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.     

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.     

Effectiveness of lamotrigine in the prophylaxis of migraine with aura: an open pilot study

We report a small open pilot study to evaluate the efficacy of lamotrigine (100 mg/day) in the prevention of migraine with aura attacks. We studied 24 patients affected by migraine with aura with a high frequency of attacks. Following a 1-month run-in period, the patients took lamotrigine for 3 months. Mean attack number per month was reduced from 6.1 +/- 4.1 during the run-in period to 0.7 +/- 1.3 at the 3rd month of treatment (p < 0.0001). In 13 out of 21 patients who completed the study, the attacks were completely abolished at the 3rd month of treatment, while only one patient was completely unresponsive to the drug. Lamotrigine seems worthy of a controlled trial as prophylaxis of a migraine with aura.     

Beta-blockers and migraine. Efficacy of time-release propranolol versus placebo

The efficacy and safety of long-acting propranolol (LA.P) 160 mg once-daily in the prophylactic treatment of migraine were tested against placebo in a multicentric, double-blind, randomized study comparing the two groups in a parallel manner over a treatment period of 12 weeks, and following a 4 week-placebo run-in period. Fifty-five out of the 74 patients who entered the trial included at the end of the run-in period. Forty-one patients completed the study. Out of the 14 patients who withdrew from the study, none discontinued because of side-effects. The statistical analysis was done according to the "intention to treat" principle. LA.P was significantly more efficient 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. 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 an 17 item questionnaire. None of the observed side effects led to a withdrawal of treatment.     

A Placebo-Controlled Crossover Trial of Nimodipine in Pediatric Migraine

An 8-month, double-blind, placebo-controlled crossover trial was carried out on the use of nimodipine in migraine prophylaxis in 37 patients aged 7 to 18 years old. After a 4-week medication-free run-in period, 19 subjects (Group 1) received a placebo while 18 (Group 2) received nimodipine (10-20 mg t.i.d., according to body weight), for 12 weeks. After a 4-week wash-out period, the groups switched therapy for a further 12 weeks. 30 patients completed the trial and the number of dropouts was comparable in the 2 groups. The only side-effect during nimodipine treatment was mild abdominal discomfort (3 cases). The treatments were evaluated on the basis of frequency and duration of attacks. There was a significant reduction in both parameters during the first period of treatment. During the second period of treatment, nimodipine proved to have a significantly greater effect than the placebo with regard to frequency, whereas the response was similar with the placebo as regards duration of attacks. The latter parameter shows a significant decrease during the treatment periods, regardless of type of 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.     

Flunarizine Versus Metoprolol in Migraine Prophylaxis: A Double-Blind, Randomized Parallel Group Study of Efficacy and Tolerability

The prophylactic effect of flunarizine and metoprolol was studied in a multi-center randomized, double-blind trial of 149 patients with migraine with or without aura. After a 4-week placebo run-in period, patients were randomly allocated to treatment with flunarizine 10 mg daily or metoprolol 200 mg daily for 16 weeks (parallel group design). Both drugs reduced the number of migraine days per month by 37% (95% confidence interval 21-53%) compared with the placebo run-in period. All efficacy parameters were significantly reduced by both drugs and no significant difference was found between the two drugs at any time of the treatment period. However, calculation of the 95% confidence limits showed that each drug may have a superiority of more than 100% on a single main effect parameter. The most common adverse experiences were day-time sedation (both drugs) and weight gain (flunarizine). Depression was the most serious side-effect occurring in 8% on flunarizine and 3% on metoprolol. We conclude that both drugs are effective in the prevention of migraine attacks but a higher number of dropouts occurred on flunarizine because of depression or weight gain.     

European Multicenter Trial of Nimodipine in the Prophylaxis of Classic Migraine (Migraine With Aura)

SYNOPSIS
This double-blind, randomized study of the Nimodipine 40 mg t.i.d. vs placebo in the prophylaxis of classic migraine (migraine with aura) included 89 patients. Required migraine frequency was 2–8 migraine days/4 weeks and at least two of the attacks within the last 6 months had to be with aura. The study was carried out at 11 European centers. After a 4 week run-in period, patients were randomly allocated to nimodipine or placebo for 12 weeks (parallel groups). There were 7 dropouts, 3 on Nimodipine, and 4 on placebo. A gradual and verymarked improvement was seen both with Nimodipine and placebo amounting to between 60 and 90 per cent during the last 4 weeks. Statistical analysis on all included patients (intention to treat) revealed no difference between Nimodipine and placebo for migraine days or migraine index. In patients "valid for analysis of efficacy" there were also no significant difference. Due to a very marked placebo effect and use of the parallel groups design, the present trial is relatively weak despite a fairly large sample size. It cannot rule out the possibility of an important effect of Nimodipine in classic migraine with a high degree of certainty.     

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 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.     

Magnesium in the prophylaxis of migraine-a double-blind, placebo-controlled study

The migraine prophylactic effect of 10 mmol magnesium twice-daily has been evaluated in a multicentre, prospective, randomized, double-blind, placebo-controlled study. Patients with two to six migraine attacks per month without aura, and history of migraine of at least 2 years, were included. A 4-week baseline period without medication was followed by 12 weeks of treatment with magnesium or placebo. The primary efficacy end-point was a reduction of at least 50% in intensity or duration of migraine attacks in hours at the end of the 12 weeks of treatment compared to baseline. With a calculated total sample size of 150 patients, an interim analysis was planned after completing treatment of at least 60 patients, which in fact was performed with 69 patients (64F, 5M), aged 18–64 years. Of these, 35 had received magnesium and 34 placebo. The number of responders was 1 in each group (28.6% under magnesium and 29.4% under placebo). As determined in the study protocol, this was a major reason to discontinue the trial. With regard to the number of migraine days or migraine attacks there was no benefit with magnesium compared to placebo. There were no centre-specific differences, and the final assessments of treatment efficacy by the doctor and patient were largely equivocal. With respect to tolerability and safety, 45.7% of patients in the magnesium group reported primarily mild adverse' events like soft stool and diarrhoea in contrast to 23.5% in the placebo group.     

The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis--a double-blind,multicentre, randomized placebo-controlled dose-response study

Tanacetum parthenium (feverfew), is a well-known herb for the prophylactic treatment of migraine. The primary objective was to show a dose-response of a new stable extract (MIG-99) reproducibly manufactured with supercritical CO2 from feverfew (T. parthenium). Furthermore, the study should provide data on the safety and tolerability of MIG-99. In a randomized, double-blind, multicentre, controlled trial with an adaptive design, the clinical efficacy and safety of three dosages of MIG-99 (2.08 mg; 6.25 mg; 18.75 mg t.i.d.) were compared with placebo. The patients (n = 147) suffered from migraine with and without aura according to International Headache Society (IHS) criteria and were treated with one of the study medications for 12 weeks after a 4-week baseline period. The primary efficacy parameter was the number of migraine attacks during the last 28 days of the treatment period compared with baseline. Secondary endpoints were total and average duration and intensity of migraine attacks, mean duration of the single attack, number of days with accompanying migraine symptoms, number of days with inability to work due to migraine as well as type and amount of additionally taken medications for the treatment of migraine attacks. The design of the study included a pre-planned adaptive interim analysis for patients with at least four migraine attacks within the baseline period. With respect to the primary and secondary efficacy parameter, a statistically significant difference was not found between the overall and the confirmatory intention-to-treat (ITT) sample in the exploratorily analysed four treatment groups. The frequency of migraine attacks for the predefined confirmatory subgroup of patients (n = 49) with at least four migraine attacks during the baseline period decreased in a dose-dependent manner (P = 0.001). The highest absolute change of migraine attacks was observed under treatment with 6.25 mg t.i.d. (mean +/- SD = -1.8 +/- 1.5 per 28 days) compared with placebo (-0.3 +/- 1.9; P = 0.02). Overall, 52 of 147 (35%) patients reported at least one adverse event (AE). The incidence of AEs in the active treatment groups was similar to that in the placebo group, and no dose-related effect was observed in any safety parameter. MIG-99 failed to show a significant migraine prophylactic effect in general. Accordingly, in the ITT analysis a dose-response relationship could not be observed. MIG-99 was shown to be effective only in a small predefined subgroup of patients with at least four attacks during the 28-day baseline period where the most favourable benefit-risk ratio was observed with a dosage of three capsules of 6.25 mg MIG-99 extract per day. Because of the low number of patients, these findings need to be verified in a larger sample. The incidence of AEs was similar for all treatment groups.     

Long-acting propranolol in the prophylaxis of migraine: a comparative study of two doses

A randomized double-blind, cross-over study using treatment periods of 12 weeks with a 2-week washout, comparing two long-acting formulations of propranolol ('Inderal' LA 160 mg daily and Half-'Inderal' LA 80 mg daily) was performed after a placebo run-in of 4 weeks on 51 patients. The study indicated that both long-acting formulations were significantly better than placebo in reducing the frequency of migraine attacks (p less than 0.01). After 12 weeks there was a significantly lower (p = 0.03) frequency of migraine attacks in patients on the higher dose formulation than in those on the lower dose formulation. There was no significant difference in the frequency of side effects produced by the two formulations.     

Effect of low-intensity acenocoumarol on frequency and severity of migraine attacks

OBJECTIVE: To investigate the effect of low-intensity acenocoumarol treatment (target INR 1.5 to 2.0) on the frequency and severity of migraine attacks. BACKGROUND: The positive effect of anticoagulation on migraine has been described in case reports and observational studies. METHODS: We conducted a randomized, open, crossover study in migraine patients. After a run-in period of 8 weeks, all patients received acenocoumarol or propranolol during a period of 12 weeks and, after a washout period of 2 weeks, propranolol or acenocoumarol during a second period of 12 weeks. RESULTS: Nineteen patients fulfilling the criteria were included. In 12 patients with complete data collection, only one good responder could be noted. In the other patients, treatment with low-intensity acenocoumarol did not show improvement of migraine symptoms compared with the run-in period. Treatment with propranolol showed a trend towards improvement compared with the run-in period. No serious adverse events were observed. CONCLUSIONS: Overall, low-intensity acenocoumarol treatment has no prophylactic effect in migraine patients.     

A Placebo-Controlled Crossover Trial Using Trazodone in Pediatric Migraine

SYNOPSIS
An 8-month, double-blind, placebo-controlled cross-over trial was carried out on the use of trazodone in pediatric migraine prophylaxis. It involved 40 patients aged 7 to 18 years old and suffering from migraine without aura, randomly divided into 2 groups.
After a 4-week run-in period, Group A received oral trazodone (1 mg/kg a day divided into 3 doses) for 12 weeks, while Group B received a placebo. After a further 4-week washout period, Group A was given the placebo and Group B was treated with trazodone for a further 12 weeks. The trial was completed by 35 patients, the number of drop-outs being comparable in the two groups.
During the first treatment period, both the frequency and the duration of the migraine episodes were significantly reduced in both groups. During the second, a significant further improvement in both parameters was only observed in Group B. No side-effects were observed at any time. Our results showed that, like other antidepressants, trazodone is a valid prophylactic agent for juvenile migraine.     

A negative trial of sodium valproate in cluster headache: methodological issues

We report the result of a double-blind placebo controlled study of sodium valproate (SV) (1000-2000 mg/day) in the prophylaxis of cluster headache CH. Episodic and chronic CH were defined according to the International Headache Society classification. Ninety-six patients were included, 50 in the SV group and 46 in the placebo group. After a 7-day run-in period, patients were treated for 2 weeks. The primary efficacy criterion was the percentage of patients successfully improved, i.e having an at least 50% reduction in the average number of attacks per week between the run-in period and the last week of treatment. Whatever the type of CH, there was no difference between the two groups: 50% of subjects in the SV group and 62% in the placebo group were successfully improved (P = 0.23). This high success rate observed in the placebo group, which is likely to be due to the spontaneous remission of the episode, does not allow us to draw any valid conclusion with regard to the true efficacy of SV in the prophylaxis of CH.     

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.     

European Multicenter Trial of Nimodipine in the Prophylaxis of Common Migraine (Migraine Without Aura)

SYNOPSIS
This double blind, randomized study of the calcium antagonist Nimodipine 40 mg t.i.d. vs placebo in the prophylaxis of common migraine (migraine without aura) included 192 patients. Patients with 2–8 migraine days/4 weeks, age 18–60, who had no other types of recurring headaches except up to 6 interval headaches/4 weeks were included. The study was carried out at 11 European centers. After a 4 week run-in period, patients were randomly allocated to Nimodipine or placebo for 12 weeks (parallel groups). There were 19 drop-outs, 12 on Nimodipine and 7 on placebo, A gradual and marked improvement was seen both with Nimodipine and with placebo amounting to approximately 60% during the last 4 weeks. Statistical analysis on all included patients (intention to treat) revealed no difference between Nimodipine and placebo for migraine days (P = 0.69) or migraine index (p = 0.91). In patients "valid for analysis of efficacy" there were also no significant differences. Due to a very marked placebo effect and use of the parallel groups design, the present trial was not very powerful despite the large number of patients and a satisfactory compliance. We cannot rule out that Nimodipine might have up to 30% effect on a single main outcome parameter, but the uniform lack of response in all tested parameters makes this unlikely. Therefore Nimodipine probably has only a small or no effect in common migraine (migraine without aura).     

Classic migraine: Effective prophylaxis with metoprolol

Metoprolol slow-release tablets (Durules®), 200 mg, given once daily in the morning were compared with placebo in the prophylaxis of classic migraine. The trial comprised eight Scandinavian neurologic centres and was designed as a double-blind cross-over study with 4 weeks' run-in, four weeks washout, and 8 weeks of either treatment. Seventy-seven patients with two to eight migraine attacks per month were entered in the trial, and 73 completed it. A total of 1119 attacks with aura symptoms and 374 without were recorded. Metoprolol was significantly better than placebo with regard to the total frequency of attacks (1.8 versus 2.5 attacks/4 weeks), mean duration of attacks (6.0 versus 8.0 h/attack), mean global rating, and consumption of analgesics per attack: Similar differences could be shown for attacks with aura symptoms alone, except for the duration of attacks. Metoprolol is the first drug for which a prophylactic effect in classic migraine has been convincingly demonstrated.     

Prophylactic botulinum type A toxin complex (Dysport®) for migraine without aura

(Headache 2011;51:52‐63) Objective.— To evaluate the efficacy, safety, and optimum dose of a highly purified Clostridium botulinum type A toxin‐hemagglutinin complex (Dysport) for migraine prophylaxis. Background.— Botulinum toxin type‐A has demonstrated good efficacy in several open‐label studies of patients with migraine, involving either individualized or standardized protocols, although data from placebo‐controlled trials have been conflicting. Methods.— A 12‐week, double‐blind, randomized trial of Dysport (120 or 240 units) vs placebo was conducted in 6 centers in Thailand to evaluate the efficacy, safety, and optimum dose of botulinum toxin type‐A (Dysport) for migraine prophylaxis. A total of 128 patients with migraine without aura were enrolled. The primary end point was the change in the mean number of migraine attacks per 4‐week period from the pre‐treatment period to 8‐12 weeks post injection. Secondary efficacy measures included the change in the mean total intensity score from the pre‐treatment period to 8‐12 weeks, the investigator and patient global assessments of change at each visit compared with pre‐treatment, and Migraine Disability Assessment and Short Form‐36 scores. Results.— Change in number of migraine attacks from pre‐treatment to weeks 8‐12 was not significantly different. There was a greater improvement in total intensity score at weeks 8‐12 with Dysport‐240 (not significant), and interim visit data showed that this was significant at weeks 0‐4 (P = .03 Dysport‐240 vs placebo). The mean duration of headache during weeks 0‐4 was lower with Dysport‐240 (P = .04 vs placebo). Improvements in patient and investigator global assessments of change between weeks 0‐4 and 8‐12 were significant for the Dysport‐240 group (both P < .05 vs placebo). Conclusions.— Limitations in study design and assessment tools employed may have contributed to the inconclusive nature of the primary end point data. Dysport‐240 showed significant benefit over placebo at some end points and further trials with more appropriate outcome measures are required to evaluate effectively this treatment.