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.     

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.     

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.     

Nimodipine, a New Calcium Antagonist, in the Prophylactic Treatment of Migraine

SYNOPSIS
The prophylactic effect of the calcium antagonist nimodipine was assessed in a double-blind placebo controlled parallel design study in 60 patients. After a drug-free interval of two weeks, placebo or nimodipine were given for 13 weeks each. The dose of nimodipine was 40 mg t.i.d. Ten patients (eight on placebo, two on nimodipine) withdrew because of therapeutic failure. In the 50 patients who completed the trial there was a significant beneficial effect in the nimodipine treated group, with regard to number of migraine attacks and duration during the last two months of treatment. Side effects were negligible.     

Nimodipine in migraine prophylaxis

Nimodipine is a compound that is thought to block the influx of calcium through channels in vascular smooth muscle. This paper describes a double-blind parallel-group comparison of 40 mg nimodipine three times a day and placebo. Sixty-eight patients received treatment after a run-in period of 2 months, and of these, 57 completed 8 weeks or more of the trial. All but five of these completed the full 6-month trial. The nimodipine and placebo groups showed no significant differences in the frequency of attacks, severity or duration of headache, or gastrointestinal or other symptoms.     

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.     

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.     

Nimodipine in the treatment of headache in chronic cerebral ischemia

The aim of this study was to evaluate the influence of nimodipine on non-migrainous vascular headache in patients with chronic cerebral ischemia. Eighty-six patients were examined in a double-blind trial for 16 weeks (12 weeks of nimodipine or placebo, followed by a 4-week placebo period). Fifty-six patients were studied in an open trial for 12 months. In the total material of the double-blind study there was no difference as far as improvement of headache was concerned when comparing the patients treated with nimodipine with those receiving placebo. However, in a group of 38 patients with a higher degree of headache intensity, selected in accordance with the Sandoz Clinical Assessment Geriatric scale, a statistically significant difference was found in favor of nimodipine. The results obtained in the long-term open trial seem to confirm the effect of nimodipine on headache. The underlying mechanisms of the beneficial effect of the drug have been discussed.     

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.     

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.     

ENALAPRIL IN RAYNAUD''S PHENOMENON

The effect of enalapril in the treatment of Raynaud's phenomenon was assessed in a prospective double-blind cross-over trial in 17 patients (nine primary Raynaud's, eight Raynaud's associated with scleroderma). Each patient received 20 mg enalapril daily and placebo for 3 weeks with a 2-week washout period in between. The severity and frequency of Raynaud's attacks were measured subjectively by a diary count and objectively by measurement of finger systolic pressure changes in response to cooling (cold challenge test). Enalapril was associated with a reduction in the frequency of Raynaud's attacks, especially in patients with primary Raynaud's, compared with placebo, but there was no effect on the cold challenge test. We conclude that enalapril, like other vasodilator drugs, helps the symptoms of Raynaud's phenomenon, especially in patients with idiopathic or primary disease.     

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.     

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 FOR MIGRAINE PROPHYLAXIS

SYNOPSIS
The preventive effect of propranolol on migraine attacks was compared to placebo in a double-blind cross-over trial. Thirty-two patients with serious and prolonged migraine participated in the 12-week study. The effect of propranolol was significantly better than that of placebo. The number of migraine attacks during the propranolol period was reduced in 22 patients (69%), and in 11 of these (34%) a reduction of more than 50% was seen. The intensity of headache was significantly reduced during the propranolol period. The intake of analgesics and preparations containing ergotamine was significantly reduced during the propranolol period also. No serious side effects were noted.     

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.     

Incidence of infection during efalizumab therapy for psoriasis: analysis of the clinical trial experience

BACKGROUND: Because many therapies for psoriasis disrupt the normal inflammatory cascade and could theoretically impair the body's ability to respond to external pathogens, a possible increase in the incidence of infection is a concern with any new psoriasis therapy that affects the immune system. Efalizumab is a biologic therapy targeted to inhibit T cells. Its efficacy has been shown in clinical trials encompassing >3500 patients with psoriasis. OBJECTIVES: The aims of this article were to review the incidence of infection observed in efalizumab-treated patients during 12-week, Phase III clinical trials, compare the incidence rate with that in patients receiving placebo, and evaluate the incidence of infection observed in patients with extended (>12-week) efalizumab use. METHODS: Adverse events (AEs) of infection were tabulated from a pooled data set of 2335 patients enrolled to receive 12 weeks of subcutaneous (SC) efalizumab 1 or 2 mg/kg . wk or placebo in 4 randomized, double-blind, placebo-controlled, Phase III efalizumab clinical studies. The incidence of infection was further evaluated using pooled data from 1115 patients who received up to 24 weeks of efalizumab therapy during 5 clinical trials with treatment extension arms and from 170 patients who received up to 108 weeks (27 months) of continuous therapy in an open-label, Phase III efalizumab trial of 36 months' total duration. RESULTS: The incidence and severity of AEs of infection during 12 weeks of efalizumab therapy were comparable to those observed in patients receiving placebo (overall, 28.6% vs 26.3%). Infections did not appear to increase with extended therapy of up to 27 months. Serious infections requiring hospitalization occurred in 1.1% of efalizumab-treated patients. CONCLUSION: The present review of the available Phase III clinical trial suggests that efalizumab is not associated with an increased risk for infection in patients receiving initial or long-term (27-month) treatment for moderate to severe chronic plaque psoriasis.     

Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study

In order to evaluate the prophylactic effect of oral magnesium, 81 patients aged 18–65 years with migraine according to the International Headache Society (IHS) criteria (mean attack frequency 3.6 per month) were examined. After a prospective baseline period of 4 weeks they received oral 600 mg (24 mmol) magnesium (trimagnesium dicitrate) daily for 12 weeks or placebo. In weeks 9–12 the attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared to the baseline (p <0.05). The number of days with migraine and the drug consumption for symptomatic treatment per patient also decreased significantly in the magnesium group. Duration and intensity of the attacks and the drug consumption per attack also tended to decrease compared to placebo but failed to be significant. Adverse events were diarrhea (18.6%) and gastric irritation (4.7%). High-dose oral magnesium appears to be effective in migraine prophylaxis.     

Combination Treatment with Sustained-Release Verapamil and Indapamide in the Treatment of Mild-to-Moderate Hypertension

A multicenter study of the treatment of mild and moderate hypertension compared three once-daily regimens for efficacy and safety: Group I, verapamil sustained release (SR) 240 mg; Group II, verapamil SR 480 mg; and Group III, verapamil SR 240 mg plus indapamide 2.5. mg. After a 3-week placebo washout period and a 2-week preliminary treatment period with verapamil SR 240 mg, patients with sitting diastolic blood pressures of 95--115 mm Hg were randomized in a double-blind fashion to one of the three treatment groups for a duration of 16 weeks. (Patients with diastolic BP < 95 mm Hg on this initial treatment were excluded from further study.) Efficacy assessed after 16 weeks or at the end point showed all three treatments significantly reduced sitting diastolic blood pressure from baseline levels. Compared with Group I (low-dose) verapamil SR treatment, there was a reduction in Group III combination therapy of 8.6 mm Hg systolic and 3.0 mm Hg diastolic and a significant reduction in Group II high-dose verapamil SR therapy of 7.6 mm Hg systolic and 3.9 mm Hg diastolic BP. Efficacy results were independent of age or body weight. Patients who were poor responders to lead-in verapamil SR 240 mg daily prior to randomization tended to have a greater response to combination therapy than to high-dose verapamil SR. Adverse experiences leading to withdrawal from the study occurred in 21% of patients receiving high-dose verapamil (Group II), exceeding the withdrawal from the other two treatment groups (8.5% from Group II and 4% from Group I). The most frequent adverse experiences in Group II were constipation and peripheral edema; headache was most common in Groups I and III. This trial demonstrates that adding indapamide to low-dose verapamil SR enhances efficacy and is well tolerated.     

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.