Papers by Stephen Silberstein
Objective: To assess the effect of onabotulinumtoxinA prevention on comorbid symptoms of anxiety ... more Objective: To assess the effect of onabotulinumtoxinA prevention on comorbid symptoms of anxiety and depression in people with chronic migraine (CM). Background: CM is associated with comorbidities that may exacerbate the disease. Design/Methods: The 108-week, multicenter, open-label COMPEL Study enrolled adults with CM receiving onabotulinumtoxinA 155 U with/without concomitant prevention. Data from participants with clinically significant depression and anxiety were analyzed. Depression was assessed using the Patient Health Questionnaire (PHQ-9): 0–4 (minimal), 5–9 (mild), 10–14 (moderate), 15–19 (moderately severe), and 20–27 (severe); a sum score ≥5 indicates clinically significant depression symptoms. Anxiety was assessed using the Generalized Anxiety Disorder Assessment (GAD-7): 0–4 (minimal), 5–9 (mild), 10–14 (moderate), and 15–21 (severe); a sum score ≥10 indicates clinically significant anxiety symptoms. Individuals experiencing a ≥1 severity category improvement in PHQ-9 or GAD-7 from baseline are termed psychiatric comorbidity “responders.” Adverse events were recorded. Results: Patients (N=715) had a mean (range) age of 43 (18–73) years and were mostly women (84.8%, 606/715). 74.5% (529/710) endorsed PHQ-9≥5, and 24.6% (175/711) reported GAD-7≥10 at baseline; 24.5% (174/710) reported PHQ-9≥5 and GAD-7≥10. Mean (SD) headache day frequency at week 108 significantly decreased from baseline: 22 (±4.8) to 11.3 (±7.4) days (P Conclusions: COMPEL Study results demonstrate that onabotulinumtoxinA improves symptoms of depression and anxiety among people with CM for up to 108 weeks. Future work will examine the relationship of reduction in headache days with improvement with psychiatric comorbidity. Study Supported by: Allergan plc Disclosure: Dr. Blumenfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Served on advisory boards and/or has consulted for Allergan, Pernix, Teva, Avanir, Depomed, and Supernus, and has received funding for travel, speaking, and/or royalty payments from Allergan. Dr. Blumenfeld has received royalty, license fees, or contractual rights payments from For travel, speaking, and/or royalty payments from Allergan. Dr. Tepper has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda, Alder, Allergan, Amgen, ATI, Avanir, BioVison, Charleston Laboratories, Dr. Reddy’s, electroCore, eNeura, Eli Lilly, GLG, Guidepoint Global, Kimberly-Clark, Pernix, Pfizer, Scion Neurostim, Supernus, Teva, Zosano. Dr. Robbins has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Speaker for Avanir, Pernix and Merck. Dr. Manack Adams has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Allergan plc. Dr. Manack Adams holds stock and/or stock options in Allergan plc, which sponsored research in which Dr. Manack Adams was involved as an investigator. Dr. Manack Adams holds stock and/or stock options in Allergan plc. Dr. Buse has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avanir, Amgen, Biohaven, Eli Lilly and Company and Promeius. Dr. Silberstein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Receives honoraria from Alder Biopharmaceuticals; Allergan, Inc.; Amgen; Avanir Pharmaceuticals, Inc.; eNeura; ElectroCore Medical, LLC; Labrys Biologics; Medscape, LLC; Medtronic, Inc.; Neuralieve; NINDS; Pfizer, Inc.; and Teva Pharmaceuticals. Dr. Silberstein has received research support from His employer receives research support from Allergan, Inc.; Amgen; Cumberland Pharmaceuticals, Inc.; ElectroCore Medical, Inc.; Labrys Biologics; Eli Lilly and Company; Merz Pharmaceuticals; and Troy Healthcare.
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Journal of Neurology, Neurosurgery, and Psychiatry, Jan 10, 2019
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Toxicon, Dec 1, 2018
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Cephalalgia, Jul 1, 2006
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Neurology, Apr 23, 2012
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Objective: Evaluate effect of eptinezumab on duration and severity of migraine in an exploratory ... more Objective: Evaluate effect of eptinezumab on duration and severity of migraine in an exploratory analysis of the PROMISE-1 trial of frequent episodic migraine (FEM) prevention. Background: Calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. Eptinezumab, a humanized, anti-CGRP monoclonal antibody with 100% bioavailablity following iv administration, selectively inhibits CGRP. Design/Methods: 888 adults with history of migraine ≥12 months and ≤14 headache days/month, of which ≥4 met ICHD-II criteria for migraine, were randomized to quarterly infusions of eptinezumab 30, 100, or 300 mg, or placebo. The primary endpoint was reduction in migraine days over Weeks 1–12. Headache severity was measured on 3-point scale (mild, moderate, severe pain). Results: Eptinezumab 30, 100, and 300 mg decreased monthly migraine days from baseline (~8.5 days/month across groups) over Weeks 1–12 by approximately 50% (−4.0 [p=0.0045*], −3.9 [p=0.0179], and −4.3 [p=0.0001], respectively) vs −3.2 for placebo. Eptinezumab decreased mean migraine hours from baseline to Weeks 1–12 by the same magnitude (−37.8, −35.2, −42.9 vs −23.8). Similar reductions in mean migraine hours from baseline were seen by Weeks 1–4 (−42.0, −38.7, −40.7 vs −21.9) and maintained through Weeks 21–24 (−33.6, −36.7, −42.8 vs −26.9). Changes in average mean migraine attack duration (hours) from baseline were −3.4, −1.9, −3.6 vs 0 over Weeks 1–4, and +0.2, −0.5, −2.9 vs +1.7 over Weeks 21–24. Percentages of patients with severe migraine were reduced from baseline over Weeks 1–4 (−12.0%, −12.1%, −8.9% vs −7.7%) and Weeks 21–24 (−11.9%, −11.5%, −9.4% vs 12.5%). Conclusions: Quarterly eptinezumab infusions reduced migraine days and hours by approximately 50%. Migraine frequency, average duration of migraine attack and migraine intensity were reduced by eptinezumab and maintained over 2 quarterly infusions. Study Supported by: Funding and support provided by Alder BioPharmaceuticals, Inc., Bothell, WA, USA. Disclosure: Dr. Silberstein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Receives honoraria from Alder Biopharmaceuticals; Allergan, Inc.; Amgen; Avanir Pharmaceuticals, Inc.; eNeura; ElectroCore Medical, LLC; Labrys Biologics; Medscape, LLC; Medtronic, Inc.; Neuralieve; NINDS; Pfizer, Inc.; and Teva Pharmaceuticals. Dr. Silberstein has received research support from His employer receives research support from Allergan, Inc.; Amgen; Cumberland Pharmaceuticals, Inc.; ElectroCore Medical, Inc.; Labrys Biologics; Eli Lilly and Company; Merz Pharmaceuticals; and Troy Healthcare. Dr. McAllister has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Amgen Inc., Teva, Allergan. Dr. McAllister has received research support from Allergan, Amgen Inc., Eli Lilly, Teva, Scinovion, San Bio, Novartis. Dr. Berman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder. Dr. Cady has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder BioPharmaceuticals, Inc. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder BioPharmaceuticals, Inc. Dr. Biondi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder BioPharmaceuticals, Inc. Dr. Hirman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder BioPharmaceuticals, Inc.
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Objective: This subanalysis of COMPEL addresses effects of onabotulinumtoxinA prevention on comor... more Objective: This subanalysis of COMPEL addresses effects of onabotulinumtoxinA prevention on comorbid sleep disturbances and fatigue symptoms. Background: Chronic migraine (CM) is associated with comorbidities that may exacerbate the condition. Design/Methods: The 108-week, multicenter, open-label COMPEL Study enrolled adult patients with CM in Australia, Korea and the United States receiving onabotulinumtoxinA 155 U with/without concomitant preventive medication. The primary outcome was reduction in headache frequency per 28-day period at 108 weeks (9 treatments). Sleep disturbances were assessed using the Pittsburgh Sleep Quality Index (PSQI) and fatigue symptoms using the Fatigue Severity Scale (FSS). A PSQI global score >5 (range 0–21) indicates poor sleep quality, and a change ≥3 points was considered clinically significant. A FSS score ≥4 is considered indicative of fatigue, and a total score ≥36 (range 9–63) denotes significant fatigue. Adverse events (AEs) were recorded. Results: Patients (N=715) had a mean (range) age of 43 (18–73) years and were predominantly female (84.8%, 607/715). Headache day frequency at week 108 (primary endpoint) significantly decreased from a baseline mean (SD) of 22 (±4.8) days by 10.7 (±6.4) days ( P P P Conclusions: Results from the COMPEL Study indicate the effectiveness of onabotulinumtoxinA treatment for reducing headache frequency as well as improving sleep quality and fatigue symptoms up to 108 weeks (9 treatment cycles) in patients with CM. No unexpected AEs were reported. Study Supported by: Allergan plc Disclosure: Dr. Blumenfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Served on advisory boards and/or has consulted for Allergan, Pernix, Teva, Avanir, Depomed, and Supernus, and has received funding for travel, speaking, and/or royalty payments from Allergan. Dr. Blumenfeld has received royalty, license fees, or contractual rights payments from For travel, speaking, and/or royalty payments from Allergan. Dr. Tepper has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda, Alder, Allergan, Amgen, ATI, Avanir, BioVison, Charleston Laboratories, Dr. Reddy’s, electroCore, eNeura, Eli Lilly, GLG, Guidepoint Global, Kimberly-Clark, Pernix, Pfizer, Scion Neurostim, Supernus, Teva, Zosano. Dr. Robbins has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Speaker for Avanir, Pernix and Merck. Dr. Manack Adams has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Allergan plc. Dr. Manack Adams holds stock and/or stock options in Allergan plc, which sponsored research in which Dr. Manack Adams was involved as an investigator. Dr. Manack Adams holds stock and/or stock options in Allergan plc. Dr. Silberstein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Receives honoraria from Alder Biopharmaceuticals; Allergan, Inc.; Amgen; Avanir Pharmaceuticals, Inc.; eNeura; ElectroCore Medical, LLC; Labrys Biologics; Medscape, LLC; Medtronic, Inc.; Neuralieve; NINDS; Pfizer, Inc.; and Teva Pharmaceuticals. Dr. Silberstein has received research support from His employer receives research support from Allergan, Inc.; Amgen; Cumberland Pharmaceuticals, Inc.; ElectroCore Medical, Inc.; Labrys Biologics; Eli Lilly and Company; Merz Pharmaceuticals; and Troy Healthcare.
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Objective: Evaluate changes in HIT-6 at 4 and 12 weeks vs. baseline for subjects achieving 75%, 5... more Objective: Evaluate changes in HIT-6 at 4 and 12 weeks vs. baseline for subjects achieving 75%, 50%, 25%, and Background: Chronic migraine (CM) cause significant disability for millions of people worldwide. ALD403 is a humanized, IgG1, anti-CGRP antibody being developed for migraine prevention. HIT-6 is a validated measure evaluating ability to function at work, school, home and socially. Design/Methods: Randomized subjects ( n = 616) who had CM and were 18 to 55, received ALD403 or placebo. HIT-6 questionnaires were completed at randomization, 4, and 12 weeks. Post-hoc analyses assessing RR and changes in HIT-6 scores are presented. Results: Significantly more patients achieved a 50%–75% RR with 300mg (33%–57%) or 100 mg (31%–54%) of ALD403 than placebo (21%–41%) across weeks 1–12.[1] At randomization HIT-6 scores averaged 64.5. HIT–6 scores for 75% responders receiving any study dose at week 4 were 50.9 (−13.6). Scores were sustained at 12 weeks 52.2 (−12.3). At 4 weeks HIT-6 scores for 50% responders were 57.1 and at 12 weeks 56 .6. Minimal changes were noted for 25% or Conclusions: More subjects achieved 50%–75% RR with ALD403 than placebo. 2 Meaningful, rapid, and sustained improvements in HIT-6 scores were observed for subjects achieving either a 75% or 50% RR. Changes in HIT-6 scores with a 75% RR was superior to RRs of 50%, 25% or Study Supported by: Alder Biopharmaceuticals Bothell, WA 98011 Disclosure: Dr. Lipton has received personal compensation from Allergan, American Headache Society, Autonomic Technologies, Boston Scientific, Bristol Myers Squibb, Cognimed, Colucid, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, TEVA, Vedanta. Dr. Dodick has received personal compensation for activities with Allergan, Amgen, Alder, Dr Reddy’s, Merck, eNeura, Eli Lilly & Company, INSYS therapeutics, Autonomic Technologies, Teva, Xenon, Tonix, Trigemina, Boston Scientific, GBS, Merck, Colucid, and Zosano. Dr. Dodick has received personal compensation in an editorial capacity for Oxford University Press, Cambridge University Press, Healthlogix, UptoDate. Dr. Dodick has received royalty payments from Oxford University Press, Cambridge University Press, Web MD and UptoDate. Dr. Dodick holds stock and/or stock options in Epien Medical, Second Opinion, GBS, and Neuroassessment systems. Dr. Goadsby has received personal compensation for activities with Allergan, eNeura, Autonomic Technologies Inc, Amgen, AlderBio, Pfizer, DrReddy, Zosano, Colucid, Eli Lilly, Avanir, Gore,Heptares, Nupathe, Teva, Cipla, Ajinomoto, Akita,Wells Fargo, Ethicon,Promius. Dr. Goadsby has received personal compensation in an editorial capacity for JournalWatch Neurology and UptoDate. Dr. Goadsby has received research supporting from Amgen, eNeura, Allergan. Dr. Silberstein has received research support from Allergan, Inc., Amgen, Cumberland Pharmaceuticals, Inc., ElectroCore Medical, LLC., Labrys Biologics, Eli Lilly and Company, and Merz. Dr. Hirman has received personal compensation for activities with Alder. Dr. Smith has nothing to disclose. Dr. Cady has received personal compensation for activities with Alder Biopharmaceuticals Inc. as an employee, and has received personal compensation for activities with Allergan, Avanir, Autonomic Technologies, Boston Scientific, DepoMed, and Dr. Reddy’s Laboratories. Dr. Cady holds stock and/or stock options in Alder, which sponsored research in which Dr. Cady was involved as an investigator. Dr. Cady has received research support from Alder Pharmaceuticals, Allergan, Amgen, AstraZeneca, Autonomic Technologies, Avanir, Boston Scientific, Capnia, Daiichi-Sankyo, Dr. Reddy’s Laboratories, ElectroCore, Eli Lily, EPI-Q, inc., and ISIS Pharmaceuticals.
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Mayo Clinic Proceedings, Oct 1, 2011
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Neurology, Apr 18, 2017
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Neurology, Sep 25, 2001
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Neurology, Feb 25, 2013
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Cephalalgia, 2020
BackgroundNon-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache ... more BackgroundNon-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.MethodsWe conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS.ResultsFindings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed.Conclusio...
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Drugs, 2018
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Neurology, 2018
ObjectiveTo evaluate the effect of fremanezumab on the functional status on headache-free days in... more ObjectiveTo evaluate the effect of fremanezumab on the functional status on headache-free days in phase 2 episodic migraine (EM) and chronic migraine (CM) studies.MethodsFunctional status data were collected prospectively via the electronic headache diary on all headache-free days by patients answering questions regarding work/school/household chore performance, speed of work completion, concentration, and feeling of fatigue. Individuals with EM receiving monthly doses of fremanezumab 225 mg (n = 96) or 675 mg (n = 97) or placebo (n = 104) were compared. Individuals with CM receiving fremanezumab 675 mg followed by monthly 225 mg (n = 88) and 900 mg (n = 86) were also independently compared to those receiving placebo (n = 89).ResultsIn patients with EM, compared to patients receiving placebo, those receiving fremanezumab experienced an increased number of headache-free days with normal function in work/school/household chore performance and concentration/mental fatigue measures comp...
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The New England journal of medicine, Nov 30, 2017
Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), i... more Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine-specific medication...
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Regional Anesthesia and Pain Medicine, 2004
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Neurology, 2012
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American Journal of Therapeutics, 2006
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Papers by Stephen Silberstein