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.

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.

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.

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.

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.

Pain-free rates with zolmitriptan 2.5 mg ODT in the acute treatment of migraine: results of a large double-blind placebo- controlled trial.

CONTEXT: Zolmitriptan 2.5 mg orally disintegrating tablets (ODT) allow patients to take the medication without fluids, which is convenient and avoids the risk of fluid-induced exacerbation of nausea/vomiting. OBJECTIVE: To evaluate the efficacy and tolerability of zolmitriptan 2.5 mg ODT taken as soon as possible after onset of a migraine. DESIGN: Multicenter, double-blind, parallel-group, placebo-controlled two-attack trial. SETTING: Outpatient headache clinics in the US. PATIENTS: 608 patients were randomized; 566 patients treated at least 1 migraine and were included in the tolerability assessment (565 patients were included in the intent-to-treat population). INTERVENTION: Patients were randomized to either zolmitriptan 2.5 mg ODT or placebo. Patients treated up to 2 migraine attacks as soon as possible after the start of their migraine pain. MAIN OUTCOME MEASURE: Pain-free rates at 2 h. RESULTS: Zolmitriptan 2.5 mg ODT (n = 281) demonstrated a significant pain-free rate vs. placebo (n = 284) at 2 h (40% vs. 20%, p < 0.001), 1.5 h (25% vs. 15%, p < 0.001), and 1 h (13% vs. 8%, p = 0.004). Sustained pain-free rate was significantly higher than placebo (31% vs. 15%; p < 0.001). Return to normal activities favored zolmitriptan 2.5 mg ODT at 1 h (p = 0.004), 1.5 h (p < 0.001), and 2 h (p < 0.001). Adverse events associated with zolmitriptan 2.5 mg ODT were those commonly reported with the use of triptans. CONCLUSIONS: Zolmitriptan 2.5 mg ODT, taken as early as possible after onset of a migraine attack, is effective in the treatment of migraine, producing a significantly higher pain-free rate than placebo 2 h post-dose, and also at the earlier time points of 1 h and 1.5 h post-dose.

A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis.

OBJECTIVE: To evaluate the efficacy and safety of extended-release divalproex sodium compared with placebo in prophylactic monotherapy treatment of migraine headache. METHODS: This was a double-blind, randomized, placebo-controlled, parallel-group study. Subjects with more than two migraine headache attacks during a 4-week baseline were randomly assigned in a 1:1 ratio at each center to receive either extended-release divalproex sodium or matching placebo once daily for 12 weeks. Subjects initiated treatment on 500 mg once daily for 1 week, and the dose was then increased to 1,000 mg once daily with an option, if intolerance occurred, to permanently decrease the dose to 500 mg during the second week. Reduction from baseline in 4-week migraine headache rate was the primary efficacy variable. Migraine headaches separated by a < 24-hour headache-free interval were counted as single migraines in calculating migraine headache rates. Tolerance and safety were also evaluated. RESULTS: The mean reductions in 4-week migraine headache rate were 1.2 (from a baseline mean of 4.4) in the extended-release divalproex sodium group and 0.6 (from a baseline mean of 4.2) in the placebo group (p = 0.006); reductions with extended-release divalproex sodium were significantly greater than with placebo in all three 4-week segments of the treatment period. No significant differences were detected between treatment groups in either the overall incidence or in the incidence of any specific treatment-emergent adverse event; 8% of subjects treated with extended-release divalproex sodium and 9% of those treated with placebo discontinued for adverse events. CONCLUSION: Extended-release divalproex sodium is an efficacious, well-tolerated, safe, and easy-to-use once-a-day prophylactic antimigraine medication.

Preventative treatment for migraine and tension-type headaches : do drugs having effects on muscle spasm and tone have a role?

Baclofen, tizanidine and botulinum toxin A, agents used to treat disorders of muscle tone, have been studied as potential preventative treatments for migraine, tension-type headache and other related disorders. The most extensive work has been completed with botulinum toxin A. However, there is still a paucity of well controlled, clinical trials with this agent, and overall there have been conflicting and oftentimes equivocal results: studies of its use in migraine headache have suggested efficacy, whereas those of tension-type headache have not shown significant evidence of efficacy. There were few significant adverse events associated with the use of botulinum toxin A in these trials. The mechanism by which botulinum toxin A may work to prevent headache is not clear. Although changes in muscle tone may play a role in the effect of the drug, central mechanisms such as effects on neuropeptides involved in the pathogenesis of migraine may also be relevant. Further clinical trial work is in progress to help determine optimal administration schedules and choice of injection locations with botulinum toxin A for specific headache disorders. There has been limited study of the use of baclofen, an agent that acts centrally via GABA(A) receptors, in migraine and cluster headache, with only two open trials conducted to date. Both of these studies support the use of baclofen in the preventive treatment of headache.Tizanidine, which may have both a peripheral and a central mechanism in the locus ceruleus in migraine headache, has been studied in several clinical trials. Although the primary mechanism of action of this agent is, like clonidine, as an alpha-adrenoceptor agonist, it has little antihypertensive effect. Open trials of tizanidine have shown it to be useful in chronic headache. One well controlled trial, conducted as a follow-up to an open-label trial in the preventive treatment of chronic daily headache, reported tizanidine as having a statistically significant benefit over placebo. Also of interest is its use in conjunction with a long-acting NSAID to aid in the treatment of rebound headache accompanying the discontinuation of overused acute migraine therapies. In conclusion, though limited, the studies suggest the efficacy of botulinum toxin A, baclofen and tizanidine in primary headache disorders.

Cluster headache.

Cluster headache is a relatively rare episodic headache disorder.Although traditionally it is believed to be a male-related disorder,the sex ratios are changing toward a more even balance. The disorder is characterized by bouts of daily headaches with pain-free remissions for extended times. Though attacks are brief, they are severe and typically are associated with autonomic symptoms. Medical therapies are the mainstay of treatment, with the goal being prevention of headaches in a cycle. Acute therapies, although effective, may be limited in usefulness because of attack frequency. Intractable cases may benefit from histamine desensitization and surgical treatments.

Divalproex sodium in the treatment of migraine and cluster headaches.

The discovery of a new class of effective migraine-abortive medications, the triptans, has sparked a new interest in the study of vascular headache. Over the past few years, the Food and Drug Administration (FDA) has approved six new abortive pharmacologic therapies, with several others in various stages of clinical trials. Unfortunately, concurrent pharmacologic changes in headache prophylaxis have not kept pace with their abortive counterparts. However, divalproex sodium (Depakote), which is approved by the FDA as a migraine prophylactic agent, is the first in the anticonvulsant class of medication for migraine headache and has expanded the options in headache treatment. The objective of this retrospective multicenter study of 284 patients with migraine or cluster headaches was to examine the clinical efficacy and safety of divalproex sodium as prophylaxis in monotherapy and in polytherapy. Sixty-one percent of migraineurs and 73% of cluster patients noted a decrease in pain with divalproex sodium and continued that therapy for more than 3 months. Reported negative side effects included weight gain, nausea, somnolence, tremor, alopecia, dysequilibrium, and rash. However, only 14% of subjects discontinued therapy due to these side effects. Overall, divalproex sodium was found to be an effective and generally well-tolerated prophylactic treatment option as monotherapy or in polytherapy for migraine and cluster headache.

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.

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.

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.