Safety findings from Phase 3 lasmiditan studies for acute treatment of migraine: Results from SAMURAI and SPARTAN.

BACKGROUND: We assessed the safety profile of lasmiditan, a selective 5-HT1F receptor agonist without vasoconstrictive activity being developed as an acute therapy for migraine. METHODS: SAMURAI and SPARTAN were Phase 3 double-blind studies of patients with migraine, randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo to be taken within 4 hours of onset of migraine pain. Safety data from the studies were integrated. Treatment-emergent adverse events (occurring within 48 hours of first dose) were considered in the analyses. RESULTS: The safety population comprised 1262 patients assigned placebo, and 654, 1265, and 1258 assigned lasmiditan 50 mg, 100 mg, and 200 mg, respectively. There were no deaths; serious adverse events were reported for seven patients (placebo, n = 2 [0.2%]; lasmiditan 50 mg, n = 1 [0.2%]; lasmiditan 100 mg, n = 1 [0.2%]; lasmiditan 200 mg, n = 3 [0.2%]). Patients reporting ≥ 1 treatment-emergent adverse events were: Placebo, n = 174 (13.5%); lasmiditan 50 mg, n = 166 (25.4%); lasmiditan 100 mg, n = 458 (36.2%); and lasmiditan 200 mg, n = 510 (40.6%). Treatment-emergent adverse events were generally mild or moderate in severity. The most common treatment-emergent adverse events with lasmiditan were dizziness, paresthesia, somnolence, fatigue, nausea, muscular weakness and hypoesthesia. There were no ischemic events. CONCLUSIONS: As a centrally-penetrant drug, lasmiditan use was associated with neurologic treatment-emergent adverse events; most were mild or moderate in severity and self-limiting. TRIAL REGISTRATION AT CLINICALTRIALS.GOV: SAMURAI (NCT02439320) and SPARTAN (NCT02605174).

Nonmigraine Headache and Facial Pain.

The vast majority of headache patients encountered in the outpatient general medicine setting will be diagnosed with a primary headache disorder, mostly migraine or tension-type headache. Other less common primary headaches and secondary headaches, related to or caused by another condition, are the topic of this article. Nonmigraine primary headaches include trigeminal autonomic cephalalgias, primarily cluster headache; facial pain, primarily trigeminal neuralgia; and miscellaneous headache syndromes, such as hemicrania continua and new daily persistent headache. Selected secondary headaches related to vascular disease, cerebrospinal fluid dynamics, and inflammatory conditions are also reviewed.

A Qualitative Study On Patients With Chronic Migraine With Medication Overuse Headache: Comparing Frequent And Non-Frequent Relapsers.

BACKGROUND: It is common clinical experience that, after structured withdrawal, some patients with chronic migraine and medication overuse headache (CM with MOH) are more prone than others to relapse and to be in need of further structured treatments. Our aim was to explore similarities and differences between frequent relapsers (FRs) and non-frequent relapsers (NFRs) by considering their point of view, perceptions, and perspective of their subjective experience with relapse into CM with MOH. METHODS: Patients were consecutively recruited on occasion of a structured withdrawal treatment and were interviewed individually about their headache experience and their perspectives on relapse into CM with MOH. We considered FR those patients requiring 2 or more structured withdrawals for MOH within 3 years. A narrative approach with no preconceived coding schemes was employed. To facilitate coding, categorization and organization of data the software QRS NVivo 11.0 was used: themes were defined as common to FR and NFR, or peculiar (by frequency or content) to one of the 2 groups. RESULTS: Sixteen patients (13 women; mean age of 53) were interviewed: 7 were classified as FRs. A total of 22 themes emerged from 552 single quotations (the 10 most relevant covered 82% of the entire body of quotations). Four themes were commonly reported by both FR and NFR patients, and 6 were peculiar to one group only. Common aspects included issues connected to the dilemma between disclosing, concealing and the feelings of isolation around MOH, the idea of being addicted to medication, presence of anxiety, and the attempt to use non-pharmacological therapies as an alternative to medication. Peculiar aspects included causal attribution (FRs attributed headache to uncontrollable factors); future expectations at the time point of withdrawal (FRs were generally resigned); high-performance functioning (FRs believed they are "forced" to reach high levels of performance as a consequence of others' inability); coping strategies (FRs tended to "passively accept" problems and showed avoidance-related behaviors). Moreover, FRs were less frequently aware of their problems and described more frequently depressive symptoms. CONCLUSIONS: Our results highlight that some differences between FR and NFR patients with CM and MOH exist. Frequent relapsers among patients with CM and MOH reported some important peculiarities of the lived experience of having chronic migraine; clinicians should recognize these psychosocial aspects such as social relationships, future expectations, the experience of illness, medication management, and how the withdrawal experience is regarded, as they may be associated with frequent relapse into MOH.

What the pharmacological management of migraine can tell us about the future of migraine patient care.

Some of the principles of the pharmacologic management of migraine are echoed in urgent discussions of the future of headache care in the USA and around the world. From adverse events to tolerance, addiction, medication overuse and medication persistence, solutions to the pathophysiologic puzzles, and management difficulties in migraine can be found by paying closer attention to patient reports and by facilitating greater patient involvement in the treatment process. Similarly, listening to the patient as customer in the process of value-based care, so adaptable for the problem of migraine, is the solution to the health care crisis we face in so many countries.

Medication overuse headache: An entrenched idea in need of scrutiny.

It is a widely accepted idea that medications taken to relieve acute headache pain can paradoxically worsen headache if used too often. This type of secondary headache is referred to as medication overuse headache (MOH); previously used terms include rebound headache and drug-induced headache. In the absence of consensus about the duration of use, amount, and type of medication needed to cause MOH, the default position is conservative. A common recommendation is to limit treatment to no more than 10 or 15 days per month (depending on medication type) to prevent headache frequency progression. Medication withdrawal is often recommended as a first step in treatment of patients with very frequent headaches. Existing evidence, however, does not provide a strong basis for such causal claims about the relationship between medication use and frequent headache. Observational studies linking treatment patterns with headache frequency are by their nature confounded by indication. Medication withdrawal studies have mostly been uncontrolled and often have high dropout rates. Evaluation of this evidence suggests that only a minority of patients required to limit the use of symptomatic medication may benefit from treatment limitation. Similarly, only a minority of patients deemed to be overusing medications may benefit from withdrawal. These findings raise serious questions about the value of withholding or withdrawing symptom-relieving medications from people with frequent headaches solely to prevent or treat MOH. The benefits of doing so are smaller, and the harms larger, than currently recognized. The concept of MOH should be viewed with more skepticism. Until the evidence is better, we should avoid dogmatism about the use of symptomatic medication. Frequent use of symptom-relieving headache medications should be viewed more neutrally, as an indicator of poorly controlled headaches, and not invariably a cause.

Amitriptyline Dose and Treatment Outcomes in Specialty Headache Practice: A Retrospective Cohort Study.

OBJECTIVE: To characterize treatment patterns and real world outcomes in headache patients treated with amitriptyline in an academic headache center. DESIGN AND METHODS: A retrospective chart review identified 178 patients in our center who were given a new prescription for amitriptyline in treatment of headache, and who were seen in follow-up within one year. Charts were reviewed to identify dosing patterns (initial and maximum dose) and persistence, patient-reported headache benefit, and reported side effects. Variables assessed in relation to medication use were comorbid psychiatric disease, headache characteristics, and prior use of a preventive medication. RESULTS: We followed patients for an average of 6.5 months. Initial and maximum prescribed amitriptyline doses were characterized as: "very low" (≤10 mg daily), "low" (11-25 mg daily), and "traditional" (≥25 mg daily). The initial dose of amitriptyline ranged from 2.5 to 50 mg daily, though most patients were started on a dose of 10 mg daily (112/178, 63%). Approximately 3/4 of the patients were found to have improvement (134/178) and 85% (129/151) were still taking amitriptyline at the last follow-up appointment. Maximum dosing ranged from 2.5 to 100 mg daily with most patients taking 10-25 mg (86/146, 58%). The most commonly reported adverse effect was daytime fatigue (17/151, 11%). There did not appear to be any effect from gender, ethnicity, race, diagnosis of sleep apnea, chronicity of migraine, presence of aura on our outcome measures. CONCLUSION: Our study supports the common clinical practice of using low doses of amitriptyline to treat chronic headache disorders and suggests that it was effective and well tolerated at doses lower than those used in many clinical trials. Use of low dosage amitriptyline may also improve medication persistence, an important clinical consideration in the management of this common and chronic condition. A subgroup of patients may experience a dramatic benefit from amitriptyline and this could warrant further investigation.

Emerging therapeutic options for acute migraine: focus on the potential of lasmiditan.

The serotonin receptor agonist triptan drugs (5-HT1B/1D receptor agonists) have been in use for over 20 years in the abortive management of migraine. Although clearly effective, their ability to produce vasoconstriction in cerebral and coronary arteries, thought to be mediated by their high affinity for the 5-HT1B receptor, has been a limitation to their use in certain patient populations. Variable potency triptan binding at the 5-HT1F receptor occurs in addition to binding at the 5-HT1B and 5-HT1D receptors. A more selective serotonin agonist without 5-HT1B-mediated vasoconstriction might prove efficacious yet safer. The 5-HT1F receptor has been targeted as a site of action for such a drug. In experimental models, 5-HT1F receptor agonists have been shown to block neurogenic inflammation and c-Fos expression in neural tissue and, as well, show no evidence of vasoconstriction in vascular tissue models in vitro. In clinical trials, efficacy in the abortive management of migraine has been established. Lasmiditan (LY573144), a selective 5-HT1F receptor agonist (K1=2.21 µM), showed efficacy in its primary endpoint, with a 2-hour placebo-subtracted headache response of 28.8%, though with frequent reports of dizziness, paresthesias, and vertigo. Study results support an emerging central neuronal mechanism of migraine pathophysiology. This review traces the history and use of 5-HT1F receptor agonists, now referred to as neurally acting anti-migraine agents in migraine management.

Acute and preventive treatment of migraine.

PURPOSE OF REVIEW: Migraine remains underdiagnosed and undertreated despite advances in the understanding of its pathophysiology and management. This article focuses on acute and preventive treatment of migraine, including the mechanisms of action, dosing and side effects of medications, and strategies for the most effective care. RECENT FINDINGS: Best practice suggests that acute migraine treatment should be stratified based on the severity of the individual event, with a goal of returning the patient to full function within 2 hours of treatment. Migraine prevention strategies continue to be underused in the United States. More than 1 in 4 patients with migraines may be candidates for preventive therapy. To obtain the best results from preventive therapy, slow titration to an adequate dose for an adequate timeframe with good documentation of the results is recommended. SUMMARY: This article reviews several options for managing acute attacks, including information on expected efficacy, dosing, and adverse effects. Strategies for effective application of acute therapies are discussed. Prevention can be added to acute therapy depending on headache characteristics such as frequency, severity, disability, and the presence of comorbid conditions. The mechanisms of action of preventive medications and strategies for their most effective use are discussed.