Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation

Pharmacological data and early clinical experience have suggested that the calcium entry blocker flunarizine may be a valuable gain in the prophylaxis of migraine. This was supported by a study in 20 patients with classical migraine who were, after a drug free run-in phase, orally treated with either placebo or flunarizine (10 mg at night) for 3 to 4 months. Flunarizine significantly reduced the frequency, duration and severity of the migraine attacks. A corrected migraine index, based on these 3 variables was reduced by 82% in the drug group but increased by 66% in the control patients. Only 1 patient did not clearly benefit from flunarizine. In some cases flunarizine should be administered for at least 4 months before judging its efficacy. No side-effects occurred.     

A placebo-controlled, double-blind, cross-over trial of flunarizine in common migraine

After four weeks of medication-free baseline observation, 29 patients with common migraine randomly received flunarizine (10 mg daily) or placebo for a 16-week period. After four weeks wash-out they crossed treatments for another 16 weeks; 27 patients completed the trial. Compared with placebo, flunarizine significantly reduced the frequency of migraine attacks and the derived headache indices, but the duration and severity of single attacks remained unchanged (Mann-Whitney U-test). The effect of flunarizine increased during the 16-week treatment period and during the last four weeks the number of migraine attacks reduced to 50% compared to the wash-out period. The only side-effect of flunarizine was mild daytime sedation in three patients. It is concluded that flunarizine is a valuable new prophylactic agent for common migraine.     

Metoprolol and propranolol in the prophylactic treatment of classical and common migraine. A double-blind study

In a double-blind, cross-over study the effect and tolerance of the non-selective beta-blocker propranolol in a dosage of 80 mg twice daily was compared to that of the beta 1-selective beta-blocker metoprolol 200 mg once daily in Durules (a controlled-release formulation). The attack frequency, migraine days, severity score, consumption of acute medication and subjective evaluation were the main parameters used for evaluation. Thirty-six patients with classical or common migraine were included. Thirty-three completed the investigation. It is concluded from the results that there are no differences in efficacy between metoprolol and propranolol regarding the studied parameters. Both drugs reduced the migraine symptoms compared to the run-in period and were generally well tolerated.     

Alpha-dihydroergocryptine in the prophylaxis of migraine: a multicenter double-blind study versus flunarizine

This multicenter, double-blind, clinical study was designed to compare the efficacy and safety of alpha-dihydroergocryptine and flunarizine in the prophylaxis of migraine without aura. One hundred thirty-five patients fulfilling the diagnostic criteria of the International Headache Society were enrolled at five neurologic centers. The study design included a 1-month pretreatment phase with placebo; a 6-month, double-blind, double-dummy treatment phase with alpha-dihydroergocryptine (10 mg twice daily) or flunarizine (5 mg once daily); a further 3-month follow-up phase without treatment. Efficacy was assessed using the patient's diary. Laboratory tests, vital signs, and adverse events were monitored. Analysis of covariance for repeated measures was performed on the intent-to-treat sample. Both treatments led to a significant reduction in the frequency of migraine, days with headache, and use of relief medication. Overall, 51% of those treated with alpha-dihydroergocryptine and 49% of those treated with flunarizine were responders (50% or greater reduction in attack frequency), the average percentage of reduction being 64% with alpha-dihydroergocryptine and 51% with flunarizine. There was no significant difference between the two groups in terms of incidence of adverse events; dizziness and weight gain were the most frequent observed adverse events with alpha-dihydroergocryptine and flunarizine, respectively. Based on the overall improvement in migraine parameters, alpha-dihydroergocryptine can be recommended for use in migraine prophylaxis.     

Flunarizine in prophylaxis of childhood migraine

An 8-month, double-blind, placebo-controlled, crossover trial of flunarizine in the prophylaxis of migraine has been performed in 70 children. After 4 weeks of medication-free base-line observation, 35 children (group A) received flunarizine (5 mg/day) and 35 (group B) received placebo over a 12-week period. After a 4-week washout they crossed treatments for another 12 weeks. Sixty-three patients completed the trial. In both groups flunarizine significantly reduced the frequency and average duration of headache attacks. In group A efficacy was maintained after placebo crossover for the last 4 months of the study. Five subjects in group B stopped placebo because of ineffectiveness; two children in group A discontinued flunarizine treatment, one because of excessive daytime sedation and the other because therapy was ineffective. The main side effects were daytime sedation and weight gain. It is concluded that flunarizine is an effective drug for the treatment of childhood migraine. In a study of this length no serious side effects were discovered.     

A comparative study of oral acetylsalicyclic acid and metoprolol for the prophylactic treatment of migraine. A randomized, controlled, double-blind, parallel group phase III study

This study was a multinational, multicentre, double-blind, active controlled phase III trial designed to investigate efficacy and safety of 300 mg acetylsalicyclic acid (ASA) (n = 135) vs. 200 mg metoprolol (n = 135) in the prophylaxis of migraine. In total 270 (51 male and 219 female) patients, aged 18-65 years, suffering between two and six migraine attacks per month were recruited. The main objective was to show equivalence with respect to efficacy, defined as a 50% reduction in the rate of migraine attacks. A run-in phase was carried out with placebo for 4 weeks, followed by a 16-week drug phase. In both treatment groups the median frequency of migraine attacks improved during the study period, from three to two in the ASA group and from three to one in the metoprolol group; 45.2% of all metoprolol patients were responders compared with 29.6% with ASA. Medication-related adverse events were less frequent in the ASA group (37) than in the metoprolol group (73). The findings from this trial show that metoprolol is superior to ASA for migraine prophylaxis but has more side-effects. Acetylsalicylic acid is better tolerated than metoprolol. Using a strict responder criterion ASA showed a responder rate comparable with the placebo rate in the literature.     

Flunarizine and Propranolol in the Treatment of Migraine

The clinical efficacy of flunarizine and of propranolol for the prevention of migraine attacks was assessed in a multicenter double-blind study lasting four months which was preceded by a single-blind placebo period of one month. For both drugs, more than half of the patients judged the effect to be good or very good. When considering the patients' daily logs, both drugs produced a significant reduction of the number of attacks. Propranolol furthermore significantly reduced the severity of attacks and the number of analgesics used during the attacks. In both groups no severe side effects were observed.     

Comparison of the Efficacy Between Flunarizine and Nifedipine in the Prophylaxis of Migraine

SYNOPSIS
Background. Several calcium channel blockers have been evaluated in controlled clinical studies and some holdconsiderable promise for future. Efficacy in migraine prophylaxis has been claimed for drugs belonging to all threeclasses of calcium channel blockers (nifedipine-like, verapamil-like, and flunarizine-like), but the extent and quality of theevidence varies, and a comparison of efficacy between different calcium channel blockers has not been reported. Objective. The objective of the study is to assess the comparison of efficacy and safety of flunarizine and nifedipinein migraine prophylaxis. Patients and methods. The study was conducted in a prospective, double-blind, randomized controlled trial, parallelgroup design. 78 patients were studied for a 1-month period during which all patients received placebo followed by a3-month experimental period. Headache response to medication was measured monthly by compilation ofmigraine-scores derived from quantitative data recorded by patients in a daily diary.¹ Student's t-test was used tocompare results from the flunarizine (10 mg) and nifedipine (20 mg) group for each month. Results. Both groups showed a significant reduction in the migraine-scores after 3-months. No significantdifferences were detected between groups, but there was a clinical significantly different reduction of migraine-scoresbetween the groups in the first month after the run-in period (58% vs 38%). It shows that the beneficial effect offlunarizine was more rapidly manifest than that of flunarizine. Tachycardia more frequently occurred in the nifedipinegroup than in the flunarizine treatment group. Conclusion. It concluded that flunarizine is a potentially more useful agent in the prophylaxis of migraine headache.     

Effects of the cardioselective beta-blocker metoprolol in angina pectoris. A subacute study with exercise tests.

The effects of the cardioselective beta-blocker, metoprolol, were evaluated under double-blind conditions in eighteen patients with angina pectoris. During an introductory run-in period of eight weeks, a placebo was given single-blindly. Thereafter two double-blind crossover periods each of four weeks followed, either 20 mg metroprolol or placebo being given t.i.d. Metoprolol gave a significant reduction in the number of anginal attacks and in nitroglycerin consumption. The patients' subjective assessments of their daily angina pectoris symptoms also showed a significant improvement compared with the placebo. At the end of each period, a standardized exercise test was performed. In comparison with placebo, metoprolol gave a significant increase of total work performed until the appearance of 1 mm ST-segment depression and until the end of exercise. The heart rate was significantly reduced at rest and during exercise. The blood pressure was significantly reduced only during exercise. None of the patients reported any severe unwanted effects. The complaints reported were mild to moderate, and the frequency during metoprolol treatment was even lower than during placebo treatment. No signs or symptoms of cardiac failure were seen in any of these patients on any occasion. It is concluded that 20 mg metoprolol t.i.d. is of benefit in the treatment of angina pectoris but further benefit might be obtained with higher doses.     

Long Acting Propranolol in the Prophylaxis of Migraine. Comparison of the Daily Doses of 80 mg and 160 mg

SYNOPSIS
The efficacy of long acting propranolol in a dosage of 80 mg once daily in comparison to 160 mg once daily was assessed in the prophylactic treatment of migraine in a double-blind cross-over trial. 48 patients with classic or common migraine were included in the investigation, 6 patients withdrew, but only one because of side-effects. A four week run-in placebo period preceded the drug treatments, the duration of drug treatments was 12 weeks and there was a wash-out placebo period of 4 weeks between the treatments.
The two long acting propranolol doses, 80 mg and 160 mg once daily seemed to be equally effective. There was no difference in the antimigraineous effect. Long acting propranolol decreased both the frequency and severity of migraine attacks. Side-effects reported during the trial were mild, both doses were well tolerated. The treatment compliance during the once daily treatment was very good.     

Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily

This was a phase-IV double-blind equivalence trial designed to assess the efficacy and tolerability of two doses of flunarizine (10 mg o.d.=FLU 10 mg and 5 mg o.d.=FLU 5 mg) in the prophylaxis of migraine, in comparison with slow-release propranolol (160 mg o.d.). A total of 808 subjects were treated in a treatment period of 16 weeks. 142 subjects discontinued the trial prematurely, mainly because of adverse events (n=58). The mean attack frequency in the double-blind period was 2.0 for the FLU 5 mg group, 1.9 for the FLU 10 mg group, and 1.9 for the propranolol group. The mean attack frequency in the last 28 days of the double-blind period was 1.8 for FLU 5 mg, 1.6 for FLU 10 mg, and 1.7 for propranolol. Both flunarizine groups were at least as effective as propranolol (P<0.001 in one-sided test). The percentage of responders (defined as subjects for whom attack frequency decreased by at least 50% compared to run-in) in the last 28 days of the double-blind period was 46% (118/259) for FLU 5 mg, 53% (141/264) for FLU 10 mg, and 48% (125/258) for propranolol. Statistical analysis showed that FLU 10 mg is at least as effective as propranolol (P<0.001) and showed a trend for noninferiority of FLU5 and propranolol (P=0.053). No statistically significant differences between the treatment groups were found for any of the secondary parameters. Overall, 190 subjects reported one or more adverse events during the run-in phase: 54 (20.5%) in the FLU 5 mg group, 76 (27.7%) in the FLU 10 mg group and 60 (22.3%) in the propranolol group. The results of this equivalence trial show that 10 mg flunarizine daily with a drug-free weekend is at least as effective as 160 mg propranolol in the prophylaxis of migraine for all evaluated parameters (one-sided equivalence tests) after 16 weeks of treatment. In addition, 5 mg flunarizine proves to be at least as effective as 160 mg propranolol when looking at the mean attack frequency for both the whole double-blind period and the last 28 days of treatment. However, in the analysis of responders, 160 mg propranolol seems to be slightly better than 5 mg flunarizine. In addition, no significant differences between the three treatments were found with regard to safety: all three treatments were generally well-tolerated and safe.     

Comparison of flunarizine (Sibelium®) and pizotifen (Sandomigran®) in migraine treatment: A double-blind study

In this double-blind, randomized multicenter study involving 75 patients, the calcium-entry blocker flunarizine (10 mg nocte) was compared with pizotifen (2–3 mg per day in three administrations). Duration of treatment was four months. The results suggest that, in the dosage used, flunarizine is at least as effective as pizotifen in both classical and common migraine as regards effect on attack frequency. Flunarizine might tend to more markedly suppress severity of the attack, though. The weight gain seen with both drugs might be slightly less with flunarizine. A practical advantage of flunarizine is its simple dosage schedule (one intake per day).     

Efficacy of nimodipine in comparison with pizotifen in the prophylaxis of migraine

The efficacy of nimodipine in comparison with that of pizotifen was assessed in the prophylaxis of migraine in a double-blind cross-over study, in which a double-dummy technique was also utilized. The study was carried out on 43 migraine patients, of whom 15 had classic and 28 had common migraine. A 4-week run-in placebo period preceded the drug treatments, the drug treatments lasted 12 weeks, and there was a washout placebo period of 4 weeks between nimodipine and pizotifen treatments. The dosages used were 40 mg three times daily for nimodipine and 0.5 mg three times daily for pizotifen. Both nimodipine and pizotifen proved to be better than placebo, the number of migraine attacks showing a significant reduction. There was no difference between nimodipine and pizotifen in antimigrainous efficacy, but there were fewer side effects during the nimodipine period. The results suggest that nimodipine is an effective drug for the prophylaxis of migraine, with few side effects and therapeutic efficacy equal to that of pizotifen.     

Flunarizine (10 and 20 mg) i.v. versus placebo in the treatment of acute migraine attacks: a multi-centre double-blind study

In a multi-centre, randomized double-blind study, the effect and tolerance of 10 and 20 mg flunarizine i.v. versus placebo was tested on 102 migraineurs with acute migraine attacks with and/or without aura. Thirty-seven patients received 10 mg flunarizine, 32 received 20 mg and 33 received placebo. The groups were comparable. Response to treatment was defined as pain reduction of at least 50% within 60 min on a visual analogue scale after i.v. drug administration. This effect was noted on 59.4% with 20 mg flunarizine, on 24.3% with 10 mg flunarizine and on 30.3% with placebo. The tolerance of flunarizine i.v. was similar to placebo. Blood pressure and pulse rate were not affected by flunarizine. All in all, 20 mg flunarizine i.v. appeared to be a suitable alternative for treatment of acute migraine attacks.     

Prophylactic treatment of migraine with bisoprolol: a placebo-controlled study

The objective of the present study was to assess the efficacy of bisoprolol in migraine prophylaxis. A double-blind placebo-controlled study was conducted in 226 patients with migraine with or without aura, a migraine history of at least 2 years and at least 3 documented attacks during the 28 days run-in period. The duration of treatment was 12 weeks following an initial 28 days' run-in period. Patients reported the number of attacks and their severity in a diary. Treatment with bisoprolol 5 mg resulted in a significant reduction in the frequency of migraine attacks (39% vs 22%) compared to placebo treatment ( p <0.05). Treatment had no effect on the duration and severity of the attacks. Bisoprolol was well tolerated.     

Metoprolol with and without chlorthalidone in hypertension.

After a control period on a placebo, 45 patients with mild to moderate hypertension were treated with metoprolol, 100 mg twice daily alone and in free combination with chlorthalidone 50 mg daily using a double-blind crossover technique. The beta-blocker alone induced a significant fall in blood pressure; the diastolic pressure was reduced to 100 mg Hg or less in 37 of the 45 patients and to 95 mm Hg or less in 19 patients. The addition of chlorthalidone enhanced the antihypertensive effect so that in 33 patients diastolic pressure fell to 95 mm Hg or less. The drugs were well tolerated even by a small number of patients with chronic bronchitis and diabetes mellitus. None of the patients developed cardiac failure. Adding a diuretic caused a small reduction in serum potassium concentrations, and the relevance of this observation is discussed.     

Metoprolol in the Prophylaxis of Migraine: Parallel-Groups Comparison withPlacebo and Dose-Ranging Follow-Up

SYNOPSIS
88 patients in need of prophylactic treatment for classical, common or mixed migraine of at least 2years' duration were admitted to a double-blind placebo-controlled trial of the beta1-selective adrenoceptorblocker, metoprolol. All patients initially took placebo for 1 month, during which 29 were excludedprincipally because of failure to reattend or placebo-response making active treatment unnecessary. Theremaining 59 patients were randomised to continued placebo or metoprolol 50 mg b.i.d. for 2 months.Patients after this time subjectively categorizing their responses as less than optimal changed,double-blindly, from placebo to metoprolol 50 mg b.i.d., or from metoprolol 50 mg b.i.d. to 100 mg b.i.d., fora further follow-up period of up to 3 months.
Placebo response was 40% overall, and often occurred after the first month. In the first double-blindcomparative period metoprolol reduced attack frequency significantly, and more than placebo. Severity ofattacks still occurring was not altered by either treatment. Other measures of illness were alteredconsistently with these principal findings. Consistent improvements also were seen in patients switchingfrom initial placebo therapy to metoprolol 50 mg b.i.d. for the further follow-up period, and those changingto the higher dose of metoprolol showed statistically significant further improvements, and clinicallyimportant improvements overall. Side-effects were minor and reversible.
This study gives supportive evidence of the value of metoprolol in preventing migraine attacks andsuggests that individual dosage titration can substantially enhance its efficacy. Side-effects do notsignificantly impede its use and other evidence suggests that beta1-selective blockers are to be preferredover non-selective in migraine therapy.     

Long-acting propranolol in migraine prophylaxis: results of a double-blind, placebo-controlled study

The efficacy and safety of long-acting propranolol (LA.P), 160 mg once-daily, in the prophylactic treatment of migraine have been tested against placebo in a multicentric, double-blind, randomized study. The two groups are compared in a parallel manner over a treatment period of 12 weeks, following a 4-week placebo run-in period. Fifty-five of the 74 patients who entered the trial were included at the end of the run-in period. Forty-one patients completed the study. None of the 14 patients who withdrew from the study did so because of side effects. The statistical analysis was done according to the "intention to treat" principle. LA.P was significantly more effective than placebo in reducing the frequency of migraine attacks (p = 0.01 by variance analysis). LA.P reduced the average number of monthly crises by 48% on day 84. There was a slight but significant reduction of the systolic blood pressure and heart rate in the erect position, but there was no significant difference between LA.P and placebo regarding either the number of complaints or the number of side effects elicited out of a 17-item questionnaire. None of the observed side effects led to a withdrawal from treatment.     

Montelukast for migraine prophylaxis: a randomized, double-blind, placebo-controlled study

OBJECTIVE: To evaluate the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine. BACKGROUND: A previous small open-label study in migraine patients suggested prophylactic efficacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used in the treatment of asthma. We sought to confirm these findings in a randomized controlled trial. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-groups study enrolled adult migraine outpatients who experienced > or =3 and < or =8 migraine attacks per month for the last 6 months. Patients were entered into a 2-month, single-blind, placebo run-in phase. Only patients who experienced > or =3 migraine attacks in the second month were eligible to enter the subsequent 3-month, double-blind treatment phase of the study. The primary efficacy endpoint was the percentage of patients reporting at least a 50% decrease in migraine attack frequency per month during the double-blind treatment period (months 3-5) compared to baseline (run-in month 2). RESULTS: A total of 93 patients were randomized to montelukast 20 mg and 84 patients to placebo at the end of the placebo run-in month 2; 76 patients on montelukast and 72 patients on placebo completed the double-blind treatment period. Over 3 months of treatment, there was no significant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15.4% for montelukast versus 10.3% for placebo (P= .304). In addition, montelukast 20 mg was not significantly superior to placebo on any of the secondary endpoints. There were no differences between treatment groups for adverse events. CONCLUSION: Montelukast 20 mg was well tolerated in migraine patients but was not an effective prophylactic for prevention of migraine.     

Acetylsalicylic Acid vs. Metoprolol in Migraine Prophylaxis - A Double-Blind Cross-Over Study

In a double blind cross-over study, 28 patients, 5 male and 23 female, aged 31 +/- 14 years, after a run-in period of 8 weeks, were treated for 3 months with acetylsalicylic acid and for another 3 months with metoprolol, both in a prophylactic mode. Attack frequency was reduced significantly with both therapeutic regimens (ASA p less than 0.001, metoprolol p less than 0.00005). Reduction of attacks below 50% was seen with metoprolol in 14 cases, and with ASA in three cases. Even though ASA was of statistically significant efficacy in migraine prophylaxis, it clearly is not the drug of first choice in migraine prophylaxis.