Effect of telcagepant on spontaneous ischemia in cardiovascular patients in a randomized study

(Headache 2011;51:954‐960) Objective.— The primary purpose of the study was to explore the safety and tolerability of telcagepant in patients with stable coronary artery disease. Background.— Triptans are effective acute anti‐migraine drugs whose vasoconstrictive effects limit their use in patients at risk for adverse cardiovascular events. Telcagepant, a calcitonin gene‐related peptide receptor antagonist, is being developed for the acute treatment of migraine. Antagonism of calcitonin gene‐related peptide, which does not appear to cause vasoconstriction, may allow for treatment of migraine in patients with coronary artery disease. Methods.— In this randomized, double‐blind, placebo‐controlled, crossover study, patients with documented stable coronary artery disease were assigned to 1 of 2 treatment sequences: telcagepant then placebo, or placebo then telcagepant. In each treatment period, patients received 2 doses of telcagepant 300 mg or placebo 2 hours apart. They remained in the research center for 24 hours after receiving the first dose of each period, during which time continuous 12‐lead ambulatory electrocardiographic (Holter) monitoring was performed. Results.— Twenty‐eight patients were enrolled; all patients completed the study and were included in all analyses. Telcagepant was generally well tolerated. No laboratory or serious adverse experiences were reported, and no patient discontinued due to an adverse experience. There were no consistent treatment‐related changes in laboratory, vital signs or electrocardiogram safety parameters. Three patients (2 after receiving placebo and 1 after receiving telcagepant) experienced ST segment depression during the study; none of these patients reported chest pain. Conclusions.— Two doses of 300‐mg telcagepant, administered 2 hours apart, did not appear to exacerbate spontaneous ischemia and were generally well tolerated in a small cohort of patients with stable coronary artery disease. Results of this study support further evaluation of telcagepant in patients with stable coronary artery disease.     

Randomized controlled study of telcagepant plus Ibuprofen or acetaminophen in migraine

(Headache 2011;51:533‐543) Objective.— To evaluate the efficacy and tolerability of telcagepant when co‐administered with ibuprofen or acetaminophen for the acute treatment of migraine. Background.— Telcagepant is an oral calcitonin gene‐related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. Combining telcagepant with analgesics that have a different mechanism of action could produce greater efficacy. Methods.— Randomized, double‐blind, placebo‐controlled study. Patients were randomized to treat a moderate or severe migraine headache with either telcagepant 280 mg + ibuprofen 400 mg (N = 171), telcagepant 280 mg + acetaminophen 1000 mg (N = 171), telcagepant 280 mg (N = 170), or placebo (N = 171). The primary efficacy endpoint was 2‐hour pain freedom. The study had approximately 88% power to detect an additive effect of at least 15 percentage points (telcagepant combination vs telcagepant monotherapy) and 48% power to detect an additive effect of at least 10 percentage points. Safety and tolerability were assessed by adverse events and laboratory tests. Results.— The percentages of patients with 2‐hour pain freedom were greater in each active treatment group compared to placebo (P < .001): telcagepant + ibuprofen = 35.2%, telcagepant + acetaminophen = 38.3%, telcagepant = 31.2%, placebo = 10.9%. No significant differences were seen for either of the combination groups vs telcagepant monotherapy, but both were numerically larger than telcagepant monotherapy. All the active treatments were generally well tolerated. The percentage of patients reporting any adverse event within 48 hours was higher in the active treatment groups than placebo: telcagepant + ibuprofen = 30.3%, telcagepant + acetaminophen = 31.6%, telcagepant = 24.8%, placebo = 18.2%. The most common adverse events reported by ≥4 patients in one or more of the treatment groups that included telcagepant were fatigue, nausea, dizziness, somnolence, dry mouth, and tremor. Conclusions.— The combination of telcagepant 280 mg with either ibuprofen 400 mg or acetaminophen 1000 mg did not show a statistically significant difference from telcagepant alone. Numerically greater treatment effects in the combination treatment groups over the telcagepant 280 mg monotherapy suggest that telcagepant combination treatments may merit further evaluation in studies powered to detect smaller additive benefits. (Clinicaltrials.gov; NCT00758836).     

Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial

(Headache 2011;51:73‐84) Objective.— To evaluate the long‐term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.— Telcagepant is a calcitonin gene‐related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine. Methods.— Migraine patients were randomized 2:1 to double‐blind treatment with telcagepant 280/300 mg or rizatriptan 10 mg for an acute mild, moderate, or severe migraine. Patients could administer a second dose within 2‐24 hours for nonresponse or migraine recurrence. Patients could treat up to 8 attacks per month for up to 18 months. Safety assessments included spontaneous reports of adverse events and collection of vital signs, electrocardiograms, and laboratory assessments. The primary endpoint was the percentage of patients with ≥1 triptan‐related adverse events in the 14‐day period post dose. Results.— Of 1068 patients randomized, 641 (90%) patients treated ≥1 attack with telcagepant and 313 (88%) treated ≥1 attack with rizatriptan. A total of 19,820 attacks were treated with telcagepant (mean per patient = 31) and 10,981 with rizatriptan (mean per patient = 35). Fewer triptan‐related adverse events (difference: ?6.2%; 95% CI ?10.4, ?2.6; P < .001) and drug‐related adverse events (difference: ?15.6%; 95% CI ?22.2, ?9.0) were reported for telcagepant vs rizatriptan. The most common adverse events appeared to have generally similar incidence proportions between the treatment groups. Those with an incidence >5% in the telcagepant group were dry mouth (9.7%, rizatriptan = 13.7%), somnolence (9.2%, rizatriptan = 16.6%), dizziness (8.9%, rizatriptan = 10.2%), and nausea (9.0%, rizatriptan = 6.4%). Conclusions.— Telcagepant was generally well tolerated when administered for the acute intermittent treatment of migraine for up to 18 months. The incidences of triptan‐related and drug‐related adverse events favored telcagepant over rizatriptan.     

Antimigraine efficacy of telcagepant based on patient's historical triptan response

(Headache 2011;51:64‐72) Objective.— To evaluate whether the same or different patients respond to triptans and telcagepant. Background.— Telcagepant is an oral calcitonin gene‐related peptide receptor antagonist with acute antimigraine efficacy comparable to oral triptans. It is currently unknown whether migraine patients who cannot be adequately helped with triptans might benefit from treatment with telcagepant. Methods.— Post‐hoc analysis of data from a randomized, controlled trial of telcagepant (150 mg, 300 mg) zolmitriptan 5 mg, or placebo for a moderate/severe migraine. Responder rates were analyzed according to patients' self‐reported historical triptan response (HTR): (1) good HTR (N = 660): response in 75‐100% of attacks; (2) intermediate HTR (N = 248): response in 25‐74% of attacks; (3) poor HTR/no use (N = 407): response in <25% of attacks, or patient did not take triptans. A limitation of the analysis is that the last subgroup comprised mainly (91%) patients who reported that they did not take triptans, but it was not known whether these patients were triptan‐naïve or had previously used triptans and stopped taking them. Results.— For zolmitriptan, 2‐hour pain relief rates were higher in the good HTR subgroup (116/162, 72%) than in the intermediate (29/62, 47%) and poor/no use (44/111, 40%) HTR subgroups. The 2‐hour pain relief rates were similar across HTR subgroups for telcagepant 150 mg (48‐58%), 300 mg (52‐58%), and placebo (26‐31%). In the poor/no use HTR subgroup, more patients receiving telcagepant 300 mg (56/98, 57.1%) had 2‐hour pain relief than those receiving zolmitriptan (44/111, 39.6%; odds ratio = 2.11 [95% CI: 1.20,3.71], P = .009); the percentage for telcagepant 150 mg (57/119, 47.9%) was not significantly different from zolmitriptan (odds ratio = 1.41 [95% CI: 0.82, 2.40], P = .211). Conclusions.— This suggests that different patients may respond to triptans or telcagepant 300 mg. Caution should be exercised in interpreting the results because of the post‐hoc nature of the analysis (clinical trial registry: NCT00442936).     

Excellent tolerability but relatively low initial clinical efficacy of telcagepant in migraine

In 3 randomized clinical trials (n = 1585) the calcitonin gene-related peptide antagonist telcagepant 300 mg orally had an incidence of adverse events similar to placebo when used in the acute treatment of migraine. Telcagepant, thus, has excellent tolerability in migraine. Only a quarter (26%) (334/1307) of patients were, however, pain free after 2 hours, while 56% (729/1297) of patients had pain relief at 2 hours. Telcagepant 300 mg in one randomized clinical trial was equipotent to zolmitriptan 5 mg. Based on results from a meta-analysis, rizatriptan 10 mg (41%) and almotriptan (35%) seem superior to telcagepant (26%) for pain free at 2 hours whereas rizatriptan 10 mg (25%) showed no difference from telcagepant 300 mg (19 %) for sustained pain free (2-24 hours). The introduction of calcitonin gene-related peptide receptor antagonism in the acute treatment of migraine is a major step forward but so far mostly because of its specific mode of action and excellent tolerability.     

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.     

A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic™ M) in the treatment of migraine

(Headache 2011;51:1078‐1086) Background.— Therapeutic needs of migraineurs vary considerably from patient to patient and even attack to attack. Some attacks require high‐end therapy, while other attacks have treatment needs that are less immediate. While triptans are considered the “gold standard” of migraine therapy, they do have limitations and many patients are seeking other therapeutic alternatives. In 2005, an open‐label study of feverfew/ginger suggested efficacy for attacks of migraine treated early during the mild headache phase of the attack. Methods/Materials.— In this multi‐center pilot study, 60 patients treated 221 attacks of migraine with sublingual feverfew/ginger or placebo. All subjects met International Headache Society criteria for migraine with or without aura, experiencing 2‐6 attacks of migraine per month within the previous 3 months. Subjects had <15 headache days per month and were not experiencing medication overuse headache. Inclusion required that subjects were able to identify a period of mild headache in at least 75% of attacks. Subjects were required to be able to distinguish migraine from non‐migraine headache. Subjects were randomized 3:1 to receive either sublingual feverfew/ginger or a matching placebo and were instructed but not required to treat with study medication at the earliest recognition of migraine. Results.— Sixty subjects treated 208 evaluable attacks of migraine over a 1‐month period; 45 subjects treated 163 attacks with sublingual feverfew/ginger and 15 subjects treated 58 attacks with a sublingual placebo preparation. Evaluable diaries were completed for 151 attacks of migraine in the population using feverfew/ginger and 57 attacks for those attacks treated with placebo. At 2 hours, 32% of subjects receiving active medication and 16% of subjects receiving placebo were pain‐free (P = .02). At 2 hours, 63% of subjects receiving feverfew/ginger found pain relief (pain‐free or mild headache) vs 39% for placebo (P = .002). Pain level differences on a 4‐point pain scale for those receiving feverfew/ginger vs placebo were ?0.24 vs ?0.04 respectively (P = .006). Feverfew/ginger was generally well tolerated with oral numbness and nausea being the most frequently occurring adverse event. Conclusion.— Sublingual feverfew/ginger appears safe and effective as a first‐line abortive treatment for a population of migraineurs who frequently experience mild headache prior to the onset of moderate to severe headache.     

Rizatriptan for treatment of acute migraine in patients taking topiramate for migraine prophylaxis

Objective.— To assess efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treatment of acute migraine in patients using topiramate for migraine prophylaxis. Background.— There are limited data from prospective controlled trials demonstrating the benefit of triptans in patients who experience migraine attacks while taking prophylactic medication. Methods.— This was a worldwide, randomized, placebo‐controlled, double‐blind, multiple‐attack study in adults with a >1‐year history of migraine taking a stable dose of topiramate for migraine prophylaxis and experiencing ≥2 moderate/severe attacks per month. Participants treated 3 moderate/severe attacks in crossover fashion (2 with rizatriptan 10‐mg ODT, 1 with placebo) following random assignment to 1 of 3 treatment sequences. The primary end point was 2‐hour pain relief. Results.— Two‐hour pain relief was significantly greater with rizatriptan compared with placebo (55.0% vs 17.4%, P < .001). Response rates also favored rizatriptan for sustained pain relief from 2‐24 hours (32.6% vs 11.1%, P < .001), 2‐hour pain freedom (36.0% vs 6.5%, P < .001), normal functional ability at 2 hours (42.2% vs 12.7%, P < .001), and overall treatment satisfaction at 24 hours (60.8% vs 33.6%, P < .001). Few participants reported adverse experiences (16 [15.8%] with rizatriptan, 3 [3.2%] with placebo); none were serious. Conclusion.— Rizatriptan 10‐mg ODT was superior to placebo at all pain end points for treatment of acute migraine in patients using topiramate for migraine prophylaxis. Rizatriptan was generally well tolerated in this population. These results are comparable with those from clinical trials in patients not using prophylaxis, suggesting that the use of topiramate does not affect the efficacy or tolerability of rizatriptan for acute migraine treatment.     

Evaluation of Carisbamate for the Treatment of Migraine in a Randomized, Double-Blind Trial

Objective.— This study explored the dose‐response relationship of carisbamate administered at doses of 100 mg per day, 300 mg per day, or 600 mg per day, in the prevention of migraine. Background.— Carisbamate ([S]‐2‐O‐carbamoyl‐1‐o‐chlorophenyl‐ethanol; RWJ 333369) is a new chemical entity being studied for efficacy as adjunctive therapy in partial onset epilepsy. Because some antiepileptic drugs are also efficacious in migraine, for example, topiramate and valproate sodium, we tested carisbamate in migraine prophylaxis. Design/Methods.— This was a double‐blind, placebo‐controlled trial, approximately 22‐week duration. The primary efficacy variable was the percent reduction from baseline through the double‐blind phase in average monthly migraine frequency using a 48‐hour rule. Patients were randomized 1 : 1 : 1 : 1 to treatment with carisbamate 100, 300, or 600 mg per day, or placebo. Migraine attacks were counted during a prospective 4‐week baseline period, which was followed by a 2‐week titration period, a 12‐week maintenance period, a 1‐week medication reduction period, and a 3‐week observation period. Patients had an established history of migraine, with or without aura, for at least 1 year and a 3‐month history of 3‐12 migraine attacks per month. Results.— Patients (n = 323) were predominantly women (85%) and white (89%); mean age was 41 years. There were no statistically significant differences between any of the carisbamate groups and placebo (P ≥ .6) for the median (range) percentage reduction from baseline to end point in average monthly migraine frequency (P value vs placebo): 37% (?250%, 100%) for placebo; 33% (?210%, 100%; P = .7) CRS 100 mg/day; 27% (?100%, 100%; P = .8) CRS 300 mg/day; and 35% (?87%, 100%; P = .6) CRS 600 mg/day. Results for secondary efficacy measures (responder rate, percent reduction in average monthly migraine frequency using the 24‐hour rule, and percent reduction in average monthly migraine days) were consistent (P ≥ .075). The proportion of patients discontinuing because of adverse events was similar for placebo and carisbamate‐treated patients (13% each). The most common (occurring in ≥5% of patients) treatment‐emergent adverse events in patients treated with carisbamate were fatigue (17%) and nasopharyngitis (13%). Fatigue appeared to be dose related. Conclusions.— Carisbamate was not more efficacious in migraine prophylaxis than placebo in this well‐controlled study that included a suitable population. However, carisbamate monotherapy was well tolerated at doses up to 600 mg per day.     

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.     

Rizatriptan efficacy in ICHD-II pure menstrual migraine and menstrually related migraine

Objective.— To examine the efficacy of rizatriptan for the treatment of pure menstrual migraine (PMM). Background.— In 2004, the International Headache Society proposed new research criteria for menstrual migraine (International Classification of Headache Disorders [ICHD‐II]). Two subtypes were defined: PMM, in which attacks occur exclusively with menstruation, and menstrually related migraine (MRM), in which attacks may also occur at other times of the cycle. Methods.— The 2 protocols (MM1 and MM2) were identical randomized, double‐blind studies. Adult patients with ICHD‐II menstrual migraine were assigned to either rizatriptan 10‐mg tablet or placebo (2:1). Patients were to treat a single menstrual migraine attack of moderate or severe pain intensity. This prospectively planned substudy pooled data from patients with a diagnosis of PMM from both studies. The primary substudy endpoint was 2‐hour pain relief. Efficacy data were summarized for patients with a diagnosis of MRM. Results.— Of 707 (MM1: 357, MM2: 350) patients treated in the study, 146 patients (MM1: 81, MM2: 65) had a diagnosis of PMM. The percentage of patients reporting 2‐hour pain relief was significantly greater for rizatriptan than for placebo for both PMM (73% vs 50%, P = .006) and MRM subgroups (71% vs 52%, P < .001). Most other efficacy endpoints favored rizatriptan compared with placebo in patients with either PMM or MRM. Conclusion.— Rizatriptan 10 mg was superior to placebo for the treatment of PMM, as measured by 2‐hour pain relief. Rizatriptan was also effective for the treatment of MRM and for relief of migraine‐associated symptoms for both headache subtypes.     

Efficacy and Safety of 400 and 800 mg Etodolac vs. 1,000 mg Paracetamol in Acute Treatment of Migraine: A Randomized,Double‐blind,Crossover, Multicenter,Phase III Clinical Trial

Aim: We aimed to determine the efficacy and safety of etodolac, in acute migraine attacks in comparison with paracetamol (acetaminophen). Methods: We designed a randomized, double‐blind, crossover phase III clinical trial for patients diagnosed with migraine for at least 1 year, according to ICHD‐II criteria. Two hundred and twenty‐nine adult patients having 2 to 8 attacks monthly from 17 centers were included. The patients were instructed to use 3 attack treatment packages consisting of 1,000 mg paracetamol, 400 mg etodolac, and 800 mg etodolac on 3 migraine attacks of moderate–severe intensity each in a 3‐month treatment period, interchangeably. Results: Any pain medication was used in 1,570 migraine attacks while study treatments were used in 1,047 attacks. The results for 1,000 mg paracetamol, 400 mg etodolac, and 800 mg etodolac were as follows: response of headache at 2 hours 44.9%, 48.3% and 46.1%; pain‐free at 2 hours 19.2%, 19.3% and 24.1%; sustained pain‐free from 2 to 24 hours 34.3%, 38.3% and 41.1%; relapse rates in 2 to 24 hours 7.3%, 14.3% and 9.7%. There were no statistically significant differences between the groups regarding the headache response, pain‐free, sustained pain‐free, and relapse rates. Nausea, vomiting, phonophobia, or photophobia decreased similarly in all groups within 24 hours of treatment administration. Drug‐related adverse events were noted in 8 patients with 1,000 mg paracetamol, in 9 patients with 400 mg etodolac and in 9 patients for 800 mg etodolac during the study. Comment: Our study showed that etodolac is a safe and effective alternative in acute migraine treatment and showed comparable efficacy to paracetamol 1,000 mg. Etodolac may be considered as an alternative option for acute treatment of migraine.     

Divalproex sodium in migraine prophylaxis: a dose-controlled study

Objective : To evaluate the efficacy and safety of divalproex sodium (DVPX) when used as prophylactic monotherapy in patients with migraine. Design : Multicenter, double-blind, placebo-controlled, parallel group. Patients were previously untreated or had failed no more than two adequate trials of prophylactic therapy. During the 4-week (single-blind) baseline, patients received placebo and completed a headache diary. Patients with two or more migraine attacks during the baseline were randomized to receive a DVPX daily dose of 500, 1000, or 1500 mg, or to placebo. The experimental phase (EP) lasted 12 weeks, the first 4 weeks for dose escalation to randomized dose, and the remaining 8 weeks for maintenance at that dose. The primary efficacy variable was 4-week migraine attack frequency during the EP. Results : One-hundred-and-seventy-six patients (44 placebo, 132 DVPX) were randomized; 171 provided efficacy data and 137 completed the study. During the EP, after adjustment for differences in baseline migraine attack frequencies, mean reductions in the DVPX groups were 1.7 (500 mg), 2.0 (1000 mg) and 1.7 (1500 mg) migraine attacks per 4 weeks compared to a mean reduction of 0.5 migraine attacks in the placebo group ( p 0.05 vs placebo). Forty-four to 45% of DVPX-treated patients, compared to 21% of patients in the placebo group achieved 50% reduction in their migraine attack frequencies ( p 0.05 vs placebo). The recommended initial dose of DVPX in migraine prophylaxis is 500 mg per day, although some patients may benefit from higher doses. Adverse events were similar in the DVPX and placebo treatment groups except for nausea, dizziness and tremor, in which incidence rates were significantly higher in the DVPX 1500 mg group (nausea was also higher in 500 mg group) than in the placebo group. Conclusion : Divalproex sodium is an effective prophylactic treatment in migraine and is generally well tolerated.     

Treatment of Acute Migraine Attack: Ibuprofen and Placebo Compared

The efficacy of ibuprofen in comparison with that of placebo was assessed in the treatment of acute migraine attacks. The material consisted of 40 migraine patients. Each treatment period continued for five migraine attacks. The initial dose of ibuprofen was 800 mg, with additional 400 mg taken if and when needed. The mean duration of migraine attacks treated with ibuprofen was significantly shorter than the duration of migraine attacks treated with placebo. Need for supplementary medication was also significantly lower in the ibuprofen-treated migraine attack group. Ibuprofen was well tolerated and no marked side effects were reported during the trial.     

Early treatment of migraine with rizatriptan: a placebo-controlled study

OBJECTIVE: To evaluate the efficacy of rizatriptan when administered early during a migraine attack. BACKGROUND: Several studies indicate that triptans are more efficacious when administered early during a migraine attack, when the pain is still mild. METHODS: One hundred and twelve rizatriptan-na?ve patients aged 20 to 64 years with a history of migraine with or without aura that progressively worsened when left untreated were instructed to treat a total of three migraine attacks with either rizatriptan 10 mg or placebo as early as possible during each attack. Seventy-four patients (68 women and 6 men) were assigned to use the active drug and 38 (35 women and 3 men) to placebo. The primary efficacy endpoint was pain-free response at 2 hours after administration of the study drug. Secondary efficacy measures were pain-free response at 1 hour and sustained pain-free response lasting between 2 and 24 hours. RESULTS: A total of 216 attacks were treated in the rizatriptan group and 109 in the placebo group. Pain-free response at 2 hours after early treatment was noted in 151 (70%) of attacks in the rizatriptan group and in 24 (22%) in the placebo group (P < .01). Pain-free response at 1 hour occurred in 97 (45%) and 9 (8%) attacks, respectively (P < .01). When the attacks were categorized by headache severity at the time of treatment, the pain-free response at 2 hours was higher for mild attacks than for moderate or severe attacks (P < .01). Sustained pain-free response after treatment was significantly higher for attacks treated with rizatriptan (60%) than for those treated with placebo (17%) (P < .001). Adverse events were observed in 62 patients in the rizatriptan group and 15 in the placebo group. Only 1 patient taking rizatriptan discontinued the study because of adverse events, and no serious adverse events were reported. CONCLUSIONS: Rizatriptan is significantly more likely than placebo to produce a pain-free response within 2 hours when the drug is administered early in the migraine attack, when pain is mild rather than moderate or severe.     

A Randomized, Double Blind, Placebo-Controlled Study of MAP0004 in Adult Patients With Migraine

Background.— Dihydroergotamine mesylate (DHE) is an effective treatment for acute migraine, but its effective use is often limited by the inconvenience and inconsistency of intranasal, intramuscular, or subcutaneous routes of administration. A new formulation of DHE delivered through the lungs by the novel Tempo^® inhaler is being developed and is designed to offer fast onset, consistent dosing, and sustained response. Objective.— This proof of principle and dose setting study evaluated the efficacy and tolerability of inhaled DHE delivered by a breath‐synchronized, plume‐controlled inhaler (Tempo) in adult migraineurs. Methods.— This was a randomized, double blind, placebo‐controlled, 2‐period study conducted at 9 headache centers in the United States. Adult men and women with a documented history of acute migraine for at least 12 months, with an average of 2 to 8 attacks per month in the preceding 6 months were treated with MAP0004 0.5 or 1.0 mg systemic equivalent dose (1.0 or 2.0 mg nominal dose) or matching placebo during Treatment Period 1 (TP1). Patients who responded to treatment during TP1 were re‐randomized in Treatment Period 2 (TP2) to receive MAP0004 0.25 mg systemic equivalent dose or placebo. Results.— Of 86 patients randomized to treatment, 69 were included in the As‐Treated population in TP1. Pain relief at 2 hours was greater for MAP0004 0.5 mg (72%, P = .019) and 1.0 mg (65%, P = .071) than for placebo (33%). Pain relief at 10 (32%), 15 (46%), and 30 (55%) minutes was significantly (P < .05) greater with MAP0004 0.5 mg than with placebo (0%, 7% and 14%, respectively). Pain‐free at 2 hours was significantly greater with MAP0004 0.5 mg (44%, P = .015) and 1.0 mg (35%, P = .050) than with placebo (7%). Total migraine relief at 2 hours was significantly (P = .019) greater with MAP0004 0.5 mg (72%) than with placebo (33%). Sustained pain relief and pain‐free rates exhibited a therapeutic gain of 30% (P = .066) and 31% (P = .037) at 24 hours and 28% (P = .096) and 30% (P = .057) at 48 hours with MAP0004 0.5 mg vs placebo. MAP0004 was well tolerated with no serious or severe adverse events. Dysgeusia was reported as treatment‐related in 2 patients on placebo, 0 patients on MAP0004 0.5 mg, and 6 patients on MAP0004 1.0 mg. No clinically relevant changes were noted in spirometry, vital signs, electrocardiogram, or clinical laboratory values. No significant differences between treatments were observed in TP2. Conclusions.— In this study MAP0004 0.5 mg and 1.0 mg were well tolerated and effective at delivering clinically significant, rapid, and sustained pain relief in adult migraine patients. No additional benefit was observed with the higher dose, thus the MAP0004 0.5 mg systemic equivalent dose has been selected as the dose for further clinical study.     

Sumatriptan in the treatment of acute migraine with aura

The efficacy of the selective 5HT1-like agonist sumatriptan in acute treatment of classical migraine (i.e. migraine with aura) was assessed in a double-blind, placebo-controlled, parallel group randomized trial. An oral dose of 200 mg was chosen on the basis of the efficacy rates achieved (70-85%) with 70-280 mg in open studies (1, 2). The dose of 200 mg was also chosen for the study because preliminary data from an oral pilot study indicated that efficacy increased with increasing dose up to 200 mg. Each patient was treated for a maximum of three separate attacks of migraine with aura within a three months' period. Three attacks were treated so that we could examine consistency of response across more than one attack. For attack 1, 200 mg sumatriptan was significantly more effective, safe and well tolerated than placebo at relieving headache 2 h after treatment was given (p = 0.023). In subsequent attacks, i.e. in attacks 2 and 3, there was no such significant effect of sumatriptan compared with placebo in relieving headache. This reduced efficacy of sumatriptan in the second and third attacks may be due to a high incidence of vomiting induced by the high dose of dispersible formulation and also by the bitter taste of the tablets. In addition, there was an increase in placebo response in attacks 2 and 3 compared to the first attack.     

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

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

Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment

Objective.— To evaluate the efficacy and tolerability of coadministration of rizatriptan and acetaminophen in the acute treatment of migraine.
Background.— Rizatriptan is a selective 5-HT_1B/1D agonist approved for the acute treatment of migraine. Acetaminophen has been studied for acute migraine treatment. In consideration of the prominent central and peripheral mechanisms in migraine, the use of "multi-mechanism therapy" is gaining momentum in the treatment of acute migraine attacks.
Study Design.— This was a randomized, double-blind, placebo-controlled trial conducted at 10 centers. Eligible patients with migraine according to International Headache Society criteria treated a single migraine attack of moderate or severe intensity within 4 h from pain onset. Patients were randomized into 1 of 4 groups (rizatriptan 10 mg + acetaminophen 1000 mg [RA], rizatriptan alone [R], acetaminophen alone [A], and placebo [P]). There were 3 co-primary hypotheses tested sequentially for 2-h pain relief: (1) RA would be superior to P; (2) if the first was fulfilled, RA would be superior to A; and (3) if the first 2 were fulfilled, RA would be superior to R.
Results.— Of 173 patients who treated a migraine, 123 patients (71.5%) achieved pain relief within 2 h. RA (90%) was significantly better than P (46%) and A (70%), but only numerically better than R (77%) for 2-h pain relief. No significant differences were seen between the active treatment groups in adverse events.
Conclusion.— Rizatriptan coadministered with acetaminophen achieved 2 of the 3 primary hypotheses, proving superior to both acetaminophen and placebo for 2-h pain relief, but failing to achieve superiority to rizatriptan alone. RA was as well tolerated as each of the individual agents.