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Durham P.L.,Missouri State University | Cady R.,Headache Care Center
Headache | Year: 2011

OnabotulinumtoxinA has recently been approved by regulatory agencies in the UK and United States for treatment of chronic migraine based on data generated from the PREEMPT studies. As such, onabotulinumtoxinA is the only prophylactic therapy specifically approved for chronic migraine. Most headache clinicians would agree that acute episodic migraine and chronic migraine differ in their pathophysiology, etiology, diagnosis, and response to pharmacological as well as nonpharmacological therapies. Of the 7 botulinum neurotoxin serotypes, botulinum neurotoxin type A (onabotulinumtoxinA) has been the most thoroughly investigated in preclinical and clinical studies. Based on preclinical studies, onabotulinumtoxinA is known to inhibit the release of excitatory neurotransmitters from both motor and sensory neurons by preventing vesicle fusion to the cell membrane. In addition to the well-documented myorelaxant effects of this neurotoxin, onabotulinumtoxinA can exert a direct analgesic effect that likely involves inhibition of primary and secondary nociceptive neurons. The inhibitory effects of onabotulinumtoxinA are also likely to involve suppressing the activity of myogenic trigger points and decreasing the persistent nociceptive barrage that promotes and maintains central sensitization. This article describes possible mechanisms to explain how onabotulinumtoxinA functions as a therapy for chronic migraine and considers why treatment with the neurotoxin is not effective in some chronic migraineurs. © 2011 American Headache Society.


Goadsby P.J.,University of California at San Francisco | Goadsby P.J.,King's College London | Grosberg B.M.,Montefiore Headache Center | Mauskop A.,New York Headache Center | And 2 more authors.
Cephalalgia | Year: 2014

Background: We sought to assess a novel, noninvasive, portable vagal nerve stimulator (nVNS) for acute treatment of migraineMethods: Participants with migraine with or without aura were eligible for an open-label, single-arm, multiple-attack study. Up to four migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a six-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain.Results: Of 30 enrolled patients (25 females, five males, median age 39), two treated no attacks, and one treated aura only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching (n= 1), raspy voice (n= 1) and redness at the device site (n= 1). No unanticipated, serious or severe adverse events were reported. The pain-free rate at two hours was four of 19 (21%) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22%).Conclusions: nVNS may be an effective and well-tolerated acute treatment for migraine in certain patients. © 2014 International Headache Society.


Cady R.,Headache Care Center | O'Carroll P.,Newport Beach Neurologists | Dexter K.,Headache Care Center | Freitag F.,Medical College of Wisconsin | Shade C.L.,Banyan Group
Headache | Year: 2014

Objective: This pilot study explored the potential for 2 recognized acute migraine medications, 85 mg of sumatriptan plus 500 mg of naproxen sodium in a combination tablet (SumaRT/Nap) and 500 mg of naproxen sodium, to treat and modify the disease progression of migraine. In other words, can these medications both abort an acute attack of migraine and reduce the number of future migraine attacks? Background: Patients suffering with moderate to severe attacks of migraine desire acute treatment. As migraine frequency increases, so does the need for more frequent relief of acute attacks. This may lead to medication overuse and potentially medication overuse headache (MOH). Ideally, acute medication would have the ability to abort an attack of migraine and reduce the likelihood of future attacks. Study Design: The primary endpoint of this study was a reduction in migraine headache days from baseline through month 3 of the study. Subjects were randomized 1:1 to treat 14 or fewer migraines per month with SumaRT/Nap (Group A) or naproxen sodium (Group B) for 3 months. Subjects in group A utilized SumaRT/Nap were encouraged, but not required, to treat migraine headache within 1 hour of onset of headache when the pain was mild. They could re-treat if needed after 2 hours. Subjects in group B utilized the same treatment strategy with 500 mg of naproxen sodium. Tablets of study medication were identical for both groups. Subjects recorded headache days, migraine attacks, duration of attacks, treatment, and treatment results daily on paper diaries. Subjects took the Migraine Disability Assessment Test (MIDAS) at randomization and 3 months later at the end of study. Results: Naproxen sodium was associated with a statistically significant reduction in migraine headache days at month 3 compared to baseline (P =.0002). SumaRT/Nap was also associated with a reduction of migraine headache days, but this decrease did not reach statistical significance (P =.2). In addition, subjects in the naproxen sodium group had a statistically significant reduction of migraine attacks in all 3 months of the study compared to baseline. A greater than 50% reduction in the number of migraine headache days at month 3 occurred in 43% (6/14) of subjects in group B compared to 17% (3/18) of subjects in group A. Consistent with large regulatory studies comparing the efficacy of SumaRT/Nap with naproxen sodium, SumaRT/Nap in this study was statistically superior to naproxen sodium at 2 hours in reducing headache severity during months 2 and 3. There was a reduction of acute medication used from baseline to month 3 and improvement in MIDAS scores for both groups. Conclusion: Naproxen sodium, when used as a sole acute treatment early in attacks, appears to reduce the frequency of headache days and migraine attacks for a select number of subjects over a 3-month period. SumaRT/Nap is more effective at 2-hour headache reduction than naproxen sodium alone, but has less impact on reducing attack frequency or the number of headache days. Both treatments were well tolerated, and there was no convincing evidence that either medication led to MOH. © 2013 American Headache Society.


Cady R.,Headache Care Center | Saper J.,Michigan Head Pain and Neurological Institute | Dexter K.,Headache Care Center | Manley H.R.,Clinvest
Headache | Year: 2015

Objective To determine if repetitive sphenopalatine ganglion (SPG) blocks with 0.5% bupivacaine delivered through the Tx360® are superior in reducing pain associated with chronic migraine (CM) compared with saline. Background The SPG is a small concentrated structure of neuronal tissue that resides within the pterygopalatine fossa (PPF) in close proximity to the sphenopalatine foramen and is innervated by the maxillary division of the trigeminal nerve. From an anatomical and physiological perspective, SPG blockade may be an effective acute and preventative treatment for CM. Method This was a double-blind, parallel-arm, placebo-controlled, randomized pilot study using a novel intervention for acute treatment in CM. Up to 41 subjects could be enrolled at 2 headache specialty clinics in the US. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by the second edition of the International Classification of Headache Disorders appendix definition. They were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer-generated lists of 2:1 to receive 0.5% bupivacaine or saline, respectively. The primary end-point was to compare numeric rating scale scores at pretreatment baseline vs 15 minutes, 30 minutes, and 24 hours postprocedure for all 12 treatments. SPG blockade was accomplished with the Tx360®, which allows a small flexible soft plastic tube that is advanced below the middle turbinate just past the pterygopalatine fossa into the intranasal space. A 0.3 cc of anesthetic or saline was injected into the mucosa covering the SPG. The procedure is performed similarly in each nostril. The active phase of the study consisted of a series of 12 SPG blocks with 0.3 cc of 0.5% bupivacaine or saline provided 2 times per week for 6 weeks. Subjects were re-evaluated at 1 and 6 months postfinal procedure. Results The final dataset included 38 subjects, 26 in the bupivacaine group and 12 in the saline group. A repeated measures analysis of variance showed that subjects receiving treatment with bupivacaine experienced a significant reduction in the numeric rating scale scores compared with those receiving saline at baseline (M = 3.78 vs M = 3.18, P = .10), 15 minutes (M = 3.51 vs M = 2.53, P < .001), 30 minutes (M = 3.45 vs M = 2.41, P < .001), and 24 hours after treatment (M = 4.20 vs M = 2.85, P < .001), respectively. Headache Impact Test-6 scores were statistically significantly decreased in subjects receiving treatments with bupivacaine from before treatment to the final treatment (Mdiff = -4.52, P = .005), whereas no significant change was seen in the saline group (Mdiff = -1.50, P = .13). Conclusion SPG blockade with bupivacaine delivered repetitively for 6 weeks with the Tx360® device demonstrates promise as an acute treatment of headache in some subjects with CM. Statistically significant headache relief is noted at 15 and 30 minutes and sustained at 24 hours for SPG blockade with bupivacaine vs saline. The Tx360® device was simple to use and not associated with any significant or lasting adverse events. Further research on sphenopalatine ganglion blockade is warranted. © 2014 The Authors. Headache published by Wiley Periodicals, Inc. on behalf of American Headache Society.


Cady R.K.,Headache Care Center | Schreiber C.P.,Citizens Memorial Hospital Neurology Clinic | Porter J.A.H.,Advance Neurology and Pain | Blumenfeld A.M.,Neurology Center | Farmer K.U.,Headache Care Center
Headache | Year: 2011

Objective.-This multi-center pilot study compared the efficacy of onabotulinumtoxinA with topiramate (a Food and Drug Administration approved and widely accepted treatment for prevention of migraine) in individuals with chronic migraine (CM). Methods.-A total of 59 subjects with CM were randomly assigned to one of 2 groups: Group 1 (n = 30) received topiramate plus placebo injections, Group 2 (n = 29) received onabotulinumtoxinA injections plus placebo tablets. Subjects maintained daily headache diaries over a 4-week baseline period and a 12-week active study period. The primary endpoint was the Physician Global Assessment, which measured the treatment responder rate and indicated improvement in both groups over 12 weeks. Secondary endpoints, measured at weeks 4 and 12, included headache days per month, migraine days, headache-free days, days on acute medication, severity of headache episodes, Migraine Impact & Disability Assessment, Headache Impact Test, effectiveness of and satisfaction with current treatment on the amount of medication needed, and the frequency and severity of migraine symptoms. At 12 weeks subjects were re-evaluated and tapered off oral study medications over a 2-week time period. Subjects not reporting a >50% reduction of headache frequency at 12 weeks were invited to participate in a 12-week open label extension study with onabotulinumtoxinA. Of these, 20 subjects, 9 from the Topiramate Group and 11 from the OnabotulinumtoxinA Group, volunteered for this extension from weeks 14 to 26. Results.-This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM. Overall, the results were statistically significant within groups but not between groups. By week 26, subjects had a reduction of headache days per month compared with baseline. This was a significant within-group finding. Conclusion.-OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures. © 2010 American Headache Society.


Cady R.,Headache Care Center
Expert Opinion on Pharmacotherapy | Year: 2015

Introduction: Oral triptans have dominated the prescription market for acute treatment of migraine for nearly 25 years. Today, patients often express dissatisfaction with prescribed acute treatment in part because they do not have confidence that the therapy will provide consistent efficacy over time. Major limitations to sustained successful use of oral triptans are their relatively slow onset of meaningful clinical benefit and variable absorption/efficacy due to impaired gastrointestinal function during migraine. AVP-825, a new intranasal delivery system for sumatriptan, may be an effective alternative to oral triptans.Areas covered: This article reviews AVP-825, which deposits low-dose sumatriptan powder deep into the vascular mucosa of the posterior nose, allowing rapid absorption of drug into the systemic circulation. Studies suggest that AVP-825 is a highly effective, well-tolerated acute treatment for episodic migraine.Expert opinion: Oral triptans are limited in providing effective patient-centered outcomes to migraine patients. Failed or suboptimal abortive treatment of migraine is a major driver of migraine chronification and increases in healthcare costs. AVP-825 is an easy to use, novel, breath-powered intranasal delivery system that provides early onset of efficacy with low systemic drug exposure and few triptan-associated adverse events. AVP-825 will be a welcomed therapeutic tool for the acute treatment of migraine. © 2015 Informa UK, Ltd.


Introduction: AVP-825, formerly OptiNose Sumatriptan, is an investigational Breath-PoweredTM Bi-DirectionalTM intranasal delivery system containing low-dose sumatriptan (22 mg intranasal powder) that avoids limitations of other types of intranasal administration by taking advantage of unique features of nasal anatomy and physiology.Areas covered: This review summarizes intranasal drug delivery for migraine, how the breath-powered technology works, and AVP-825 pharmacokinetic, efficacy and safety/tolerability findings. To identify AVP-825 clinical studies, a PubMed/MEDLINE database search was conducted with the terms AVP-825, OptiNose, OptiNose Sumatriptan, Breath-Powered Nasal Delivery or sumatriptan powder. Of 20 articles, 5 clinical studies were identified, including the head-to-head comparative COMPASS trial (AVP-825 vs oral sumatriptan) and two placebo-controlled studies.Expert opinion: AVP-825 has faster sumatriptan absorption versus oral tablets or traditional liquid nasal spray. In Phase II/III randomized, double-blind, placebo-controlled trials, AVP-825 produced early and sustained efficacy with minimal triptan-related adverse effects. In COMPASS, AVP-825 produced earlier reduction of migraine pain intensity and migraine-associated symptoms than 100 mg oral sumatriptan, and higher early rates of pain relief and pain freedom, similar sustained efficacy, and fewer atypical sensations. AVP-825 has the potential to provide migraine patients with improved intranasal administration of sumatriptan that may enhance efficacy and tolerability. © 2015 © Informa UK, Ltd.


Lipton R.B.,Yeshiva University | Lipton R.B.,Montefiore Headache Center | Fanning K.M.,Vedanta Research | Serrano D.,Yeshiva University | And 5 more authors.
Neurology | Year: 2015

Objective: To test the hypothesis that ineffective acute treatment of episodic migraine (EM) is associated with an increased risk for the subsequent onset of chronic migraine (CM). Methods: In the American Migraine Prevalence and Prevention Study, respondents with EM in 2006 who completed the Migraine Treatment Optimization Questionnaire (mTOQ-4) and provided outcome data in 2007 were eligible for analyses. The mTOQ-4 is a validated questionnaire that assesses treatment efficacy based on 4 aspects of response to acute treatment. Total mTOQ-4 scores were used to define categories of acute treatment response: very poor, poor, moderate, and maximum treatment efficacy. Logistic regression models were used to examine the dichotomous outcome of transition from EM in 2006 to CM in 2007 as a function of mTOQ-4 category, adjusting for covariates. Results: Among 5,681 eligible study respondents with EM in 2006, 3.1% progressed to CM in 2007. Only 1.9% of the group with maximum treatment efficacy developed CM. Rates of newonset CM increased in the moderate treatment efficacy (2.7%), poor treatment efficacy (4.4%), and very poor treatment efficacy (6.8%) groups. In the fully adjusted model, the very poor treatment efficacy group had a more than 2-fold increased risk of new-onset CM (odds ratio = 2.55, 95%confidence interval 1.42-4.61) compared to the maximum treatment efficacy group. Conclusion: Inadequate acute treatment efficacy was associated with an increased risk of newonset CM over the course of 1 year. Improving acute treatment outcomes might prevent newonset CM, although reverse causality cannot be excluded. © 2015 American Academy of Neurology.


Igarashi H.,Headache Care Center
Clinical Neurology | Year: 2013

Migraine is a common neurological disorder that produces substantial disability for sufferers. Chronic migraine (≧15 headache days/month; CM) was significantly more disabling than episodic migraine (< 15 headache days/month; EM). CM was associated with greater impairment of occupational and social aspects of quality of life. Lost productivity time was substantially higher among CM participants than persons with EM. Full time employment was lower in CM participants because of medical leave. The medical costs were two or three times higher for CM than EM. These results suggest that migraine chronification is associated with substantial economic burden.


Cady R.K.,Headache Care Center
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Migraine is a highly prevalent disorder with the potential to progress into a chronic disease. The disability and health effects associated with frequent episodes of migraine underscore the value of preventive pharmacotherapy. Areas covered in this review: OnabotulinumtoxinA has been studied as a migraine preventive in numerous clinical trials and in a variety of subpopulations with migraine. Overall, results from the clinical trials are mixed. However, the largest and most recent parallel studies (n 1330) conducted on subjects with chronic migraine achieved statistically significant efficacy on numerous endpoints including the primary endpoint of reduction of headache days. What the reader will gain: This article reviews several clinical studies using onabotulinumtoxinA in migraine prevention and highlights some of the inherent difficulties defining study endpoints and outcomes that are relevant to clinician, patients, and regulatory agencies. Take home message: Clinical trials utilizing onabotulinumtoxinA as a preventive therapy for migraine has revealed mixed results. In part this reflects the inherent difficulties in study design such as defining different subpopulations of migraine sufferers and trial end points that are meaningful to patient populations. Recent studies of subjects with chronic migraine appear to have positive results. If confirmed this would be the first preventive medication indicated specifically for chronic migraine. © 2010 Informa UK Ltd.

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