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.     

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.     

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.     

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.     

Propranolol in the treatment of acute migraine attacks

The efficacy of the beta-adrenoceptor antagonist propranolol in the acute treatment of patients in attacks of either classical (migraine with aura) or common migraine (migraine without aura) headache was assessed in a double-blind placebo-controlled crossover trial with fixed doses. The trial was carried out on 25 patients. The treatment period was set at eight weeks, with the provision of shortening or lengthening it if necessary with a maximum period of seventeen weeks. A minimum of three migraine attacks were treated during each treatment period. Patients were assessed according to: the mean duration and mean severity per treatment period of migraine attacks. The secondary efficacy assessment was made on the basis of the percentage of attacks requiring escape medication per treatment period. The study, based on the t-distribution statistical model with a confidence level of 95%, showed that propranolol had no significant effect in aborting acute attacks of migraine when compared with placebo.     

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.     

Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: a double-blind study versus placebo

Omega-3 polyunsaturated fatty acids (OPFA) have beneficial effects on inflammatory reactions and production of cytokines. They decrease the release of 5HT by platelets and possess vasorelaxant activity. This led them to be tried in the prophylactic treatment of migraine. After 4 weeks of a single-blind placebo run-in period, patients were randomized and treated in double-blind condition by placebo or OPFA 6 g a day for 16 weeks, followed by a 4-week placebo run-out period. The intention to treat population included 196 patients. Those who received all four treatment periods included 96 patients taking OPFA and 87 taking placebo. The primary efficacy analysis was the number of migraine attacks during the last 4 weeks of treatment. During this period, the mean number of attacks was 1.20 +/- 1.40 in the OPFA group and 1.26 +/- 1.11 in the placebo group (NS). The total number of attacks during the 4-month period of the study was significantly different between groups: 7.05 in the placebo group, 5.95 in the OPFA group (P = 0.036). Mean intensity, mean duration of the attacks and rescue medication use, were not significantly different between the two groups. Except for a significant difference against OPFA for eructations, the tolerance was satisfying. Despite a run-in placebo period of 1 month, a very strong placebo effect was observed in this trial: 45% reduction of the attacks between run-in and 4-month treatment period (55% in the OPFA group, P = 0.058). Finally, this large study did not confirm two previous studies based on a small number of patients.     

Cyclandelate in the prophylaxis of migraine: a placebo-controlled study

The prophylactic action of cyclandelate was investigated in a multicentre, randomized, placebo-controlled, parallel group study. A 4-week baseline period was followed by a 4-week placebo phase and a 16-week treatment period with either 1600 mg cyclandelate or placebo. Patients (n = 251) with two to six migraine attacks/month were randomized. Neither the primary study endpoint (reduction of migraine days from baseline to the last 28 days) nor most of the secondary endpoints (reduction in the number of migraine attacks, severity or duration of attacks, frequency of autonomic disturbances, medication for treatment of attacks) showed a difference between cyclandelate and placebo. Cyclandelate, however, was superior to placebo in a global impression of efficacy rated by the patients and the treating physicians. Both treatments were well tolerated. In conclusion, cyclandelate was not superior to placebo in the prophylaxis of migraine with regard to parameters usually used in migraine prophylaxis trials.     

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.     

Nadolol and Propranolol in Migraine Management

SYNOPSIS
The prophylactic effects of nadolol once daily and propranolol b.i.d. were studied in 28 patients with common or classic migraine. Following screening procedures, the subjects entered a 28- to 120-day placebo period, which was followed by a 24-week randomized, double-blind treatment period. The prophylactic effects were evaluated by frequency of migraine attacks, consumption of acute migraine-relief tablets, duration of attacks, ratings of headache and nausea severity, and duration of incapacitation. Compared to placebo, both beta blockers brought about a highly significant (p < 0.01 ) reduction in attack frequency and consumption of acute migraine-relief tablets, while no significant changes were found with regard to the other variables. No significant differences were found between the two beta blockers. The results indicate that nadolol once daily is as effective as propranolol b.i.d. in migraine management and that the main effect of beta blockers in migraine is in preventing attacks from breaking out, while the capacity for reducing the intensity or duration of unsuppressed attacks is less prominent.     

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.     

Acupuncture in Migraine: Long-term Outcome and Predicting Factors

Twenty-six patients (19 women, 7 men), who suffered from chronic migraine according to IHS criteria, underwent acupuncture. In order to evaluate the long-term stability of treatment effects, patients documented frequency, duration, and intensity of attacks as well as analgesic intake in a migraine diary, which was kept for 5-week periods before treatment, immediately after treatment, and 3 years later. Data showed improvement greater than 33% for 18 patients (69%) at posttreatment and 15 patients (58%) at 3-year follow-up. Drug intake was reduced to 50% and did not re-increase until follow-up. Treatment outcome was associated with personality traits, but not depending on demographic data or severity of migraine.     

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.     

Short migraine attacks of less than 2 h duration in children and adolescents

We studied the duration of migraine attacks among children and adolescents who reported headache attacks lasting <2 h. Among the 720 children who attended our specialist headache clinic, over a period of 6 years, 231 children had migraine with or without aura fulfilling the International Headache Society (IHS) criteria for the diagnosis of migraine. A further 15 children reported headache attacks typical of migraine, but of duration <2 h. They were asked to fill prospective headache diaries in order to determine with accuracy the duration of their headache attacks. Ten (67%) of these children provided prospective fully analysable headache diaries and recorded a total of 120 headache attacks, 66 attacks (55%) lasting for <1 h each, 30 attacks (25%) lasting between 1 and 2 h, and 24 attacks (20%) lasting >2 h. Patient-based analysis of the headache diaries showed that only three children consistently had headache attacks lasting <1 h. Seven children had some of their headache attacks lasting for at least 1 h and four had some of their headache attacks lasting at least 2 h. This study shows that headache attacks in children with migraine can be variable, and brief attacks are rare. A combination of short (<1 h) and long (>2 h) attacks of headache can coexist in the same patient. The IHS diagnostic criteria of 1988 for migraine in children should therefore acknowledge such variation and allow reduction of the duration of migraine attacks to 1 h.     

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.     

Treatment of acute migraine attack: naproxen and placebo compared

A double-blind, cross-over, randomized study of acute migraine attack compared treatment results of naproxen with that of placebo. Each treatment period continued for either three months or six migraine attacks, whichever occurred first. The initial dose of naproxen was 750 mg, with additional 250-500 mg doses taken if and when required, to a maximum of five 250 mg tablets within a period of 24 h in each migraine attack. Forty-one patients were enrolled in the study; they had all experienced at least two but not more than eight migraine attacks a month during the preceding year. Thirty-two patients completed the two treatment periods. Naproxen was statistically significantly superior to placebo in reducing the severity of head pain, nausea, and photophobia; in shortening the duration of head pain, nausea, vomiting, photophobia, and lightheadedness; in diminishing the frequency of vomiting; and in decreasing the need for escape medication. Both patient and physician treatment preferences significantly favoured naproxen. Nine side effects were experienced by seven patients while receiving placebo and seven by five patients during naproxen treatment. Mild gastrointestinal discomfort was the main complaint. Only one patient withdrew from treatment because of a side effect, which occurred while receiving placebo.     

Sodium valproate prophylaxis in childhood migraine

Migraine is a cause of recurrent headache in childhood. The efficacy of sodium valproate is well known in the prophylactic treatment of adult migraine, but there are few studies involving the drug's effect in pediatric migraine. OBJECTIVE: To determine the efficacy of sodium valproate in the prophylactic treatment of childhood migraine. METHODS: Fifteen children with migraine according to International Headache Society criteria were included in the study. Headache severity was measured and assessed by Algology unit by a using visual analog scale and a numerical rating scale. All of the subjects were asked to keep a headache diary for 8 weeks. Three subjects who had no headache attacks during the baseline period and two cases who were lost to follow up were excluded. Thus, sodium valproate was initiated in 10 subjects (six boys, four girls), 500 mg/night, and the daily dose was increased up to 1000 mg according to blood levels. Their ages ranged from 9 to 17 (mean age 13.6 +/- 3.2 years). Therapy continued for at least 12 weeks. RESULTS: Headache severity as measured via the mean visual analog score was 6.8 +/- 1.8 at baseline and was 0.7 +/- 1.2 at the end of the treatment period (P = 0.000). Mean headache attacks per month were 6 +/- 4.2 at baseline and were 0.8 +/- 1.9 at the end of the treatment period (P = 0.002). The duration of headache was significantly decreased from a mean of 5.5 +/- 3.9 hours to 1.1 +/- 2.5 hours with treatment (P = 0.001). The observed side effects were dizziness, drowsiness, and increase in appetite; none required drug withdrawal. In two cases, headache attacks recurred after the cessation of valproate, and therapy was restarted. Headache control lasted for six months following cessation of the drug in the remainder of the subjects. CONCLUSION: Sodium valproate appears to be effective and safe in selected patients with childhood migraine.     

Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study

OBJECTIVE: This exploratory trial evaluated the safety and efficacy of multiple treatments of botulinum toxin type A (BoNTA; BOTOX, Allergan, Inc., Irvine, CA, USA) as prophylactic treatment of episodic migraine headaches. DESIGN AND METHODS: This was an 11-month randomized, double-blind, placebo-controlled, exploratory study. Patients were screened during a 30-day baseline period, and eligible patients with 4 or more migraine episodes and < or =15 headache days entered a single-blind 30-day placebo run-in period. Patients were classified as placebo nonresponders (PNR) if they had at least 4 moderate-to-severe migraine episodes and did not experience at least a 50% decrease from baseline in the frequency of migraine episodes following their placebo treatment. All other subjects were classified as placebo responders (PR). Patients were randomized within each stratum (PNR, PR) to 3 treatments with BoNTA (110 to 260 U of BoNTA per treatment cycle) or placebo at 90-day intervals using a modified follow-the-pain treatment paradigm. The primary efficacy outcome measure was the mean change from baseline in the frequency of migraine episodes for the 30 days prior to day 180 in the PNR group. Secondary efficacy measures included the proportion of patients with a decrease from baseline of 50% or more migraine episodes per 30-day period. Patients were allowed to take concomitant acute and prophylactic headache medications. Adverse events were reported. RESULTS: A total of 809 patients were screened and 369 patients (89.2% female; mean age, 45 years; range, 20 to 65 years) entered the placebo run-in period and were subsequently randomized to BoNTA or placebo. The mean total dose of BoNTA was 190.5 units (U) (range, 110 U to 260 U). The predetermined primary efficacy endpoint was not met. Substantial mean improvements of 2.4 and 2.2 fewer migraine episodes per month at day 180 in the PNR stratum treated with BoNTA and placebo, respectively, were observed (P > .999). From day 180 through the end of the study (day 270) at least 50% of all patients in each treatment group had a decrease from baseline of 50% or more migraine episodes per 30-day period. However, in the group of patients with > or =12 headache days at baseline (and < or =15 headache days), BoNTA patients experienced a mean change from baseline of -4.0 headache episodes at day 180 compared with -1.9 headache episodes in the placebo group (P= .048). The majority of treatment-related adverse events were transient and mild to moderate in severity. Only 7 patients (1.9%) discontinued the study due to adverse events (6 BoNTA, 1 placebo). CONCLUSION: There were no statistically significant between-group differences in the mean change from baseline in the frequency of migraine episodes per 30-day period. There were substantial, sustained improvements during the course of the study in all groups. Multiple treatments with BoNTA were shown to be safe and well tolerated over an active treatment period lasting 9 months.     

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.     

Topiramate prophylaxis and response to triptan treatment for acute migraine

OBJECTIVE: To evaluate the effect of topiramate migraine prophylaxis on subject responsiveness to triptans used for acute symptomatic migraine treatment. BACKGROUND: Clinical experience suggests that prophylactic migraine treatment may enhance the efficacy of symptomatic medications used to treat acute migraine attacks. METHODS: This open-label, single-arm multicenter study consisted of a 6-week baseline period followed by a 16-week topiramate treatment period. Subjects meeting International Headache Society (IHS) criteria for migraine with and without aura signed consent and entered the baseline period. Those with 3 to 12 migraine periods per month during baseline received topiramate prophylactic treatment. Only patients who completed at least 12 weeks of topiramate treatment were included in the data analysis. RESULTS: Of 55 patients screened, 40 subjects entered the topiramate treatment period and 21 subjects received at least 12 weeks of treatment. Mean final dose of topiramate was 124 mg per day (range 50 to 200 mg per day). During the baseline period, the mean percentage of attacks rendered pain-free at 2 hours for the 21 subjects was 46.9% (SD = 31.9), while during the topiramate treatment period it was 44.6% (SD = 32.2) (P= .8). On topiramate, after the first 8 weeks of dosage titration, patients experienced a mean of 3.68 migraine attacks/month, compared to 4.31 during the baseline period (P < .03). Thirteen subjects discontinued because of adverse events. The most commonly reported adverse events were paresthesia, fatigue, anxiety, and dizziness. CONCLUSION: Although topiramate prophylaxis did reduce migraine attack frequency, in this pilot study topiramate prophylactic migraine treatment did not increase the proportion of patients pain-free 2 hours after symptomatic triptan therapy.