Allodynia-associated symptoms, pain intensity and time to treatment: predicting treatment response in acute migraine intervention.

OBJECTIVE: To evaluate the relationship between treatment outcomes and allodynia-associated symptoms (AAS) at the time of treatment with almotriptan. METHODS: Analyses were performed with data collected prospectively from patients in 2 recently completed early intervention trials, AXERT Early miGraine Intervention Study (AEGIS) and AXERT 12.5 mg time vs Intensity Migraine Study (AIMS): 2-hour pain free, 2-hour pain relief (AEGIS only), sustained pain free (SPF), use of rescue medication, and median headache duration (AIMS only), in the presence and absence of pretreatment AAS, which was determined by responses to a questionnaire. Analyses were conducted to evaluate possible prognostic variables. RESULTS: The presence of pretreatment AAS did not have a significant effect on 2-hour pain-free, 2-hour pain-relief or SPF rates, use of rescue medication, or headache duration. Significant factors for most favorable outcomes (greater 2-hour pain-free, 2-hour pain-relief and SPF rates, less use of rescue medication, and shorter headache duration) included treatment with almotriptan 12.5 mg, treatment of mild or moderate headache pain, and treatment within 1 hour of headache onset. CONCLUSION: Almotriptan 12.5 mg was efficacious in providing 2-hour pain free, 2-hour pain relief, SPF, and reducing rescue medication use irrespective of the presence of AAS at the time of treatment. The most optimal efficacy outcomes occurred when patients treated migraine attacks early and before the onset of severe pain. The presence of AAS, which may indicate an early phase of allodynia, did not influence the efficacy of almotriptan therapy.

Frovatriptan for the acute treatment of migraine and prevention of predictable menstrual migraine.

Frovatriptan is a 5-HT(1B/1D) receptor agonist that belongs to the triptan therapeutic class. Relative to other triptans, frovatriptan has a long half-life (26 h) and a low incidence of migraine recurrence (17%). Frovatriptan is indicated for the acute treatment of migraine with or without aura, and has a relatively good safety and tolerability profile. Recent studies have also shown that a 6-day regimen of frovatriptan scheduled during the perimenstrual period significantly reduced the incidence and severity of menstrual migraine (MM; attacks that regularly start day -2 to +3 relative to menses). Prevention may be important because MM attacks have been characterized as being of longer duration, more severe and more refractory to treatment than non-MM attacks.

Effect of pain intensity and time to administration on responsiveness to almotriptan: results from AXERT 12.5 mg Time Versus Intensity Migraine Study (AIMS).

OBJECTIVE: To determine whether time-based early treatment, independent of pain intensity, is superior to a pain intensity-based treatment, where patients are asked to treat at least moderate intensity headaches, resulting in a reduction of overall migraine headache duration. BACKGROUND: Retrospective and prospective trials have reported improved outcomes when triptans were used early or to treat mild migraine headache pain. However, tolerability as well as efficacy may be 2 of several key issues that have prevented this new treatment paradigm from becoming universally accepted. METHODS: In this multicenter, open-label, cluster-randomized study, patients with IHS-defined migraine were instructed to treat 2 sequential migraine headaches with almotriptan 12.5 mg using either Early Treatment (ET, ie, treat at earliest onset of headache pain, within 1 hour) or Standard Treatment (ST, ie, treat when headache pain intensity is moderate or severe). The novel trial design uses total migraine headache pain duration as the primary endpoint. RESULTS: Results are presented for the first headache and include an ITT population of 757 ET and 693 ST patients. Median headache duration (time from onset of headache pain until no pain) was significantly shorter in ET patients compared to ST patients (3.18 vs 5.53 hours, P < .001). An analysis of the ET subgroup treating headache pain within 1 hour of onset revealed pain intensity, ie, treating mild or moderate versus severe pain, was significantly correlated with treatment outcomes defined by total headache duration, 2-hour pain free, sustained pain free, and use of rescue medication. Multivariate analyses comparing ST subgroups that treated within 1 hour versus greater than 1 hour after headache onset, demonstrate that both pain intensity, ie, treating moderate versus severe headache pain, and treating early versus late, were significantly correlated with total headache duration, 2-hour pain free, sustained pain free, and use of rescue medication. The overall incidence of adverse events was low; nausea and dizziness were the only adverse events with an incidence > or =1% in either treatment group (nausea: 2.5% and 1.7% and dizziness 1.1% and 0.7%, in the ET and ST groups, respectively). CONCLUSION: Total headache duration was significantly shorter in the early treatment group compared to the standard treatment group. Considering time to treatment within a relatively early range of 1 hour or less, efficacy results when treating mild versus moderate pain were similar and both were associated with better outcomes than treatment of severe pain. When considering the prognostic variables of time to treatment and headache pain intensity (limited to moderate vs severe), both were independent predictors, with time to treatment a better predictor of headache duration and rescue medication use, and pain intensity a better predictor of 2-hour pain free and sustained pain free.

A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis.

UNLABELLED: We examined the effects of multiple treatments with low doses of botulinum toxin type A (BoNTA; BOTOX(R), Allergan Inc., Irvine, CA) versus placebo for prophylaxis of episodic migraine. This was a series of 3 sequential, randomized, controlled studies of 418 patients with a history of 4 to 8 moderate to severe migraines per month. In study I, patients were randomized to treatment with placebo or BoNTA (7.5 U, 25 U, or 50 U) in predetermined fixed injection sites on the front and sides of the head only. In study II, patients continued to receive, or were randomized to, 2 consecutive treatments with 25 U or 50 U. In study III, patients were randomized to placebo or continuation of 25 U or 50 U. Injection cycles were each 4 months long. BoNTA and placebo produced comparable decreases from baseline in the frequency of migraines at each time point examined (P >or= .201). No consistent, statistically significant differences were observed for any efficacy variable. Adverse events were similar among the groups within each study. In these exploratory studies of episodic migraine patients, repeated injections of low doses of BoNTA into fixed frontal, temporal, and glabellar sites were not more effective than placebo. BoNTA was safe and well tolerated. PERSPECTIVE: Beneficial effects of BoNTA in the treatment of migraine have been reported, but positive results are not universal, possibly because the optimal patient population and regimen are not yet definitively established. This study explores the effects of multiple injections of low BoNTA doses into fixed sites for episodic migraine.

Acetaminophen, aspirin, and caffeine versus sumatriptan succinate in the early treatment of migraine: results from the ASSET trial.

OBJECTIVE: To address the need for a rigorous, direct comparison of prescription and over-the-counter (OTC) migraine drugs and to expand the database on early treatment of migraine. BACKGROUND: Most people who experience migraine use OTC medications to treat their symptoms, but no head-to-head clinical trials comparing these agents with prescription migraine therapies have been published. In addition, even though most migraineurs treat early in the attack, few studies have been conducted to reflect this treatment pattern. METHODS: We compared a combination of nonprescription migraine medication (acetaminophen 500 mg, aspirin 500 mg, and caffeine 130 mg) with a prescription migraine product (50 mg sumatriptan) in a randomized, controlled clinical trial in which subjects treated at the first sign of a migraine attack. Subjects who reported vomiting during more than 20% of migraine episodes or who required bedrest during more than 50% of migraine episodes were excluded from the study. Of the 188 subjects randomized, 171 took study medication and were included in the analysis. CONCLUSION: The combination of acetaminophen, aspirin, and caffeine was significantly more effective (P > .05) than sumatriptan in the early treatment of migraine, as shown by superiority in summed pain intensity difference, pain relief, pain intensity difference, response, sustained response, relief of associated symptoms, use of rescue medication, disability relief, and global assessments of effectiveness. An additional, larger clinical trial is needed to confirm these results.

Botulinum toxin type a for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study.

OBJECTIVE: To assess the efficacy and safety of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc., Irvine, CA) for the prophylaxis of headaches in patients with chronic daily headache (CDH) without the confounding factor of concurrent prophylactic medications. BACKGROUND: Several open-label studies and an 11-month, randomized, double-blind, placebo-controlled study suggest that BoNT-A may be an effective therapy for the prophylaxis of headaches in patients with CDH. DESIGN AND METHODS: This was a subgroup analysis of an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of adult patients with 16 or more headache days per 30-day periods conducted at 13 North American study centers. All patients had a history of migraine or probable migraine. This analysis involved data for patients who were not receiving concomitant prophylactic headache medication and who constituted 64% of the full study population. Following a 30-day screening period and a 30-day single-blind, placebo injection, eligible patients were injected with BoNT-A or placebo and assessed every 30 days for 9 months The following efficacy measures were analyzed per 30-day periods: change from baseline in number of headache-free days; change from baseline in headache frequency; proportion of patients with at least 30% or at least 50% decrease from baseline in headache frequency; and change from baseline in mean headache severity. Acute medication use was assessed, and adverse events were recorded at each study visit. RESULTS: Of the 355 patients randomized in the study, 228 (64%) were not taking prophylactic medication and were included in this analysis (117 received BoNT-A, 111 received placebo injections). Mean age was 42.4+/-10.90 years; the mean frequency of headaches per 30 days at baseline was 14.1 for the BoNT-A group and 12.9 for the placebo group (P=.205). After two injection sessions, the maximum change in the mean frequency of headaches per 30 days was -7.8 in the BoNT-A group compared with only -4.5 in the placebo group (P=.032), a statistically significant between-group difference of 3.3 headaches. The between-group difference favoring BoNT-A treatment continued to improve to 4.2 headaches after a third injection session (P=.023). In addition, BoNT-A treatment at least halved the frequency of baseline headaches in over 50% of patients after three injection sessions compared to baseline. Statistically significant differences between BoNT-A and placebo were evident for the change from baseline in headache frequency and headache severity for most time points from day 180 through day 270. Only 5 patients (4 patients receiving BoNT-A treatment; 1 patient receiving placebo) discontinued the study due to adverse events and most treatment-related events were transient and mild to moderate in severity. CONCLUSIONS: BoNT-A is an effective and well-tolerated prophylactic treatment in migraine patients with CDH who are not using other prophylactic medications.

Pharmacokinetics of frovatriptan in adolescent migraineurs.

Frovatriptan is a selective 5-HT(1B/1D) receptor agonist available for acute treatment of migraine in adults (18 years and older). The objective of this study was to determine key pharmacokinetic parameters of frovatriptan in adolescent migraineurs after a single 2.5-mg oral dose and to compare these results with those from an earlier study completed in adults. Subjects were stratified by age (12-14 and 15-17 years) and gender, and serial blood and urine samples were collected over 48 hours. A total of 25 subjects (13 male, 12 female) completed the study. Pharmacokinetic profiles for adolescent subjects were similar to those observed in adults. The median tmax ranged from 2 (male subjects) to 3 (female subjects) hours. The AUC0-24h and Cmax were slightly lower in adolescent subjects as compared with adults. As seen in adults, AUC0-24h and Cmax values were approximately 2-fold higher in females than in their male counterparts (AUC mean range 40.5-59.8 ng x h/mL vs 21.2-23.5 ng x h/mL and Cmax mean range 4.02-6.14 vs ng x h/mL 2.52-2.99 ng/mL, in female and male adolescent subjects, respectively). Elimination was biphasic, with an approximate terminal elimination half-life (t(1/2)) between 12.2 and 25.5 hours. Renal clearance was similar in adolescents and adults, being somewhat higher in female than male subjects. Frovatriptan was well tolerated with no serious or treatment-related adverse effects. In addition, there were no clinically significant changes in safety parameters. Overall, the pharmacokinetic profile of frovatriptan in adolescents (12-17 years) is similar to that seen in adults, and dosing adjustments are unlikely to be needed.

A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine.

BACKGROUND: Menstrually associated migraine (MAM) is often prolonged and difficult to manage with conventional therapies. Frovatriptan is a new selective 5HT(1B/1D) receptor agonist indicated for short-term management of migraine. It has a long half-life and good tolerability. These characteristics suggest that frovatriptan may be useful for the intermittent prevention of MAM. METHODS: The study was a randomized, double-blind, placebo-controlled, three-way crossover design. Patients treated each of three perimenstrual periods (PMPs) with placebo, frovatriptan 2.5 mg QD, and frovatriptan 2.5 mg BID. The 6-day treatment started 2 days before the anticipated start of MAM headache. The primary efficacy endpoint was incidence of MAM headache during the 6-day PMP. RESULTS: The population comprised 546 women (mean age, 37.6 years). Use of frovatriptan reduced the occurrence of MAM headache. The incidence of MAM headache during the 6-day PMP was 67% for placebo, 52% for frovatriptan 2.5 mg QD, and 41% for frovatriptan 2.5 mg BID. Both frovatriptan regimens were superior to placebo (p < 0.0001), and the BID regimen was superior to the QD regimen (p < 0.001). Both frovatriptan regimens also reduced MAM severity (p < 0.0001), duration (p < 0.0001), and the use of rescue medication (p < 0.01 QD; p < 0.0001 BID) in a dose-dependent manner. The incidence and type of adverse events for both regimens were similar to placebo and consistent with those reported for short-term migraine management. CONCLUSION: Frovatriptan given prophylactically for 6 days was effective in reducing the incidence of menstrually associated migraine. More than half of patients who used frovatriptan 2.5 mg BID had no menstrually associated migraine headache during the 6-day perimenstrual period. The findings are consistent with the long duration of action and good tolerability of frovatriptan observed in short-term migraine management.

Frovatriptan use in migraineurs with or at high risk of coronary artery disease.

OBJECTIVE: To investigate the cardiovascular effects of frovatriptan 2.5 mg during a migraine attack in patients with, or at high risk of, coronary artery disease. BACKGROUND: Rare occurrences of myocardial ischemia and coronary and peripheral vasospasm associated with the use of sumatriptan have triggered concern over the vasoconstrictor properties of the triptan class of drugs. METHODS: This randomized, double-blind, placebo-controlled, parallel-group study was conducted in 14 US private headache referral centers or clinics. Seventy-five patients, aged 18 years and older, with a history of migraine who were at high risk (Framingham score > or =14) of or who had previously documented coronary artery disease were evaluated. RESULTS: Incidence of clinically significant electrocardiogram changes was higher at all time points postdose with placebo than with frovatriptan, reaching statistical significance at 4 hours (40% versus 19%, P=.026). Similar proportions of patients had ischemia documented on Holter monitoring in the placebo (13%) and frovatriptan (11%) groups, and the incidence of arrhythmias was higher in the placebo group (11% versus 3%). There were no clinically significant changes in heart rate or blood pressure in either group. Adverse event profiles were similar for placebo and frovatriptan. CONCLUSIONS: In this exploratory study of migraineurs with, or at high risk of, coronary artery disease, frovatriptan 2.5 mg was well tolerated and not associated with an increase in cardiovascular monitoring abnormalities.