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.     

Flunarizine in migraine prophylaxis: predictive factors for a positive response

The efficacy o flunarizine in migraine prophylaxis is confirmed in both open and controlled trials. However, it is unknown what factors may influence a good response to prophylaxis with flunarizine. The aim of this study was to determine the possible predictive factors for therapeutic responsiveness to 3 months' treatment with flunarizine. One-hundred headache patients treated with flunarizine were evaluated. We considered "responders" those patients who recorded a reduction in migraine frequency of 75% after treatment. Statistical analysis revealed four factors which might influence therapeutic responsiveness in our patients. Positive factors were a family history ( p <0.0l) and high intensity of pain ( p <0.0l); negative factors were frequent attacks ( p <0.0l) and a history of analgesic abuse ( p <0.001). Patients with no previous history of analgesic abuse, low frequency of attacks at baseline, higher levels of migraine pain, and positive family history constitute the prototype of flunarizine long-term treatment responders.     

Sublingual Flunarizine: a New Effective Management of the Migraine Attack. A Comparison versus Ergotamine

SYNOPSIS
Flunarizine was found to be effective in the acute treatment of isosorbide dinitrate induced migraine attacks, when given in a dosage of 10 mg sublingually.
The present study consists of two parts: in the first preliminary investigation, 7 out of 8 migraine patients who developed a typical migraine attack after isosorbide dinitrate were relieved of pain within about 10 minutes. On the basis of this result a second, randomized controlled open trial was performed, in which the acute efficacy of flunarizine was compared with ergotamine tartrate, 0.25 mg i.m., on 40 migraine patients. Flunarizine was found as effective as ergotamine (75% positive responses in the flunarizine group, 70% in the ergotamine group). The mean latency of the flunarizine effect was significantly lower than that of the ergotamine ( r < 0.001, Student's t test). Moreover sublingual flunarizine was found to be virtually devoid of side effects.     

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.     

Efficacy of intravenous magnesium sulfate in severe migraine attacks

The aim of this open study was to make a preliminary estimate of the efficacy and tolerability of intravenously administered magnesium sulfate (1 g) in comparison to subcutaneously administered sumatriptan in the treatment of severe migraine attacks. The study comprised 22 consecutive patients whose attacks were treated with magnesium sulfate (5 ml of a 20% solution), and the results were compared with those of another group of 14 consecutive patients whose attacks were treated with sumatriptan (6 mg). Immediately before and 10, 20 and 30 minutes after injections, patients reported pain intensity on a verbal 0–10 scale. Pain disappearance or pain relief >50% were considered significant. Efficacy of sumatriptan was superior that of to magnesium sulfate 20 minutes after the injections (p<0.05) and comparable after 30 minutes (magnesium therapy was successful in 68% in comparison to 79% of patients treated with sumatriptan). After only 10 minutes, 3 patients treated with magnesium sulfate were pain free, with the same effect in 5 (22.5%) and 10 (45%) patients after 20 and 30 minutes, respectively. The rate of headache recurrence was low and no major adverse effects were recorded. In conclusion, magnesium sulfate may be a well-tolerated pharmacological alternative for the treatment of severe migraine attacks. Received: 12 January 2001 / Accepted in revised form: 6 July 2001     

Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks

OBJECTIVE: To study the efficacy and tolerability of 1 g of intravenous magnesium sulfate as acute treatment of moderate or severe migraine attacks. BACKGROUND: Migraine is a common disorder in which not only the pain but also the accompanying symptoms such as nausea and vomiting reduce activity and productivity of sufferers. Many drugs used for the treatment of acute migraine attacks have many side effects, are not well tolerated, are ineffective in some patients, or cannot be used during pregnancy or in patients with ischemic heart disease. Magnesium deficiency has been proposed to play a role in the pathophysiology of migraine, and recently treatment of migraine with magnesium has gained considerable interest. METHODS: This was a randomized, single-blind, placebo-controlled trial including 30 patients with moderate or severe migraine attacks. Fifteen patients received 1 g intravenous magnesium sulfate given over 15 minutes. The next 15 patients received 10 mL of 0.9% saline intravenously. Those in the placebo group with persisting complaints of pain or nausea and vomiting after 30 minutes also received 1 g magnesium sulfate intravenously over 15 minutes. The patients were assessed immediately after treatment, and then 30 minutes and 2 hours later. Intensity of pain, accompanying symptoms, and side effects were noted. RESULTS: All patients in the treatment group responded to treatment with magnesium sulfate. The pain disappeared in 13 patients (86.6%); it was diminished in 2 patients (13.4%); and in all 15 patients (100%), accompanying symptoms disappeared. In the placebo group, a decrease in pain severity but persisting nausea, irritability, and photophobia were noted in 1 patient (6.6%). Accompanying symptoms disappeared in 3 patients (20%) 30 minutes after placebo administration. All patients initially receiving placebo were subsequently given magnesium sulfate. All of these patients responded to magnesium sulfate. In 14 patients (93.3%), the attack ended; in 1 patient (6.6%), pain intensity decreased; and in all 15 patients (100%), accompanying symptoms disappeared. Both the response rate (100% for magnesium sulfate and 7% for placebo) and the pain-free rate (87% for magnesium sulfate and 0% for placebo) showed that magnesium sulfate was superior to placebo. Twenty-six patients (86.6%) had mild side effects which did not necessitate discontinuing treatment during magnesium sulfate administration. CONCLUSION: Our results show that 1 g intravenous magnesium sulfate is an efficient, safe, and well-tolerated drug in the treatment of migraine attacks. It is possible that magnesium sulfate could be used in a broader spectrum of patients than other drugs commonly used for attack treatment. In view of these results, the effect of magnesium sulfate in acute migraine should be examined in large-scale studies.     

MIGRAINE TREATMENT

Clinical trials of migraine therapy often require treatment when migraine pain intensity is moderate or severe, but many physicians find this practice artificial and patients often prefer to treat while pain is mild. This randomized, placebo-controlled study assessed the efficacy of zolmitriptan 2.5 mg in treating migraine while pain is mild, in patients who typically experience migraine attacks that are initially mild, but progress to moderate or severe. The intent-to-treat population comprised 280 patients (138 zolmitriptan; 148 placebo), with mean MIDAS grades of 29.6 (zolmitriptan) and 27.6 (placebo). Zolmitriptan 2.5 mg provided a significantly higher pain-free rate at 2 hours (43.4% vs 18.4% placebo; P < .0001). Significantly fewer zolmitriptan patients reported progression of headache pain to moderate or severe intensity 2 hours postdose (53.7% vs 70.4% placebo; P < .01), or required further medication within 24 hours (46.4% vs 71.1% placebo; P < .0001). The efficacy of zolmitriptan was more pronounced in patients treating during the first 15 minutes following pain onset. Adverse events were reported in 31.2% of patients treated with zolmitriptan (vs 11.3% for placebo), and the incidence was lower in patients who treated early after attack onset. Zolmitriptan provides high efficacy when treating migraine while pain is mild, with the clinical benefits being more pronounced when treating early after migraine onset.     

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.     

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.     

Flunarizine in Migraine Prophylaxis: An Indian Trial

Flunarizine, a calcium channel blocker is considered useful in migraine prophylaxis. We report the first Indian trial with this drug. Fifteen patients with migraine were studied in a 6 months double-blind, placebo-controlled crossover trial. Flunarizine was superior to placebo in reducing the severity and duration of the individual attacks though there was no statistically significant effect on frequency of migraine attacks. The side effects most frequently caused by flunarizine were weight gain and daytime sleepiness.     

Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo

A randomized, controlled, cross-over trial compared single doses of 50 mg diclofenac potassium sachets and tablets with placebo in 328 patients with migraine pain, treating 888 attacks. For the primary endpoint 24.7% of the patients were pain free at 2 h postdose with sachets, 18.5% for tablets and 11.7% for placebo. Treatment differences were significant for sachets vs. placebo (P<0.0001), tablets vs. placebo (P=0.0040) and for sachets vs. tablets (P=0.0035). The numbers needed to treat compared with placebo to achieve pain free at 2 h were 7.75 [95% confidence interval (CI) 5.46, 13.35] for sachets and 15.83 (95% CI 8.63, 96.20) for tablets. Sachets were also statistically superior to tablets for sustained headache response, sustained pain free and reduction in headache intensity within the first 2 h postdose measured on a visual analogue scale (P<0.05). Onset of analgesic effect was 15 min for sachets and 60 min for tablets. Fewer patients needed rescue medication, and there were marked improvements in accompanying symptoms and working ability with both sachets and tablets vs. placebo. No safety issues were identified. This study demonstrates that sachets offer patients suffering from migraine pain a more effective treatment with a faster onset of analgesia when compared with tablets.     

Efficacy of acupuncture for migraine prophylaxis: a single-blinded, double-dummy, randomized controlled trial

Insufficient clinical trial data were available to prove the efficacy of acupuncture for migraine prophylaxis. A multicenter, double-dummy, single-blinded, randomized controlled clinical trial was conducted at the outpatient departments of acupuncture at 5 hospitals in China to evaluate the effectiveness of acupuncture. A total of 140 patients with migraine without aura were recruited and assigned randomly to 2 different groups: the acupuncture group treated with verum acupuncture plus placebo and the control group treated with sham acupuncture plus flunarizine. Treated by acupuncture 3 times per week and drugs every night, patients from both groups were evaluated at week 0 (baseline), week 4, and week 16. The primary outcome was measured by the proportion of responders (defined as the proportion of patients with a reduction of migraine days by at least 50%). The secondary outcome measures included the number of migraine days, visual analogue scale (VAS, 0 to 10 cm) for pain, as well as the physical and mental component summary scores of the 36-item short-form health survey (SF-36). The patients in the acupuncture group had better responder rates and fewer migraine days compared with the control group (P < .05), whereas there were no significant differences between the 2 groups in VAS scores and SF-36 physical and mental component summary scores (P > .05). The results suggested that acupuncture was more effective than flunarizine in decreasing days of migraine attacks, whereas no significantly differences were found between acupuncture and flunarizine in reduction of pain intensity and improvement of the quality of life.     

Efficacy and tolerability of oral zolmitriptan in menstrually associated migraine: a randomized, prospective, parallel-group, double-blind, placebo-controlled study

BACKGROUND: Approximately 60% of female migraineurs report experiencing migraine in association with menstruation, while 7% to 25% experience attacks almost exclusively with menstruation. OBJECTIVE: To examine the efficacy and tolerability of oral zolmitriptan in the acute treatment of menstrually associated migraine. In this study, menstrually associated migraine was defined as migraine that consistently occurred from 72 hours before to 5 days after onset of menses. Methods.-Participants were women with regular menstrual cycles, aged 18 to 55 years, who had experienced migraine with at least two thirds of prior menstrual cycles. Subjects were randomized to treat one attack per menstrual cycle for 3 months with either zolmitriptan or placebo. Treatment was intensity based: mild migraines were treated with half of a 2.5-mg zolmitriptan tablet, moderate migraines were treated with zolmitriptan 2.5 mg, and severe migraines were treated with 5 mg (two 2.5-mg tablets) of zolmitriptan, or placebo. RESULTS: Of the 579 women enrolled in the study, 260 were treated with zolmitriptan and 251 were assigned placebo. Twelve hundred thirty-two attacks were treated, and a 2-hour headache response was achieved in 48% of zolmitriptan-treated attacks as compared with 27% of placebo-assigned attacks (P <.0001). Zolmitriptan was superior to placebo in achieving a headache response as early as 30 minutes (18% versus 14%, P=.03) and at 1 hour (33% versus 23%, P <.001). Drug-related adverse events were reported in 16% of subjects receiving zolmitriptan and 9% of subjects receiving placebo. CONCLUSION: Oral zolmitriptan exhibits efficacy and good tolerability in the treatment of menstrually associated migraine. Improvement over placebo was observed as early as 30 minutes following treatment.     

Mouth-dispersible aspirin in the treatment of migraine: a placebo-controlled study

OBJECTIVE: To compare the efficacy of mouth-dispersible aspirin 900 mg and placebo in the treatment of migraine. BACKGROUND: Aspirin is widely accepted as an effective therapy for migraine. Previous studies have indicated that gastric stasis and delayed gastric emptying, which occur during migraine attacks, delay aspirin absorption. Mouth-dispersible formulations are considered to be more quickly absorbed than solid formulations and, therefore, may be more effective in treating migraine. DESIGN: Randomized, double-blind, placebo-controlled, crossover study in four specialized migraine clinics in the United Kingdom. METHODS: One hundred one patients diagnosed with migraine (according to the International Headache Society diagnostic criteria) participated in the study. Patients received either single doses of mouth-dispersible aspirin (3 x 300 mg) or placebo for moderate pain in the treatment of two migraine attacks. Rescue medication could be taken after 2 hours, if required. The primary efficacy parameter was response to therapy at 2 hours posttreatment. Other efficacy parameters were response to treatment, pain-free, and pain intensity at all other time points. Functional disability, nausea, vomiting, photophobia, phonophobia, symptom relief, patient and investigator global evaluation, use of rescue medication, headache recurrence, and palatability and convenience were also recorded. RESULTS: Of 101 patients, 73 took both treatments. At 2 hours, 48% of patients taking mouth-dispersible aspirin responded, compared to only 19% taking placebo (P =.0005). Mouth-dispersible aspirin was significantly better than placebo for response to treatment (P<.05) and pain intensity difference (P<.01) at all time points from 30 minutes posttreatment; for pain-free (P<.05) and use of rescue medication (P<.01) from 3 hours posttreatment; for headache recurrence (P<.05); and for patients' and investigators' global evaluations of efficacy (P =.0001 in both cases). CONCLUSIONS: Mouth-dispersible aspirin 900 mg is effective compared with placebo for the treatment of moderate migraine head pain, with relief seen from as early as 30 minutes after taking medication.     

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.     

Therapie des akuten Migräneanfalls mit intravenös applizierter Acetylsalicylsäure

INTRODUCTION: The empirical use of oral acetylsalicylic acid (ASA) in the treatment of acute migraine attacks has led to the recommendation of ASA as a basic treatment of migraine. However, there are no controlled studies on the intravenous use of acetylsalicylic acid. METHODS: Forty patients with a 1- to 12-year history of migraine were included in this placebo-controlled trial. The sociodemographic data of patients receiving placebo or 500 mg ASA i.v. and migraine symptoms before treatment were identically distributed. Pain relief during attacks was documented by the Visual Analogue Scale (VAS) for 1 h at 5-min intervals. Furthermore, the change of concurrent non-pain symptoms was evaluated by self-rating (worse-unchanged-better-absent). RESULTS: The VAS showed a mean pain reduction of about 60% after 1 h versus placebo. Efficacy varied significantly between patients. We observed a small number of socalled non-responders as well as patients with complete pain relief. The most common concomitant symptoms were nausea, photophobia, vertigo, vomiting and sweating. During the time of observation these symptoms were significantly reduced compared to placebo. The study shows a maximum placebo effect of about 17% (mean value). Significant differences in pain ratings were measured 25-30 min after application (P=0.0008). CONCLUSIONS: In this study i.v. ASA showed a significant reduction in pain intensity during migraine attacks. In addition, most concomitant non-pain symptoms were equally reduced. The onset of pain relief did not correspond with the inhibition of platelet aggregation (after 2-4 min) or with peak plasma concentrations of ASA (immediately after application) or salicylic acid (after 2-3 h). More efficacy studies with higher doses and longer periods of observation are necessary to optimize the treatment of migraine attacks with intravenous ASA. Studies including neurophysiological and vascular parameters are recommended to confirm the results of this study.     

Evaluation of the efficacy of intravenous acetaminophen in the treatment of acute migraine attacks: a double-blind, placebo-controlled parallel group multicenter study

The efficacy of intravenous acetaminophen (1000mg) in the treatment of acute migraine attacks as an alternative to parenteral application of lysine acetylsalicylate or triptans was investigated, using a multi-center, randomized, double-blind, placebo controlled study design. Migraine diagnosis was made according to the International Headache Society Classification. Sixty patients were included in three headache outpatient centers (Neurology Departments of the Universities of Regensburg, Münster and München). In the acute migraine attack patients were treated intravenously with either 1000mg paracetamol (acetaminophen) or placebo. The primary end point was pain-free after 2h. Secondary efficacy criteria were pain-free after 24h or pain relief after 2hours and after 24hours. With regard to the efficacy criteria, 37% of patients reported pain relief or painfree after two hours, 12 patients after treatment with acetaminophen and 10 patients after treatment with placebo. Out of these, 3 patients in the acetaminophen and 4 patients in the placebo group were painfree. After 24hours 86% of the patients reported pain relief: 24 treated with acetaminophen and 27 treated with placebo. The results indicate, that 1000mg intravenous acetaminophen is not superior to placebo in treating severe acute migraine attacks.     

Aborting a Migraine Attack: Naproxen Sodium v Ergotamine plus Caffeine

SYNOPSIS
The tolerability and efficacy of naproxen sodium and of ergotamine tartrate plus caffeine (ergotamine) were compared in the treatment of acute migraine attacks and associated symptoms. In this multicenter, double-blind, parallel study of up to six headaches over a 3-month period, patients took naproxen sodium 825 mg, ergotamine 2 mg, or placebo at the time of the first symptom of an attack; 30 minutes later, if necessary, patients repeated naproxen sodium 275 mg, ergotamine 1 mg or placebo, as appropriate. Rescue medication was allowed 30 minutes following the second dose if needed. Active drugs provided notably better relief of head pain than did placebo; 1 hour following the first dose the difference between naproxen sodium and placebo was statistically significant. Naproxen sodium was as efficacious as ergotamine in the relief of migraine attacks and associated symptoms. Relief of vomiting, nausea, photophobia, and motor symptoms favored naproxen sodium over ergotamine; these differences were statistically significant for nausea and motor symptoms. Ergotamine-treated patients reported more complaints and had more severe and longer-lasting complaints than patients on the other two regimens. Overall tolerance ratings by both investigators and patients indicated that naproxen sodium and placebo were tolerated significantly better than ergotamine.     

Benefits of treating highly disabled migraine patients with zolmitriptan while pain is mild

Clinical trials of migraine therapy often require treatment when migraine pain intensity is moderate or severe, but many physicians find this practice artificial and patients often prefer to treat while pain is mild. This randomized, placebo-controlled study assessed the efficacy of zolmitriptan 2.5 mg in treating migraine while pain is mild, in patients who typically experience migraine attacks that are initially mild, but progress to moderate or severe. The intent-to-treat population comprised 280 patients (138 zolmitriptan; 148 placebo), with mean MIDAS grades of 29.6 (zolmitriptan) and 27.6 (placebo). Zolmitriptan 2.5 mg provided a significantly higher pain-free rate at 2 h (43.4% vs. 18.4% placebo; P < 0.0001). Significantly fewer zolmitriptan patients reported progression of headache pain to moderate or severe intensity 2 h postdose (53.7% vs. 70.4% placebo; P < 0.01), or required further medication within 24 h (46.4% vs. 71.1% placebo; P < 0.0001). The efficacy of zolmitriptan was more pronounced in patients treating during the first 15 min following pain onset. Adverse events were reported in 31.2% of patients treated with zolmitriptan (vs. 11.3% for placebo), and the incidence was lower in patients who treated early after attack onset. Zolmitriptan provides high efficacy when treating migraine while pain is mild, with the clinical benefits being more pronounced when treating early after migraine onset.