Pooled analysis of the safety and tolerability of onabotulinumtoxinA in the treatment of chronic migraine.

BACKGROUND AND PURPOSE: OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double-blind, placebo-controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double-blind, placebo-controlled trials were analyzed. METHODS: The pooled analysis included two phase 2 and two phase 3 double-blind, placebo-controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests. RESULTS: OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA-associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA. CONCLUSIONS: Multiple treatments with onabotulinumtoxinA at doses of 75-260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM.

OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program.

OBJECTIVE: Chronic migraine (CM) is a prevalent and disabling neurological disorder. Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program assessed efficacy and safety of onabotulinumtoxinA (BOTOX(®)) for prophylaxis of headaches in adults with CM. This secondary analysis assessed patients who received all five treatment cycles and completed the study. MATERIALS AND METHODS: PREEMPT (two phase III studies: 24-week double-blind, placebo-controlled [DBPC], parallel-group phase, followed by 32-week open-label [OL] phase) evaluated the efficacy and safety of onabotulinumtoxinA in CM (≥15 days/month with headache lasting ≥4 h a day). Patients were randomized (1:1) to onabotulinumtoxinA or placebo every 12 weeks for two cycles, followed by onabotulinumtoxinA for three cycles. Multiple headache symptom measures were evaluated. Results for the completer (five cycles) subgroup of patients are reported. RESULTS: Of 1384 total PREEMPT patients, 1005 received all five treatment cycles (513 received onabotulinumtoxinA only [onabotulinumtoxinA/onabotulinumtoxinA (O/O)] and 492 received two cycles of placebo then three cycles of onabotulinumtoxinA [placebo/onabotulinumtoxinA (P/O)]). Demographics were similar between treatment groups. At Week 56, after all patients were treated with onabotulinumtoxinA, there continued to be significant between-group differences favoring the O/O vs P/O group for the following headache symptom measures: LS mean change from baseline in frequencies of headache days (-12.0 O/O, -11.1 P/O; P = 0.035), migraine days (-11.6 O/O, -10.7 P/O; P = 0.038), and moderate/severe headache days (-11.0 O/O, -10.1 P/O; P = 0.042). For other measures (cumulative hours of headache on headache days, frequency of headache episodes, and percentage with severe Headache Impact Test (HIT)-6 score, and total HIT-6 and Migraine-Specific Quality of Life Questionnaire scores), there were also large mean improvements from baseline. The percent of patients with a ≥50% reduction from baseline in frequency of headache days was significantly greater for the onabotulinumtoxinA-only group at Week 56 (69.6% O/O, 62.8% P/O; P = 0.023). The treatment-related adverse event rate was 28.5% for onabotulinumtoxinA vs 12.4% for placebo in the DBPC phase and 34.8% for patients treated with onabotulinumtoxinA for all five cycles throughout the 56-week trials. CONCLUSIONS: This subgroup analysis demonstrated improvements with onabotulinumtoxinA treatment (five cycles) vs placebo (two cycles)/onabotulinumtoxinA (three cycles) for multiple headache symptom measures and suggests that at Week 56, patients treated earlier with onabotulinumtoxinA had better outcomes. These findings demonstrate the continued need and cumulative benefit over time with continued prophylaxis, an important and clinically pragmatic observation for clinicians and patients.

Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society.

OBJECTIVE: To provide updated evidence-based recommendations for the preventive treatment of migraine headache. The clinical question addressed was: What pharmacologic therapies are proven effective for migraine prevention? METHODS: The authors analyzed published studies from June 1999 to May 2009 using a structured review process to classify the evidence relative to the efficacy of various medications available in the United States for migraine prevention. RESULTS AND RECOMMENDATIONS: The author panel reviewed 284 abstracts, which ultimately yielded 29 Class I or Class II articles that are reviewed herein. Divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and should be offered to patients with migraine to reduce migraine attack frequency and severity (Level A). Frovatriptan is effective for prevention of menstrual migraine (Level A). Lamotrigine is ineffective for migraine prevention (Level A).

Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society.

OBJECTIVE: To provide updated evidence-based recommendations for the preventive treatment of migraine headache. The clinical question addressed was: Are nonsteroidal anti-inflammatory drugs (NSAIDs) or other complementary treatments effective for migraine prevention? METHODS: The authors analyzed published studies from June 1999 to May 2009 using a structured review process to classify the evidence relative to the efficacy of various medications for migraine prevention. RESULTS: The author panel reviewed 284 abstracts, which ultimately yielded 49 Class I or Class II articles on migraine prevention; of these 49, 15 were classified as involving nontraditional therapies, NSAIDs, and other complementary therapies that are reviewed herein. RECOMMENDATIONS: Petasites (butterbur) is effective for migraine prevention and should be offered to patients with migraine to reduce the frequency and severity of migraine attacks (Level A). Fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, MIG-99 (feverfew), magnesium, riboflavin, and subcutaneous histamine are probably effective for migraine prevention (Level B). Treatments considered possibly effective are cyproheptadine, Co-Q10, estrogen, mefenamic acid, and flurbiprofen (Level C). Data are conflicting or inadequate to support or refute use of aspirin, indomethacin, omega-3, or hyperbaric oxygen for migraine prevention. Montelukast is established as probably ineffective for migraine prevention (Level B).

Randomized, placebo-controlled trial of propranolol added to topiramate in chronic migraine.

OBJECTIVE: To assess the efficacy and safety of adding propranolol to topiramate in chronic migraine subjects inadequately controlled with topiramate alone. METHODS: This was a double-blind, placebo-controlled, randomized clinical trial conducted through the National Institute of Neurological Disorders and Stroke Clinical Research Collaboration, expected to randomize 250 chronic migraine subjects inadequately controlled (≥10 headaches/month) with topiramate (50-100 mg/day) to either propranolol LA (long acting) (240 mg/day) or placebo. Primary outcome was 28-day moderate to severe headache rate reduction at 6 months (weeks 16 to 24) compared with baseline (weeks -4 to 0). RESULTS: A planned interim analysis was performed after 48 sites randomized 171 subjects. The data and safety monitoring board recommended ending the trial after determining that it would be highly unlikely for the combination to result in a significant reduction in 28-day headache rate compared with topiramate alone if all 250 subjects were randomized. No safety concerns were identified. At study closure, 191 subjects were randomized. The 6-month reduction in moderate to severe 28-day headache rate and total 28-day headache rate for combination therapy vs topiramate alone was not significantly different: 4.0 vs 4.5 days (moderate to severe 28-day headache rate; p = 0.57) and 6.2 vs 6.1 days (total 28-day headache rate; p = 0.91). CONCLUSIONS: This study does not provide evidence that the addition of propranolol LA to topiramate adds benefit when chronic migraine is inadequately controlled with topiramate alone. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that propranolol LA, added to topiramate, is ineffective in chronic migraine patients who fail topiramate monotherapy.

OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine.

OBJECTIVE: To assess the effects of treatment with onabotulinumtoxinA (Botox, Allergan, Inc., Irvine, CA) on health-related quality of life (HRQoL) and headache impact in adults with chronic migraine (CM). METHODS: The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program (PREEMPT 1 and 2) included a 24-week, double-blind phase (2 12-week cycles) followed by a 32-week, open-label phase (3 cycles). Thirty-one injections of 5U each (155 U of onabotulinumtoxinA or placebo) were administered to fixed sites. An additional 40 U could be administered "following the pain." Prespecified analysis of headache impact (Headache Impact Test [HIT]-6) and HRQoL (Migraine-Specific Quality of Life Questionnaire v2.1 [MSQ]) assessments were performed. Because the studies were similar in design and did not notably differ in outcome, pooled results are presented here. RESULTS: A total of 1,384 subjects were included in the pooled analyses (onabotulinumtoxinA, n = 688; placebo, n = 696). Baseline mean total HIT-6 and MSQ v2.1 scores were comparable between groups; 93.1% were severely impacted based on HIT-6 scores ≥60. At 24 weeks, in comparison with placebo, onabotulinumtoxinA treatment significantly reduced HIT-6 scores and the proportion of patients with HIT-6 scores in the severe range at all timepoints including week 24 (p < 0.001). OnabotulinumtoxinA treatment significantly improved all domains of the MSQ v2.1 at 24 weeks (p < 0.001). CONCLUSIONS: Treatment of CM with onabotulinumtoxinA is associated with significant and clinically meaningful reductions in headache impact and improvements in HRQoL. CLASSIFICATION OF EVIDENCE: This study provides Class 1A evidence that onabotulinumtoxinA treatment reduces headache impact and improves HRQoL.

Proceedings from the Ice Hockey Summit on concussion: a call to action.

The objective of this proceedings is to integrate the concussion in sport literature and sport science research on safety in ice hockey to develop an action plan to reduce the risk, incidence, severity, and consequences of concussion in ice hockey. A rationale paper outlining a collaborative action plan to address concussions in hockey was posted for review two months prior to the Ice Hockey Summit: Action on Concussion. Focused presentations devoted specifically to concussion in ice hockey were presented during the Summit and breakout sessions were used to develop strategies to reduce concussion in the sport. This proceedings and a detailed scientific review (a matrix of solutions) were written to disseminate the evidence-based information and resulting concussion reduction strategies. The manuscripts were reviewed by the authors, advisors and contributors to ensure that the opinions and recommendations reflect the current level of knowledge on concussion in hockey. Six components of a potential solution were articulated in the Rationale paper and became the topics for breakout groups that followed the professional, scientific lectures. Topics that formed the core of the action plan were: metrics and databases; recognizing, managing and return to play; hockey equipment and ice arenas; prevention and education; rules and regulations; and expedient communication of the outcomes. The attendees in breakout sessions identified action items for each section. The most highly ranked action items were brought to a vote in the open assembly, using an Audience Response System (ARS). The strategic planning process was conducted to assess: Where are we at?; Where must we get to?; and What strategies are necessary to make progress on the prioritized action items? Three prioritized action items for each component of the solution and the percentage of the votes received are listed in the body of this proceedings.

OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial.

OBJECTIVES: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX) for prophylaxis of headaches in adults with chronic migraine. METHODS: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U-195U; n = 347) or placebo (n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21-24 post-treatment. RESULTS: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (-9.0 onabotulinumtoxinA/-6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events. CONCLUSIONS: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.

OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial.

OBJECTIVES: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine. METHODS: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U-195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. RESULTS: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (-5.2 vs. -5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. CONCLUSIONS: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

Review of comorbidities and risk factors for the development of migraine complications (infarct and chronic migraine).

A number of comorbid disorders, behavioural traits and associated risk factors in patients with migraine are known to increase the risk of complications such as ischaemic vascular events and chronic migraine, a syndrome that is more disabling and resistant to treatment with acute and preventative medications than episodic migraine. Reduction of cardiovascular risk factors, smoking cessation and use of non-oestrogen-containing oral contraceptives in female patients are beneficial strategies to reduce the risk of ischaemic events in patients with migraine (especially those with aura). Attack frequency, acute medication overuse, obesity and coexisting depression and anxiety disorders are particularly strong but potentially modifiable independent risk factors for progression to chronic migraine. Identifying and managing comorbidities and associated risk factors for complications of migraine are likely to require an integrated disease management strategy involving several disciplines and allied health services. Such a disease-oriented model of care may potentially interrupt the cycle of progression and disability and improve quality of life for patients with migraine.

Utility of topiramate for the treatment of patients with chronic migraine in the presence or absence of acute medication overuse.

Chronic migraine has been linked to the excessive use of acute headache medications. Medication overuse (MO) is commonly considered the most significant risk factor for the progression of migraine from an episodic to a chronic condition. Managing MO is a challenge. Discontinuation of the acute medication can result in withdrawal headache, nausea, vomiting and sleep disturbances. This review summarizes the results from two similarly designed, randomized, placebo-controlled, multicentre studies of chronic migraine conducted in the USA and European Union. Both studies demonstrate the efficacy and safety of the migraine preventive medication, topiramate, for the treatment of chronic migraine in patient populations both with and without MO. These studies may have important implications for the future of chronic migraine management, suggesting that detoxification prior to initiating prophylactic therapy may not be required in all patients if MO is present.

Proposals for new standardized general diagnostic criteria for the secondary headaches.

Headache classification is a dynamic process through clinical testing and re-testing of current and proposed criteria. After publication of the second edition of the International Classification of Headache Disorders (ICHD-II), need arose for revisions in the classification of medication overuse headache and chronic migraine. These changes made apparent a further need for broader revisions to the standard formulation of diagnostic criteria for the secondary headaches. Currently, the fourth criterion makes impossible the definitive diagnosis of a secondary headache until the underlying cause has resolved or been cured or greatly ameliorated by therapy, at which time the headache may no longer be present. Given that the main purpose of diagnostic criteria is to enable a diagnosis at the onset of a disease in order to guide treatment, this is unhelpful in clinical practice. In the present paper we propose maintaining a standard approach to the secondary headaches using a set of four criteria A, B, C and D, but we construct these so that the requirement for resolution or successful treatment is removed. The proposal for general diagnostic criteria for the secondary headaches will be entered into the internet-based version of the appendix of ICHD-II. During 2009 the Classification Committee will apply the general criteria to all the specific types of secondary headaches. These, and other changes, will be included in a revision of the entire classification entitled ICHD-IIR, expected to be published in 2010. ICHD-IIR will be printed and posted on the website and will be the official classification of the International Headache Society. Unfortunately, it will be necessary to translate ICHD-IIR into the many languages of the world, but the good news is that no major changes to the headache classification are then foreseen for the next 10 years. Until the printing of ICHD-IIR, the printed ICHD-II criteria remain in place for all other purposes. We issue a plea to the headache community to use and study these proposed general criteria for the secondary headaches in order to provide more evidence for their utility-before their incorporation in the main body of the classification.

ACGME competencies in neurology: web-based objective simulated computerized clinical encounters.

OBJECTIVE: The American Headache Society developed an innovative Web-based neurology resident educational program to 1) meet the objectives of the Accreditation Council for Graduate Medical Education Outcomes Project; 2) provide measurable improvement of a neurology resident's understanding of headache and the performance within each core competency; 3) assist residents and program directors in identifying knowledge gaps; and, ultimately, 4) improve the quality of patient care through enhanced educational initiatives. METHODS: Quantitative analysis focused on pretest and post-test results, level attainment on case-based simulations, competency achievement, and interactions between cases. One of four validated global scores was related to each resident response on all competency learning opportunities and was measured, from one case to another, to determine improvement and understanding. The pretest and post-test each consisted of 50 randomized questions that tested baseline and improvement on specific core competencies and understanding of headache. RESULTS: The pretest mean score was 30.08, and the post-test mean score was 34.79. A paired sample t test analysis showed a significant difference from pretest to post-test scores (M = -4.72, SD = 4.88, t[91] = -9.269, p < 0.001). There was significant improvement in the competencies as the residents moved through the cases as well as in each of the competencies from the pretest to the post-test. Results showed that residents increased their knowledge and performance by synthesizing the content. CONCLUSIONS: This outcomes analysis demonstrates the effectiveness of the American Headache Society Neurology Resident's Program in improving the resident's knowledge of headache medicine and Accreditation Council for Graduate Medical Education core competencies.

Consistency of response to sumatriptan/naproxen sodium in a placebo-controlled, crossover study.

Two identical randomized, placebo-controlled, crossover studies were conducted to evaluate consistency of response to sumatriptan/naproxen sodium 85/500 mg (S/NS) over four attacks in adults with migraine. Patients were instructed to treat within 1 h of pain onset while pain was mild. Co-primary end-points were pain-free response at 2 h (2hPF) and 24-h sustained pain-free response (24hSPF) calculated as percentages of all attacks. In Study 1, 570 patients treated 1693 attacks with S/NS and 424 with placebo. In Study 2, 565 patients treated 1678 attacks with S/NS and 422 with placebo. Compared with placebo, S/NS conferred higher 2hPF rates (Study 1: S/NS 52%, placebo 25%; Study 2: S/NS 50%, placebo 20%; both P < 0.001) and higher 24hSPF rates (Study 1: S/NS 37%, placebo 17%; Study 2: S/NS 34%, placebo 12%; both P < 0.001). 2hPF was reported in at least two of the first three S/NS-treated attacks in 55.0% of patients in Study 1 and 52.1% of patients in Study 2. 24hSPF was reported in at least two of the first three S/NS-treated attacks in 35.7% of patients in Study 1 and 32.6% of patients in Study 2. The incidences of any adverse event and of specific adverse events were low and generally similar between S/NS and placebo.

Clinical and electrodiagnostic findings in copper deficiency myeloneuropathy.

INTRODUCTION: Copper deficiency is an increasingly recognised cause of neurological impairment. This retrospective review highlights clinical and electrodiagnostic findings in patients diagnosed at our institution with copper deficiency. METHODS: Clinical, radiographic and electrodiagnostic findings were reviewed in patients with evidence of copper deficiency. Patients with other potential causes of myelopathy or neuropathy were excluded. RESULTS: The predominant clinical feature in all six patients was a sensory ataxia, resulting in marked gait unsteadiness. Nerve conduction studies and needle EMG were performed in all patients and revealed a mild to moderate distal, axonal, sensorimotor peripheral neuropathy. Median and tibial somatosensory evoked potentials were abnormal in all five patients in which it was performed, showing impaired conduction in central or proximal peripheral somatosensory pathways. CONCLUSIONS: This pattern of electrodiagnostic findings suggests that impairment in somatosensory pathways demonstrated by somatosensory evoked potential testing is the main cause of the sensory ataxia in patients with copper deficiency.

Applying the benefits of the AwM study in the clinic.

The Act when Mild (AwM) Study has illustrated the benefits to migraineurs of taking triptan medication when their migraine pain is still mild and within 1 h of the onset of symptoms. Yet many patients wait until the attack has fully developed before taking their medication, with potentially inferior outcomes. In order to reproduce the benefits of early intervention using the AwM paradigm in daily practice, a number of key barriers need to be addressed at both the physician and patient level. Notable physician-related barriers to be overcome, particularly at the primary care level, include accuracy of an early diagnosis of migraine in newly presenting patients, communication skills that generate a therapeutic engagement with migraine patients and enhance patient confidence, the application of knowledge about up-to-date strategies to optimize treatment outcomes, and the setting of achievable goals to avoid unrealistic expectations. Patient-related obstacles that need to be identified and overcome encompass patient attitude, expectations, and behaviour. Migraine patients may be reluctant to consult their physician, and, of those who do, many stop consulting because they perceive that physicians can do little to improve their situation. For this reason, migraine patients need to be counselled about the most appropriate medication for their level of symptoms. Moreover, patients need to be confident before they will adhere routinely to the advice they receive, and high in the priority of advice is the use of medication, particularly triptans, at the first sign of a migraine attack, rather than waiting until their attack has progressed to moderate or severe intensity. Patients who adhere to this advice are likely to experience a notable reduction in the pain, disability and time lost that they would otherwise suffer. The beneficial effects of early triptan intervention illustrated in the AwM Study can therefore be best reproduced in the clinic if the correct advice given to patients is not only accepted and applied by them, but also followed up by their physician.