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

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

A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis

BACKGROUND: Impaired mitochondrial phosphorylation potential may play a role in migraine pathogenesis. Metabolic enhancers, such as riboflavin or coenzyme Q, are effective in migraine prophylaxis and quasi-devoid of adverse effects. Thioctic acid (-lipoic acid) is another substance known to enhance energy metabolism in mitochondria and to be beneficial in diabetic neuropathy. OBJECTIVE: After an open pilot study suggesting its therapeutic antimigraine potentials, we embarked therefore in a randomized controlled trial of thioctic acid (Thioctacid) in migraine prophylaxis steered by the Belgian Headache Society. METHODS: Five Belgian centers recruited 54 migraineurs (43 migraine without aura, 11 with aura; mean age 38 +/- 8 years; 7 males). After a 1-month single-blinded run-in period, 44 patients received either placebo (n = 18) or thioctic acid 600 mg p.o./day (n = 26) for 3 months. RESULTS: Statistical analysis was carried out on an intention-to-treat basis. Monthly attack frequency tended to be reduced between run-in and the 3rd month of treatment in the thioctic acid group compared to placebo (P= .06). The proportion of 50% responders was not significantly different between thioctic acid (30.8%) and placebo (27.8%). Within-group analyses showed a significant reduction of attack frequency (P= .005), headache days (P= .009), and headache severity (P= .03) in patients treated with thioctic acid for 3 months, while these outcome measures remained unchanged in the placebo group. No adverse effects were reported. For logistical reasons this trial was interrupted before the planned 80 patients were enrolled. CONCLUSION: Albeit underpowered, this study tends to indicate that thioctic acid may be beneficial in migraine prophylaxis. Before any firm conclusion can be drawn, however, a large multicenter trial is necessary.     

Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine. A double-blind investigation

The prophylactic anti-migraine effect of the serotonin antagonist pizotifen and the beta 1-selective beta-adrenoceptor antagonist metoprolol was compared in a double-blind cross-over study. The dosage of pizotifen was 0.5 mg t.i.d. and that of metoprolol 50 mg b.i.d. Thirty-five patients with classical or common migraine were included in the investigation. Five patients withdrew during the course of the study; four because of side effects (three on pizotifen, one on metoprolol) and one because of unassociated illness. The results show that there was no statistically significant difference in efficacy between metoprolol and pizotifen. The tolerance, especially regarding weight gain, was the major drawback with pizotifen, while metoprolol was generally well tolerated.     

A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches

Our aim was to evaluate the safety and efficacy of botulinum toxin type A (BoNTA; BOTOX) for prophylaxis of episodic migraine. In this double-blind, placebo-controlled study, patients were randomized to 225, 150 or 75 U of BoNTA or placebo after a 30-day placebo run-in for three 90-day treatment cycles. The primary efficacy end-point was the mean reduction from baseline in the frequency of migraine episodes at day 180 in the placebo non-responder stratum. All groups (N = 495) improved, with no significant differences. At day 180, the frequency of migraine episodes was reduced from baseline means of 4.3, 4.7, 4.7 and 4.4 by 1.6, 1.7, 1.5 and 1.4 for BoNTA 225 U, 150 U and 75 U and placebo, respectively. The primary end-point was not met. Treatment-related adverse events were transient and mild to moderate. BoNTA treatment was safe and well tolerated but did not result in significantly greater improvement than placebo in this study. Several factors may have confounded the results.     

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.     

A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine

(Headache 2011;51:21‐32) Objective.— This multi‐center pilot study compared the efficacy of onabotulinumtoxinA with topiramate (a Food and Drug Administration approved and widely accepted treatment for prevention of migraine) in individuals with chronic migraine (CM). Methods.— A total of 59 subjects with CM were randomly assigned to one of 2 groups: Group 1 (n = 30) received topiramate plus placebo injections, Group 2 (n = 29) received onabotulinumtoxinA injections plus placebo tablets. Subjects maintained daily headache diaries over a 4‐week baseline period and a 12‐week active study period. The primary endpoint was the Physician Global Assessment, which measured the treatment responder rate and indicated improvement in both groups over 12 weeks. Secondary endpoints, measured at weeks 4 and 12, included headache days per month, migraine days, headache‐free days, days on acute medication, severity of headache episodes, Migraine Impact & Disability Assessment, Headache Impact Test, effectiveness of and satisfaction with current treatment on the amount of medication needed, and the frequency and severity of migraine symptoms. At 12 weeks subjects were re‐evaluated and tapered off oral study medications over a 2‐week time period. Subjects not reporting a >50% reduction of headache frequency at 12 weeks were invited to participate in a 12‐week open label extension study with onabotulinumtoxinA. Of these, 20 subjects, 9 from the Topiramate Group and 11 from the OnabotulinumtoxinA Group, volunteered for this extension from weeks 14 to 26. Results.— This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM. Overall, the results were statistically significant within groups but not between groups. By week 26, subjects had a reduction of headache days per month compared with baseline. This was a significant within‐group finding. Conclusion.— OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures.     

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.     

Central mechanisms of controlled-release metoprolol in migraine: a double-blind, placebo-controlled study

beta-Blockers are widely used in the prophylaxis of migraine and have been described as very effective drugs in many studies. Some investigators have demonstrated that the clinical improvement of migraine corresponds to the normalization of the contingent negative variation (CNV), a slow cortical potential measuring cortical information processing. However, most of these studies have contained a variety of methodological pitfalls, which we attempted to address in the current study. Twenty patients suffering from migraine without aura were randomly divided into two groups. The groups were treated either with controlled-release metoprolol or placebo for 3 months, using a double-blind design. Twice before and once after each month of the treatment the CNV was recorded. After 3 months, a significant reduction of migraine frequency, duration and intensity was demonstrated for the metoprolol compared with the placebo group. The CNV was characterized by a marked reduction of the amplitude of the total CNV and postimperative negative variation and normalization of the eartly CNV habituation following treatment. Therefore, metoprolol may exert its prophylactic effect in migraine through the influence on cortical information processing and excitability represented by the CNV.     

Lamotrigine in the prophylactic treatment of migraine aura--a pilot study

The aim of this study was to evaluate the efficacy of lamotrigine, a glutamate antagonist blocking voltage-sensitive sodium channels, in the prophylaxis of migraine aura symptoms. Glutamate is one of the main neurotransmitters involved in the development of cortical spreading depression. The study was conducted as an open longitudinal trial over 7 months, with a treatment phase of 4 months and a post-treatment period of 3 months. Thirteen patients suffering from migraine with aura and 2 patients with aura but without migraine were enrolled and treated with lamotrigine. The dose was gradually increased in steps of 25 mg up to 100 mg per day, depending on the patient's aura symptoms. Aura symptoms were reduced from baseline (an average of 1.3 aura episodes per month) to month 4 (0.1, p < 0.001). High statistical significance was also observed with regard to aura duration (23 min at baseline vs 4 min at 4 months, p < 0.001). In all 15 cases, increases in aura frequency (on average sevenfold, p < 0.001) and aura duration (minutes; on average more than threefold, p < 0.001) were evident following cessation of treatment. A number of mild to moderate adverse events without any medical consequences occurred. The study outcome suggests that lamotrigine is effective in preventing migraine aura symptoms and in influencing migraine headache frequency.     

Efficacy of frovatriptan in the acute treatment of menstrually related migraine: analysis of a double-blind,randomized, cross-over,multicenter, Italian,comparative study versus rizatriptan

The objectives of this study are to assess the efficacy and safety of frovatriptan, and rizatriptan in the subgroup of women with menstrually related migraine of a multicenter, randomized, double blind, cross-over study. Each patient received frovatriptan 2.5 mg or rizatriptan 10 mg in a randomized sequence: after treating 3 episodes of migraine in not more than 3 months with the first treatment, the patient had to switch to the other treatment. Menstrually related migraine was defined according to the criteria listed in the Appendix of the last IHS Classification of Headache disorders. 99 out of the 125 patients included in the intention-to-treat analysis of the main study were of a female gender: 93 had regular menstrual cycles and were, thus, included in this analysis. A total of 49 attacks classified as menstrually related migraine were treated with frovatriptan and 59 with rizatriptan. Rate of pain relief at 2 h was 58% for frovatriptan and 64% for rizatriptan (p = NS), while rate of pain free at 2 h was 31 and 34% (p = NS), respectively. At 24 h, 67 and 81% of frovatriptan-treated, and 61 and 74% of rizatriptan-treated patients were pain free and had pain relief, respectively (p = NS). Recurrence at 24 h was significantly (p < 0.01) lower with frovatriptan (10 vs. 32% rizatriptan). Frovatriptan was as effective as rizatriptan in the immediate treatment of menstrually related migraine attacks while showing a favorable sustained effect with a lower rate of migraine recurrence. These results need to be confirmed by randomized, double-blind, prospective, large clinical trials.     

Divalproex extended-release in adolescent migraine prophylaxis: results of a randomized, double-blind, placebo-controlled study

Objective.— To evaluate the efficacy, tolerability, and safety of 3 different doses of divalproex sodium extended‐release vs placebo in the prophylaxis of migraine headaches in adolescents. Background.— Divalproex sodium has been approved for migraine prophylaxis in adults, and previous uncontrolled data suggest divalproex sodium may be effective in preventing migraine in children and adolescents with acceptable tolerability. Methods.— This was a 12‐week, phase 3, randomized, placebo‐controlled, double‐blind, parallel‐group, multicenter study in approximately 300 adolescents aged 12 to 17 years with migraine headaches. At the end of the baseline phase, subjects still meeting study criteria were randomized in a 1 : 1 : 1 : 1 ratio to receive divalproex sodium extended‐release 250 mg, 500 mg, or 1000 mg once daily, or placebo. The primary efficacy variable was reduction from baseline in 4‐week migraine headache rate for each active treatment group vs placebo. Standard safety assessments were conducted and testosterone and sex hormone‐binding globulin levels were collected for postmenarchal females. Results.— There was no statistically significant treatment difference between any divalproex sodium extended‐release dose group and placebo for the primary efficacy variable, reduction from baseline in 4‐week migraine headache rate. There were no statistically significant differences in adverse events between any active treatment group and placebo. A notable dose‐related decrease in platelets was observed, and individuals in all 4 treatment groups had increases in ammonia levels; treatment differences in other laboratory variables were generally small. Among postmenarchal female subjects who were not taking hormonal contraceptives or other steroids, there was no statistically significant change in testosterone levels, but a statistically significant dose‐related increase in sex hormone‐binding globulin was observed. Conclusions.— In the current study, divalproex sodium extended‐release did not differentiate from placebo in the prophylactic treatment of migraine headaches but was generally well‐tolerated in adolescents aged 12 to 17 years.     

Efficacy and safety of tonabersat, a gap-junction modulator, in the acute treatment of migraine: a double-blind, parallel-group, randomized study

The ability of tonabersat to relieve the symptoms of migraine attacks with or without aura was evaluated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients received 20 or 40 mg of tonabersat, or 50 mg of sumatriptan (positive control), or placebo at the onset of a moderate or severe attack. Headache intensity, relief and recurrence were recorded for 24 h after dosing. On the basis of primary or secondary efficacy measures, tonabersat did not provide a clinically or statistically significant advantage over placebo. Tonabersat generally was well tolerated and had no effect on vital signs, electrocardiogram recordings or laboratory values. The lack of efficacy may be a function of the slow absorption of tonabersat. As a consequence of slow absorption, daily administration of tonabersat as prophylaxis for migraine attacks is under investigation in ongoing studies.     

Naratriptan as short-term prophylaxis of menstrually associated migraine: a randomized, double-blind, placebo-controlled study

OBJECTIVE: To determine the efficacy of naratriptan 1-mg and 2.5-mg tablets twice daily compared with placebo as short-term prophylaxis of menstrually associated migraine. BACKGROUND: Approximately 60% of women with migraine report headaches associated with their menstrual cycles. Results from an open-label study suggest that short-term administration of sumatriptan is useful in the prophylaxis of menstrually associated migraine. METHODS: A randomized, double-blind, three-arm, parallel-group, placebo-controlled study was conducted in women aged 18 years or older with a history of migraine with or without aura, as defined by the International Headache Society, of at least 6 months. Two dose strengths of naratriptan (1 mg, 2.5 mg) or identical-appearing placebo tablets (1:1:1) were administered twice daily for 5 days starting 2 days prior to the expected onset of menses across four perimenstrual periods. End points included the number of menstrually associated migraines, total migraine days, peak headache severity, lost work/activity time, migraine-related quality of life, and incidence of adverse events. RESULTS: Overall, the intent-to-treat population comprised 206 women (naratriptan 1 mg, n = 70; naratriptan 2.5 mg, n = 70, and placebo, n = 66); 171 women treated four perimenstrual periods. Significantly more perimenstrual periods per subject treated with naratriptan, 1 mg, were headache-free compared with placebo (50% versus 25%, P =.003). Naratriptan, 1 mg, significantly reduced the number of menstrually associated migraines (2.0 versus 4.0, P <.05) and menstrually associated migraine days (4.2 versus 7.0, P <.01) compared with placebo. More patients treated with naratriptan, 1 mg, were headache-free across all treated perimenstrual periods compared with placebo (23% versus 8%). No difference in headache severity was observed in breakthrough headaches. The incidence and severity of adverse events was similar across treatment groups. Naratriptan, 2.5 mg, was not statistically superior to placebo for any measure. CONCLUSIONS: Naratriptan, 1 mg, with tolerability similar to placebo, is an effective, short-term, prophylactic treatment for menstrually associated migraine.     

Remote electrical neuromodulation for migraine prevention: A double-blind,randomized, placebo-controlled clinical trial

Objective

To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine.

Background

Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine.

Methods

We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary.

Results

Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval −3.9 to −1.5], p < 0.001). The significance was maintained when analyzing the episodic (−3.2 ± 3.4 vs. −1.0 ± 3.6, p = 0.003) and chronic (−4.7 ± 4.4 vs. −1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group.

Conclusion

Applied every other day, REN is effective and safe for the prevention of migraine.     

A comparative study of magnesium, flunarizine and amitriptyline in the prophylaxis of migraine

Circumstantial evidence points to the possible role of magnesium (Mg⁺²) deficiency in the pathogenesis of migraine and has raised questions about the clinical utility of magnesium as a therapeutic regimen in migraine. This was a prospective, randomized, double-blind, placebo-controlled trial comparing the efficacy and tolerability of 1830 mg magnesium citrate (23 patients), 10 mg flunarizine (22 patients) and 10 amitriptyline (20 patients) in the prophylaxis of migraine diagnosed according to the criteria of the International Headache Society. Patients were evaluated for attack frequency, severity and drug side effects monthly for 3 months. Magnesium, flunarizine and amitriptyline were all superior to placebo (p<0.001) in reducint both attack frequency and severity after the first month. There was no significant difference between the 3 active drugs in reduction of attack frequency and severity. No serious side effects were observed and the frequencies of side effects were not significantly different in all treatment groups. Our results show that oral magnesium is an effective and well tolerated drug in the prophylaxis of migraine and compares well to established drugs like flunarizine and amitriptyline both in effectiveness and occurence of side effects. Magnesium may be an alternative drug in migraine prophylaxis, but more and larger comparative trials are needed to confirm these results. Received: 28 August 2000 / Accepted in revised form: 10 January 2001     

Botulinum toxin A in the prophylactic treatment of migraine--a randomized, double-blind, placebo-controlled study

Botulinum toxin A has been suggested to be effective in the prophylactic treatment of migraine. However, only very few randomized, double-blind, placebo-controlled studies are available. We designed such a study with a specific focus on different injection sites. Sixty patients with a migraine according to the criteria of the International Headache Society were randomly assigned to receive either placebo in the frontal and neck muscles, or to receive 16 U botulinum toxin A in the frontal muscles and placebo in the neck muscles, or to receive in total 100 U botulinum toxin A in the frontal and neck muscles. The observation period was 3 months. In both treatment groups, 30% of patients showed a reduction of migraine frequency in month 3 by at least 50% compared with baseline, in the placebo group 25% of the patients showed such a reduction (P = 0.921). There were no significant differences between the three study groups with respect to reduction of migraine frequency, number of days with migraine, and the number of total single doses to treat a migraine attack. In the post hoc analysis, the reduction of all accompanying symptoms was significantly higher in the 16 U treatment group compared with the placebo group. In the 100 U treatment group significantly more adverse events occurred compared with the placebo group. All adverse events were mild and transient. Our study did not show any efficacy of botulinum toxin A in the prophylactic treatment of migraine. Only accompanying symptoms were significantly reduced in the 16 U but not in the 100 U treatment group. Future studies should focus on the efficacy of botulinum toxin A in specific subgroups of patients, on the efficacy of repetitive injections, and on other injection sites.     

A comparative ID migraine screener study in ophthalmology, ENT and neurology out-patient clinics

Migraine is more likely to be misdiagnosed in patients with comorbid diseases. Not only primary care physicians, but also specialists might misdiagnose it due to the lack of diagnostic criteria awareness. The ID migraine test is a reliable screening instrument that may facilitate and accelerate migraine recognition. This study aimed to compare the prevalence and characteristics of migraine in a large sample of patients admitted to clinics of ophthalmology (OC), ear, nose and throat diseases (ENTC) and neurology (NC), as well as to validate the use of the ID migraine test in OC and ENTC settings. This was a multicentre (11 cites) study of out-patients admitting either to NC, ENTC or OC of the study sites during five consecutive working days within 1 week. From each of the clinics, 100 patients were planned to be recruited. All recruited patients were interviewed and those having a headache complaint received an ID migraine test and were examined for headache diagnosis by a neurologist, blinded to the ID migraine test result. A total of 2625 subjects were recruited. Only 1.3% of OC patients and 5.4% of ENTC patients have been admitted with a primary complaint of headache, whereas the percentage of NC patients suffering from headache was 37.6%. Whereas 138 patients (19.3%) in OC, 154 (17.3%) in ENTC and 347 (34%) in NC were found to be ID migraine test positive, 149 patients (20.8%) in OC, 142 (16%) in ENTC and 338 (33.1%) in NC were diagnosed with migraine. The sensitivity, specificity, and positive and negative predictive ratios of the ID migraine test were found to be similar in all clinics. An important fraction of the patients admitted to NC, as well as to OC and ENTC, for headache and/or other complaints were found out to have migraine by means of a simple screening test. This study validated the ID migraine test as a sensitive and specific tool in OC and ENTC, encouraging its use as a screening instrument.