common migraine. There were 13 women and 2 men; their ages ranged from 20-43 years (mean 30.46 years). These were the patients who completed both phases of the trial. Eight patients followed a placebo-flunarizine sequence while the other seven followed a flunarizine-placebo sequence. There were 14 dropouts from among the 29 patients who were started on the trial. Ten of these patients dropped out while on placebo while the other 4 patients did so while on flunarizine. One 24 year old patient was asked to discontinue within 2 weeks of starting the trial as she became pregnant. A 40 year old female patient developed galactorrhea, after being on flunarizine for 2 months-she was asked to stop the drug, and to undergo investigation as to the cause of galactorrhea, but she did not return for follow up. The other 12 patients dropped out during varying phases of the trial without giving any specific reason for doing so. They did not report back to the hospital or respond to letters sent out to them. EFFICACY OF TREATMENT
The number of individual patients with a beneficial reduction of the various indices was not statistically significant, although the trend was in favour of flunarizine rather than placebo (Table 1). When the
Parameters
Flunarizine
HUI HI HUIc RMI Global appreciation
Table 1 Placebo Overlap
Unchanged
X2Valuee
5 8 8 5
2 2 2 2
3 4 3 0
5 1 2 8
0.58(N.S.) 2.5(N.S.) 2.5(N.S.) 0.58(N.S.)
10
3
0
2
2.8(N.S.)
median values of indices for the group as a whole were considered, flunarizine brought about a statistically significant reduction as compared to placebo (Table 2). Headache Unit Index (HUI) was reduced by half or more in 5 patients with flunarizine and in 2 patients with placebo. There was an overlap of benefit with flunarizine and placebo in 3 patients. In 5 patients, the reduction was less than half with both flunarizine and placebo, and was considered as 'No benefit' when assessing efficacy. The chi-square value of 0.25 was not significant, suggesting that flunarizine showed no advantage over placebo in reducing the number of migraine attacks per visit period (Table 3). Index
Baseline
Flunarizine
HUI HI HUIc
4.0 6.7 4.0
3.0 3.0 1.0
Table 2 Placebo 3.3 6.0 4.0
Flunarizine Vs. Baseline P
