New Approaches to Shifting the Migraine Treatment Paradigm.

The standard of care paradigm for migraine treatment has been based almost exclusively on approaches that grew out of the happenstance use of market pharmaceuticals. Only methysergide, which has long since been removed from use for safety concerns, the ergotamine family of drugs, and the triptans were explicitly developed with migraine and other vascular headaches in mind. While the forward and innovative thinking to utilize the broad array of agents to treat migraine served millions well, their therapeutic efficacy was often low, and adverse event profiles were troublesome in the least. Advances in biochemical and molecular biology and the application of advanced "designing drugs" methods have brought about a potentially significant shift in treatment. The gepants have efficacies similar to the triptans but without vascular safety or medication overuse concerns. Preventative gepants offer innovative approaches to prevention and efficacy that exceed even the CGRP monoclonal antibodies. Those monoclonal antibodies brought rapid and highly effective outcomes across the spectrum of migraine. They outpaced older oral medication efficacy and eliminated most adverse events while potentially improving compliance with monthly or quarterly dosing. Other serotonin receptors beyond the 5HT1B and1D receptors have been targeted for decades. They now lead us to better formulations of dihydroergotamine for efficacy, convenience, and tolerability, and a 5HT1F-specific acute treatment like the gepants opens new options for acute management. Neuromodulation goes back to the mid-1800's. Our improved understanding of applied biomedical engineering has brought forward several tantalizing devices, including the application of currents distant from the target and patient regulated. Whether these advances change the paradigm of migraine treatment and standards of care remains to be seen, and issues such as cost and patient acceptance will help mold it.

The efficacy and safety of sumatriptan intranasal powder in adults with acute migraine.

INTRODUCTION: There are multiple choices of agents for the acute management of migraine available. Patient-specific factors such as associated symptoms including nausea, vomiting, and gastroparesis are important considerations. Oral administration may often be the patient-preferred route of delivery because of comfort or convenience but when it is important to bypass gut absorption then either parenteral or intranasal administration may be appropriate delivery approaches. A new formulation of a low-dose sumatriptan intranasal powder administered via a novel breath-powered delivery device may be a viable option Areas covered: Our search of the available literature pertaining to the topic of intranasal sumatriptan powder yielded pharmacokinetic studies and randomized, double-blind, placebo-controlled trials (including The TARGET Study, The COMPASS study) published between 2010 and 2015. Expert commentary: A new formulation of a low-dose sumatriptan intranasal powder administered via a novel breath-powered delivery device appears to be a safe and efficacious option for the acute management of a migraine ideally suited for this situation. It appears to have superior efficacy to sumatriptan 100 mg oral tablets with superior pain freedom by 15 minutes and pain relief over the initial 30 minutes post-dose.

Current and investigational drugs for the prevention of migraine in adults and children.

There are only a handful of drugs that have been submitted for and received an indication for the preventative treatment of migraine by the US Food and Drug Administration, as well as international governmental regulatory agencies. However, there are a wide variety of agents that are used for this indication with different levels of evidence for efficacy and tolerability. Several guidelines have been published in recent years examining the evidence-based medicine of migraine preventative therapy and these provide guidance especially for the primary care clinician, but also for neurologists whose primary focus is not headache medicine. Some of the therapies are used in children and adolescents while others are used more commonly in adults. In the adult population, an evolutive state of migraine is more commonly seen than in young persons, that is chronic migraine. There is a paucity of evidence for medications for this stage of migraine but there is a single agent that is approved for this use but not for use in the treatment of episodic migraine. There have been few advances in the field of migraine-preventative medications in recent years but potential novel approaches are in development.

Medical management of adult headache.

We review the therapies for primary headache disorders: migraine, chronic migraine, tension-type headache, and cluster headache. Recommendations follow the evidence-based treatments so far as is possible with expert opinion to give clinical guidance. Headache has 2 levels of care: acute treatments designed to stop a headache from progressing and alleviate all symptoms associated with the headache and preventive therapies for patients whose headache frequency is such that by itself produces significant disability and impact on quality of life, or where the frequency of use of acute medications, regardless of efficacy, poses risks in terms of overuse or adverse events.

Migraine disability, healthcare utilization, and expenditures following treatment in a tertiary headache center.

Headache is among the most common disabling pain complaints. While many patients are managed in primary care or referral neurology practices, some patients have refractive situations that necessitate referral to a tertiary headache center. Increasing frequency of headache is strongly associated with increasing disability and workplace absenteeism as well as increased healthcare utilization. Previous studies have demonstrated that headache care in a dedicated tertiary center is associated with a decrease in headache frequency and improvement in other characteristics that persist over extended periods of time. Previous studies have not examined the impact of this treatment on subsequent healthcare utilization and associated expenditures. In this study we examined the changes in healthcare utilization and expenditures as well as the impact on disability and workplace productivity with treatment in a tertiary headache care center that used initial treatment settings of inpatient and outpatient care and considered the difference between those with episodic migraine and those with chronic migraine and its complications. Tertiary care was found to produce positive reductions in disability, healthcare utilization, and expenditures. These results suggest that earlier tertiary-level intervention may avoid the complications of migraine that occur in some patients and the increasing costs and utilization of care associated with higher disability.

A review of needle-free sumatriptan injection for rapid control of migraine.

The treatment of migraine was transformed in 1992 with the introduction of the first triptan-based therapy, subcutaneous (SC) sumatriptan. SC sumatriptan has high efficacy and a rapid onset of action compared with other available triptans and formulations presumably because of its short Tmax, high Cmax, and avoidance of enteral absorption. Because of these characteristics, SC sumatriptan is still considered the most reliably and rapidly effective self-administered medication available for acute migraine. Even so, it is relatively little used possibly in part because of patient "needle-phobia." The needle-free sumatriptan injection system (Sumavel DosePro) was developed to address this concern. Clinical trials have shown that the needle-free system is bioequivalent to needle-based injection systems, easy to use, and capable of providing rapid and effective symptom relief for many migraine episodes. Sumavel DosePro is an effective treatment for migraine and should be part of the therapeutic armamentarium, particularly in cases where a rapid onset of action is critical or where oral administration is problematic.

Why do migraines often decrease as we age?

Migraine undergoes both an evolving state in the formative years but also has a remitting state which bears resemblance to the former. Underlying genetics may contribute to the initiating sequence for these processes but the patient's lifetime environment may influence the expression of the disease. Systems rarely thought of in terms of neurologic disease such as the inflammatory system may have significant contributions to modulating this process and accounting for the clinical presentation of migraine.

Sumatriptan needle-free subcutaneous (Sumavel(®) DosePro™) approved for the acute treatment of migraine, with or without aura, and cluster headaches.

Sumatriptan subcutaneous administration is the fastest and most effective of the triptans for relief of acute migraine headache. This occurs even when the patient has already developed symptoms related to central sensitization, a key parameter in determining the effectiveness of these agents. In patients whose migraine attacks have historically failed to respond to oral triptans, this route of administration has also proven to be more consistent and effective. Until recently this method of drug delivery was dependent upon a needle for administration. A new method of delivery for this agent, Sumavel(®) DosePro™, eliminates the needle and disposal issues coupled with an improved ease of use of drug delivery and acceptable tolerability for patients in clinical trials.

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.

Pharmacoeconomic benefits of almotriptan in the acute treatment of migraine.

Almotriptan is one of seven oral triptans available in the USA and much of the rest of the world. Reviews of its efficacy and tolerability demonstrate it to be among the most effective and well tolerated of this class. Studies of almotriptan in a variety of early intervention paradigms demonstrate significant improvements in efficacy and further improved tolerability compared with standard treatment of headaches of at least moderate severity. The nature of migraine pain and symptoms is such as to produce impairment of the individual in their usual activities, including work, and leads to a significant cost of migraine to the workplace. Utilizing both specific studies examining this and drawing conclusions upon the results of additional trials suggests that, despite the direct costs of this agent, the economic advantages and personal advantages to the patients more than compensate.

Botulinum Toxin Type A in the treatment of chronic migraine without medication overuse.

INTRODUCTION: Chronic migraine is a recent diagnostic term that has undergone evolution from its original description. Clinically it has been believed that medication overuse contributed to its development and would block attempts at prevention. Previous studies with Botulinum Toxin Type A have demonstrated that it is effective even in patients with medication overuse. This study undertakes to examine the effects of Botulinum Toxin Type A in the absence of medication overuse in patients with chronic migraine. STUDY DESIGN: Double-blind placebo-controlled randomized trial of Botulinum Toxin Type A 100 units administered in a fixed dose and site paradigm. PATIENTS: In total, 86 patients were enrolled. A total of 60 patients were randomized and 41 patients were treated with the study medication or placebo. Five patients failed to complete the study, which lasted 4 months after the study medication was injected. RESULTS: Botulinum Toxin Type A was statistically superior to placebo for the primary endpoint of reduction in migraine headache episodes. Six patients on Botulinum Toxin Type A compared with 3 patients on Placebo had at least a 50% reduction in their migraine episodes. Active treatment was superior to placebo for the secondary endpoints of total headache days, headache index, and quality of life measures. It showed numerical superiority to placebo for acute medication use and Migraine Disability Assessment Scores. Adverse events were rare and similar in both treatment groups. CONCLUSIONS: The use of Botulinum Toxin Type A may be an effective treatment for chronic migraine when the patient does not have concomitant medication overuse. It was well tolerated in this trial.

The cycle of migraine: patients' quality of life during and between migraine attacks.

BACKGROUND: Despite advances in therapy, the prevalence of migraine has remained constant over the past 17 years. The current diagnostic procedure for migraine does not take into account the entire cycle of migraine, which includes both the pain of the acute attack and the worry between attacks. OBJECTIVES: This review discusses the effects of migraine on health-related quality of life. The focus is on the impact of migraine between attacks and more successful clinical management of the complete cycle of migraine in both the neurology and primary care settings. METHODS: A search of MEDLINE (January 1997-January 2007) was conducted to determine the impact of migraine on quality of life and the need for and use of migraine preventive treatment. The search terms were migraine prevention, migraine prophylaxis, bead-ache and quality of life, migraine disability, and head-ache disability. The inclusion of specific studies was based on subjective, comparative evaluation and standard levels of evidence. Older publications were included to provide a historical perspective. RESULTS: Worry in expectation of the next migraine attack can have negative effects on the family and social lives and work productivity of patients with migraine. The benefits of preventive pharmacotherapy for migraine may be measured over time in terms of changes in the frequency of acute attacks, impact of acute treatment on headache recurrence within the next 24 hours, and reduction in overall functional impairment. Optimizing the acute treatment outcome and reducing the frequency of episodes may help alleviate the cycle of migraine. The clinical assessment of migraine should include multiple dimensions. Several questionnaires, such as the Migraine Disability Assessment and the 6-item Headache Impact Test, have been developed to help clinicians assess the dimensions of migraine. These questionnaires should be used in conjunction with open communication techniques that elicit any underlying worry associated with migraines. Preventive therapies that have been approved by the US Food and Drug Administration include the neurostabilizers divalproex sodium and topiramate, and the beta-blockers timolol and propranolol. Despite not being approved for this indication, the antidepressant amitriptyline has shown levels of evidence of efficacy in preventing migraine in controlled trials similar to those for the approved medications. CONCLUSION: The assessment of whether patients with migraine may benefit from preventive therapy should include the use of open communication techniques to uncover possible impairment between attacks.

Botulinum toxin type A in chronic migraine.

The use of botulinum toxin type A continues to be investigated by the US FDA for potential use in the treatment of headache. As part of this process there has been extensive research conducted by individual study sites as well as multicenter trials. To date, the majority of the focus has been on migraine headache as well as on tension-type headache. The results of these studies have been mixed. A variety of issues may contribute to the mixed results, including difference in the dose of toxin used, the number of injection sites utilized, the treatment paradigm itself, confounding medications, high and prolonged placebo response, as well as patient selection issues. Currently, the focus on botulinum toxin type A is on those patients who have chronic daily headache with a migraine component to their clinical picture. The results of two large trials in this population produced positive findings, especially when consideration is given to the a priori additional analyses of this complex patient population. The results of these studies have allowed a more focused program to be undertaken in the Phase III evaluation. At the same time, additional work has been performed to understand the mechanism by which botulinum toxin type A may work to alleviate migraine. This work may contribute substantially to improving outcomes with botulinum toxin type A. Characterization of the mechanism of action in pain may be crucial to outcomes because many issues are related to central sensitization.

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.

Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. METHODS: This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. RESULTS: The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P= .010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. CONCLUSIONS: Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.

Oral sumatriptan for the acute treatment of probable migraine: first randomized, controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of sumatriptan tablets in adults who meet International Headache Society (IHS) criteria for probable migraine but who do not meet IHS criteria for migraine with or without aura. BACKGROUND: Headaches with some but not all of the features of migraine meet criteria for probable migraine, a form of migraine recognized by the IHS. Probable migraine attacks are also prevalent and frequently underdiagnosed. METHODS: This was a randomized, multicenter, double-blind, placebo-controlled, parallel-group study. Adults (18 to 65 years) with a 1-year history of headaches that met 2004 IHS criteria for probable migraine without aura (same operational definition as 1988 IHS migrainous disorder) were eligible for enrollment. All patients were triptan- and ergot-naïve and had never been diagnosed with migraine. Patients were randomized in a 1:1:1:1 fashion to receive sumatriptan 25, 50, or 100 mg conventional tablets or matching placebo and were instructed to treat a single moderate or severe probable migraine attack. A post hoc analysis was conducted to evaluate the population of patients who achieved headache relief sustained throughout the immediate posttreatment period. Patients who reported relief within 2 hours and subsequently lost headache relief within 4 hours were considered nonresponders. RESULTS: At 2 hours, more patients treated with sumatriptan achieved headache relief, the primary efficacy measure, compared with placebo, but differences only approached statistical significance for 100 mg (P= .053). The 2-hour headache relief rate in the sumatriptan 25 or 50 mg groups was not significantly different than placebo. The time to use of rescue was significantly shorter in the placebo group compared with the sumatriptan 100 mg group (P= .002). The time to use of rescue in the sumatriptan 25 or 50 mg groups was not significantly different than placebo. More patients treated with placebo (22%) lost headache relief within 4 hours compared with patients treated with sumatriptan 25 mg (17%), 50 mg (14%), or 100 mg (7%). A post hoc analysis demonstrated that at 2 hours, headache relief sustained through 4 hours (S 0-4 hours) was achieved in 44%, 49%, and 57% of patients treated with sumatriptan 25, 50, and 100 mg, respectively, compared with 34% of patients treated with placebo (P < .05 for sumatriptan 50 and 100 mg vs. placebo). All doses of sumatriptan were well tolerated and no serious adverse events were reported. CONCLUSION: These results suggest that oral sumatriptan may be effective and is well tolerated for the acute treatment of probable migraine without aura, however, the difference between sumatriptan and placebo was not statistically significant for the a priori defined primary endpoint.