Stephen D Silberstein

• Thomas Jefferson University

Objective To characterize the long‐term (56‐week) benefits of continuous onabotulinumtoxinA treatment response in individuals with chronic migraine (CM) who achieved reduction to <15 headache days/month with treatment. Background There are limited data exploring reductions in monthly headache days to levels consistent with episodic migraine among...

Migraine is a primary headache disorder characterized by enhanced sensitivity of the nervous system associated with a combination of neurological, gastrointestinal and autonomic disturbances (Silberstein, 2004). Chronic headache is a heterogeneous group of headache disorders that include chronic migraine (CM), chronic TTH (CTTH) and other headache...

Migraine is a neurologic disease with a complex pathophysiology that can be controlled with current treatment options but not cured. Therefore, treatment expectations are highly variable. The concept of migraine freedom was recently introduced and can mean different things, with some, for example, expecting complete freedom from headache and associ...

Chronic migraine (CM) is a neurological disease characterized by frequent migraine attacks that prevent affected individuals from performing daily activities of living, significantly diminish quality of life, and increase familial burden. Before onabotulinumtoxinA was approved for CM, there were few treatment options for these seriously disabled pa...

Objective: Assess the long-term efficacy and safety of erenumab in patients with chronic migraine with acute medication overuse. Background: Overuse of acute medication in patients with chronic migraine has been linked to greater pain intensity and disability and may diminish the effectiveness of preventive therapies. Methods: This 52-week ope...

Introduction: In this article, we discuss menstrual migraine (MM), which can be categorized as menstrually related migraine (MRM) or pure menstrual migraine (PMM). MM attacks are often longer, more severe, and harder to treat than other migraine attacks. Appropriate treatment strategies include acute treatment, short term preventive treatment, and...

Introduction: Through 2018, three calcitonin gene-related peptide pathway-targeted monoclonal antibodies (CGRP mAbs) had received US Food and Drug Administration (FDA) approval for migraine prevention: erenumab, fremanezumab, and galcanezumab. Methods: This retrospective analysis evaluated adverse events (AEs) spontaneously reported to the FDA A...

Objective Evaluate the impact of onabotulinumtoxinA treatment in adults with chronic migraine. Methods Post-hoc analysis of pooled data from the 24-week, placebo-controlled, PREEMPT ( NCT00156910 , NCT00168428 ) and single-arm, 108-week COMPEL ( NCT01516892 ) studies. Percentages of participants meeting responder status at 24, 48, or 108 weeks for...

Introduction Patients with refractory chronic migraine have poor quality of life. Intravenous infusions are indicated to rapidly ‘break the cycle’ of pain. Lidocaine infusions may be effective but evidence is limited. Methods The records of 832 hospital admissions involving continuous multiday lidocaine infusions for migraine were reviewed. All pa...

Clinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches, quality of care, treatment safety and effectiveness, factors that predict treatment response, health care resource utilization, clinician adherence to guide...

Remarkable advancements have been made in the field of migraine pathophysiology and pharmacotherapy over the past decade. Understanding the molecular mechanism of calcitonin gene-related peptide (CGRP) has led to the discovery of a novel class of drugs, CGRP functional blocking monoclonal antibodies (mAbs), for migraine prevention. CGRP is a neurop...

Calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide found mostly in peptidergic sensory C-fibers, has been suggested to be implicated in the pathogenesis of migraine, which is one of the most common neurological disorders seen in medical practice, affecting almost 16% of the US population. While previously thought to be a vascular...

Background: Fremanezumab, a fully humanised monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy as a preventive treatment for adults with episodic migraine (EM) or chronic migraine (CM) and inadequate response to 2-4 prior preventive treatment classes in the phase 3b FOCUS study....

Background Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thu...

Objective: To evaluate the efficacy and safety of intravenous (IV) Ibuprofen for acute treatment of migraine. Background: IV nonsteroidal anti-inflammatory drugs (NSAIDs) are an alternative to oral NSAIDs, especially in patients with severe migraine who have emesis or gastroparesis. To date, only three IV NSAIDs (ketorolac, ibuprofen, and meloxi...

Background Atogepant is an oral, small-molecule, calcitonin gene–related peptide receptor antagonist for the preventive treatment of migraine. Methods In the double-blind, phase 3 ADVANCE trial, participants with 4–14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time cou...

Since the discovery of calcitonin gene-related peptide (CGRP), numerous studies have investigated its role in migraine pathogenesis. CGRP, the most common neuropeptide in the trigeminal system, causes vasodilation, upregulates nociception, and modulates regional immune mediators leading to neurogenic neuroinflammation and pain sensitization. Many c...

Objective: To evaluate whether the 15-day threshold of headache days per month adequately reflects substantial differences in disability across the full spectrum of migraine. Background: The monthly frequency of headache days defines migraine subtypes and has crucial implications for epidemiological and clinical research as well as access to car...

Patients with refractory chronic migraine have substantial disability and have failed many acute and preventive medications. When aggressive intravenous therapy is indicated, both lidocaine and (R,S)‐ketamine infusions have been used successfully to provide relief. Retrospective studies have shown that both agents may be associated with short‐term...

Objective: To highlight the emerging understanding of oxytocin (OT) and oxytocin receptors (OTRs) in modulating menstrual-related migraine (MRM). Background: MRM is highly debilitating and less responsive to therapy, and attacks are of longer duration than nonmenstrually related migraine. A clear understanding of the mechanisms underlying MRM is...

Background Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical tria...

Since the introduction of passive immunity for diphtheria treatment in the late nineteenth century, significant technological breakthroughs have been made in antibody-based therapeutics. Therapeutic monoclonal antibodies (mAbs) are becoming a major part of the treatment armamentarium for cancer, autoimmune disease, and neurologic disorders. Most co...

Therapeutic monoclonal antibodies targeting calcitonin-gene related peptide (CGRP) have recently emerged as major preventive medications for migraines. They are as or more effective than conventional migraine preventives with greater tolerability and more convenient dosing. Eptinezumab-jjmr, a humanized monoclonal antibody synthesized by yeast, bin...

Objective To examine the safety and efficacy of ubrogepant for acute treatment of migraine across cardiovascular (CV) disease risk categories. Methods ACHIEVE I and II were multicenter, double-blind, single-attack, phase 3 trials in adults with migraine, with or without aura. Participants were randomized 1:1:1 to placebo or ubrogepant (50 or 100 m...

Background Although observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine, randomized clinical trials have not met their primary efficacy endpoints. Objectives The authors report the results of a pooled analysis of individual participant data from the...

Objective: To evaluate the sensitivity and specificity of the 6-item Identify Chronic Migraine screener (ID-CM[6]), designed to improve the detection of chronic migraine (CM). Background: CM is often undertreated and underdiagnosed. Survey-based studies have found that approximately 75-80% of people meeting criteria for CM do not report having r...

Background Although erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3‐12 months, little is known about long‐term therapy. Methods Open‐label, 5‐year treatment phase following a 12‐week, double‐blind, placebo‐controlled trial in adults with episodic migraine. Patients initially r...

The authors noticed that unfortunately in the chapter, in Section 9 on the second paragraph lines 1 and 3, 2 numbers were replaced by 2 citations. The injection protocols commonly used are (GBD 2016 DALYs Hale Collaborators 2017) the fixed-site approach, which uses fixed, symmetrical injection sites and a range of predetermined doses (GBD 2016 Dise...

Objective To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment. Methods A daily headache diary was completed during the 12-week, double-blind treatment phase of a placebo-controlled trial comparing erenumab 70 mg, 140 mg, and placebo, and weeks 1–12, 21–24, 37–40, and 49–52 of the open-label t...

Abstract Introduction The phase 3 PREEMPT trials demonstrated efficacy and tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. OnabotulinumtoxinA significantly reduced headache frequency from baseline vs. placebo at 24 weeks; however, this measure may not fully capture the benefits of treatment. We evaluated...

IntroductionThe double-blind, phase 3 PREEMPT trials demonstrated the efficacy and tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis evaluated the effect of onabotulinumtoxinA on clinically meaningful changes in headache severity, headache-related impact, and quality of life.Methods P...

Introduction Triptans, the most commonly prescribed acute treatments for migraine attacks are, per FDA labeling, contraindicated in cardiovascular (CV) disease patients and have warnings and precautions for those with CV risk factors. Methods Headache specialists, cardiologists, and health economics and outcomes researchers convened to identify di...

Background: PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of repeat intravenous (IV) doses of the calcitonin gene-related peptide-targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with chronic migraine. This report describes the results of PROMIS...

Background: We evaluated the efficacy of fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, in patients with chronic migraine (CM) with and without medication overuse (MO). Methods: In a 12-week, phase 3 trial, patients with CM were randomized to fremanezumab quarterly (675 mg/placebo/pl...

Purpose of review: To explain our current understanding of headache attributed to rhinosinusitis, an often inappropriately diagnosed secondary headache. Recent findings: Recent studies have shown that headache attributed to rhinosinusitis is often over-diagnosed in patients who actually have primary headache disorders, most commonly migraine. Fa...

Objective: To assess the long-term safety, tolerability, and efficacy of fremanezumab, a fully humanized monoclonal antibody approved for the preventive treatment of migraine. Methods: A 52-week, multicenter, randomized, double-blind, parallel-group study evaluated fremanezumab monthly or quarterly in adults with chronic migraine (CM) or episodi...

The disproportionate prevalence of migraine among women in their reproductive years underscores the clinical significance of migraine during pregnancy. This paper discusses how migraine evolves during pregnancy, secondary headache disorders presenting in pregnancy and puerperium, and acute and preventive options for migraine management during pregn...

Background: Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been identified. Methods: We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanist...

Background During the novel coronavirus - COVID-19 pandemic, health care systems are facing one of its greatest challenges.ResultsSecondary headaches may need urgent care at an emergency department. Primary headaches exacerbations may require intravenous infusion. Treatment optimization is key for a better outpatient management.Conclusion We give r...

Tremendous progress has been made in the past decades for the treatment of headache disorders. Chronic migraine is the most disabling type of headache and requires the use of acute and preventive medications, many of which are associated with adverse events that limit patient adherence. Botulinum toxin (BoNT) serotype A, a neurotoxin derived from c...

Objective: To review the literature on the mechanism of action of onabotulinumtoxinA in chronic migraine. Background: OnabotulinumtoxinA is a chronic migraine preventive treatment that significantly reduces headache frequency. The traditional mechanism described for onabotulinumtoxinA - reducing muscle contractions - is insufficient to explain i...

Noninvasive neuromodulation is a rapidly developing field that offers an attractive nonpharmacologic treatment option for headache patients. Devices that stimulate peripheral nerves (e.g., vagus nerve, trigeminal sensory nerve, somatic sensory nerve) or brain parenchyma (e.g., occipital cortex) have been developed for this purpose, with promising r...

Thunderclap headache refers to the abrupt onset of a severe headache. Characteristics of the pain are not strictly defined, but intensity is considered to peak in seconds to a minute. This chapter focuses on the work-up of alert neurologically intact patients presenting with an acute and severe headache, not related to trauma. Work-up to detect or...

Background: Triptans are the most commonly prescribed acute treatments for migraine; however, not all triptan users experience adequate response. Information on real-world resource use and costs associated with triptan insufficient response are limited. Methods: A retrospective claims analysis using US commercial health plan data between 2012 an...

Background: This study reports the long-term safety and efficacy of erenumab in chronic migraine patients. Methods: This was a 52-week open-label extension study of a 12-week double-blind treatment phase study. During the double-blind treatment phase, patients received placebo or once-monthly erenumab 70 mg or 140 mg. During the open-label treat...

Introduction: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP mAb), is a migraine-specific treatment for migraine prevention. Areas covered: This review will briefly discuss other available and emerging CGRP mAbs and the neurophysiology of fremanezumab. The review will focus on phase III trials of the e...

Objective To describe patient characteristics, treatment patterns, and health care costs among patients diagnosed with major headache disorders overall and by type (tension-type headache [TTH], migraine, cluster headache [CH], or >1 primary headache type), and secondarily to evaluate drug treatment patterns among triptan initiators with a major hea...

Introduction Migraine management is characterized by the poor use of preventive therapy and the overuse of acute medications. An analysis of current treatment patterns in migraineurs is needed to improve care in this patient population. The aim of this study was to describe treatment patterns and healthcare utilization of newly diagnosed migraine p...

Background The International Headache Society (IHS) has published four editions of Guidelines for acute clinical trials in migraine in the past 28 years. This continuous update process has been driven by the increasing amount of scientific data in the field of migraine and by the need to continuously improve the quality of trials. Objectives To il...

After publication of our article [1] we were notified that the data presented in the upper row of Fig. 7 was inadvertently the least square mean change from baseline (standard error) at Month 6 rather than the overall average of Month 3 and Month 6. The figure legend and discussion of the data in the text were and are correct. The error was only in...

Objective: To review the published findings relevant to migraine and driving performance, with an intent to encourage discussion on research which may broaden understanding in this area and help educate healthcare providers and their patients. Background: Motor vehicle crashes result in more than 35,000 deaths and more than 2 million injuries an...

Objective: To provide updated evidence-based recommendations about when to obtain neuroimaging in patients with migraine. Methods: Articles were included in the systematic review if they studied adults 18 and over who were seeking outpatient treatment for any type of migraine and who underwent neuroimaging (MRI or CT). Medline, Web of Science, a...

Objective: To provide a narrative review of clinical development programs for non-oral, non-injectable formulations of dihydroergotamine (DHE) for the treatment of migraine. Background: Dihydroergotamine was one of the first "synthetic drugs" developed in the 20th century for treating migraine. It is effective and recommended for acute migraine...

Background Efficacy and safety of erenumab have been evaluated in a comprehensive clinical development program resulting in approval for migraine prevention in over 40 countries to date. Methods This integrated safety analysis included four double-blind randomized trials and their extensions (up to three-plus years). Safety endpoints included expo...

Objective: To compare effectiveness of onabotulinumtoxinA and topiramate for chronic migraine (CM) prevention. Background: The efficacy* of onabotulinumtoxinA and topiramate has been established in placebo-controlled randomized clinical trials (*defined as the benefit of treatment under ideal conditions). The effectiveness* of the 2 preventive t...

Objective: To describe the new classes of medication for headache management and their roles in clinical practice. Background: Calcitonin gene-related peptide (CGRP) is a key component in the underlying pathophysiology of migraine. Research focused on targeting CGRP for headache treatment has led to the development of entirely new classes of med...

Episodic migraine is a debilitating condition. Preventive therapy is used to reduce frequency, duration, or severity of attacks. This review discusses principles of preventive treatment with a focus on preventive treatment options for people with episodic migraine. Specifically discussed is evidence and use of new migraine-specific treatment option...

Calcitonin‐gene‐related peptide (CGRP), a neuropeptide broadly distributed in neuronal and non‐neuronal regions throughout the body, plays a fundamental role in migraine and cluster headache (CH) pathophysiology. CGRP functional blockade alleviates neurogenic inflammation and reduces pain pathway sensitization. Two types of CGRP function‐blocking m...

Abstract Background Patients with high-frequency episodic migraine (HFEM) have a greater disease burden than those with low-frequency episodic migraine (LFEM). Acute treatment overuse increases the risk of migraine chronification in patients with HFEM. Galcanezumab, a humanized monoclonal antibody binding calcitonin gene-related peptide (CGRP), is...

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to...

Introduction: The recent approval of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway introduced the first preventive treatments for migraine that were specifically designed to target the underlying pathophysiology of the disease. Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) administered via subcuta...

Background: Two randomized, double-blind, sham-controlled trials (ACT1, ACT2) evaluated non-invasive vagus nerve stimulation (nVNS) as acute treatment for cluster headache. We analyzed pooled ACT1/ACT2 data to increase statistical power and gain insight into the differential efficacy of nVNS in episodic and chronic cluster headache. Methods: Dat...

Regular or frequent use of analgesics and acute antimigraine drugs can increase the frequency of headache, and induce the transition from episodic to chronic headache or medication overuse headache. The 1-year prevalence of this condition in the general population is between 1% and 2%. Medication overuse headache is more common in women and in peop...

Background: Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. Methods: Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or d...

Background: The Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials demonstrated efficacy/tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis assessed time of onset of onabotulinumtoxinA after the first treatment in total and responder populations and consistency...

Objective To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine. Background There is a significant unmet need for novel effective well‐tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pai...

Introduction: Since the definition of chronic migraine as a new disease entity in 2004, numerous clinical trials have examined the efficacy of preventive treatments in chronic migraine. Our aim was to assess the adherence of these trials to the Guidelines of the International Headache Society published in 2008. Methods: We searched PubMed for co...

Objective Presentation of pooled analysis of safety data for fremanezumab in patients with chronic (CM) or episodic migraine (EM) from 4 placebo‐controlled phase 2b and phase 3 studies. Background There is a need for an effective, safe, and well‐tolerated preventive therapy that specifically targets the pathophysiology of migraine to reduce the fr...

Objective: To determine the effect of erenumab, a human monoclonal antibody targeting the calcitonin gene-related peptide receptor, on health-related quality of life (HRQoL), headache impact, and disability in patients with chronic migraine (CM). Methods: In this double-blind, placebo-controlled study, 667 adults with CM were randomized (3:2:2)...

Background Antiepileptic drugs (AEDs) are an important class of agents used in the treatment of migraine, a neurological disorder that imparts significant socioeconomic burden. It is important for neurologists to understand the rationale for AEDs in migraine-preventive treatment, as well as each agent’s efficacy and tolerability profile, in order t...

Migraine is a chronic paroxysmal neurological disorder characterized by multiphase attacks of head pain and a myriad of neurological symptoms. Chronic migraine causes a great personal and societal burden. Many patients are poorly responsive to, or non-compliant with, conventional migraine preventive therapies. For this reason, physicians are consta...

Objective: To develop a claims-based algorithm to identify undiagnosed chronic migraine among patients enrolled in a healthcare system. Methods: An observational study using claims and patient survey data was conducted in a large medical group. Eligible patients had an International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) mig...

Purpose of review: Migraine is a common, highly disabling disorder. Its treatment involves acute and preventive therapy. Many of available preventive medications are not well tolerated, which results in poor compliance and limited effectiveness. Cannabinoids have been proposed for the treatment of migraine but their efficacy and tolerability are c...

The quality of clinical trials is an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for controlled trials of drugs in migraine. Scientific and clinical developments in headache medi...

Migraine is a prevalent, disabling neurological disorder involving the trigeminovascular system. Previous treatments were either originally intended for other conditions and/or associated with intolerable adverse effects (AEs). Calcitonin gene‐related peptide (CGRP) is the most prevalent neuropeptide in the trigeminal afferent neurons and plays a s...

Objective To assess the effects of onabotulinumtoxinA treatment for chronic migraine (CM) on comorbid symptoms of depression, anxiety, fatigue and poor sleep quality. Methods The Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open-Label (COMPEL) study is a multicentre, open-label, prospective study assessing the long-term safety and effica...

Background The current study aimed to describe the impact of parental migraine on adolescent children (aged 11–17) living at home with a parent with migraine. Aim Many drug classes are prescribed for migraine treatment, but all have limitations. Recently, calcitonin gene‐related peptide (CGRP) activity has shown a significant promise as a target f...

Background Migraine has a substantial impact on daily living, affecting productivity and quality of life for patients and their families. Patients frequently discontinue preventive medications in part because of a delay in headache and symptom relief due to the long dose titration procedures necessary for some migraine preventives. Objective To ev...

Objective To examine the disability, health care resource utilization, and direct annual costs among patients with migraine, categorized according to the number of headache days experienced in the past month. Background Migraine exists on a continuum of different attack frequencies and associated levels of disability. People with migraine have inc...

Calcitonin gene-related peptide (CGRP) is a neuropeptide of importance in migraine pathogenesis. Its central role in migraine was proven pharmacologically by the development of CGRP receptor antagonists. Monoclonal antibodies targeting CGRP or its receptor are effective in the preventive treatment of episodic and chronic migraine and are considered...

Migraine is a highly prevalent neurological pain syndrome, and its management is limited due to side effects posed by current preventive therapies. Calcitonin gene-related peptide (CGRP) plays a crucial role in the pathogenesis of migraine. In recent years, research has been dedicated to the development of monoclonal antibodies against CGRP and CGR...

Background Migraine is a primary headache disorder involving dysregulation of central and peripheral pain pathways. Medical treatment is often limited by drug side effects, comorbidities and poor compliance. This makes neuromodulation an ideal option for migraine treatment. Cefaly® is a transcutaneous electrical neurostimulator designed specificall...

Background and objectives: The burden of chronic headache disorders in the United States is substantial. Some patients are treatment refractory. Ketamine, an N-methyl-D-aspartate antagonist, provides potent analgesia in subanesthetic doses in chronic pain, and limited data suggest it may alleviate headache in some patients. Methods: We performed...

Importance Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. Objective To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Design and Setting Randomize...

Supplementary Table 2 -Supplemental material for A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study)

Supplementary Table 1 -Supplemental material for A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study)