Ubrogepant for the Treatment of Migraine.

BACKGROUND: Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment. METHODS: We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours. RESULTS: A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P = 0.002), and 37.7% in the 100-mg ubrogepant group (P = 0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose. CONCLUSIONS: A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.).

Real-world efficacy, tolerability, and safety of ubrogepant.

OBJECTIVE: To assess the real-world efficacy, tolerability, and safety of ubrogepant in a tertiary headache center. BACKGROUND: The efficacy and safety of ubrogepant for the acute treatment of migraine were established in phase 3 randomized controlled trials. However, there is no real-world data of patient experience with ubrogepant in a population in which the majority of patients have chronic migraine, multiple prior unsuccessful treatments, complex medical comorbidities, and concurrent use of other migraine-specific medications. METHOD: This was a post-market cohort study conducted at Mayo Clinic Arizona. All patients prescribed ubrogepant were tracked and contacted 1-3 months after the prescription to answer a list of standardized questions. Demographic information and additional headache history were obtained from chart review. RESULTS: We obtained eligible questionnaire responses from 106 patients. Chronic migraine accounted for 92/106 (86.8%) of the population. Complete headache freedom (from mild/moderate/severe to no pain) and headache relief (from moderate/severe to mild/no pain or mild to no pain) for ≥75% of all treated attacks at 2 hours after taking ubrogepant were achieved in 20/105 (19.0%) and 50/105 (47.6%) patients, respectively. A total of 33/106 (31.1%) patients reported being "very satisfied" with ubrogepant. Adverse events were reported in 42/106 (39.6%) patients, including fatigue in 29/106 (27.4%), dry mouth in 8/106 (7.5%), nausea/vomiting in 7/106 (6.6%), constipation in 5/106 (4.7%), dizziness in 3/106 (2.8%), and other adverse events in 7/106 (6.6%). Predictive factors for being a "good responder" to ubrogepant, defined as headache relief for ≥75% of all treated attacks at 2 hours after taking ubrogepant, included migraine with aura, episodic migraine, <5 prior unsuccessful preventive or acute treatment trials. Additionally, prior treatment responses to a CGRP monoclonal antibody and onabotulinumtoxinA injections are predictive of treatment responses and patient satisfaction to ubrogepant. For the 62/106 (58.5%) patients concurrently using a CGRP monoclonal antibody, there was no difference in the "good responder" rate or adverse event rate compared to those who were not on a CGRP monoclonal antibody, though the rate of moderate, as opposed to mild adverse events was higher, 11/62 (47.8%) versus 3/44 (17.6%), p = 0.048. Additionally, 16 patients had a history of significant cardiovascular or cerebrovascular diseases. No severe adverse events were reported in any patient. CONCLUSION: Our study confirms and extends the efficacy profile and tolerability of ubrogepant in a real-world tertiary headache clinic and identifies factors that may predict efficacy. Adverse event rates were higher than reported in clinical trials. Further studies are needed to confirm these findings and to evaluate the long-term efficacy and safety of ubrogepant.

Proceedings from the Ice Hockey Summit III: Action on Concussion.

The Ice Hockey Summit III provided updated scientific evidence on concussions in hockey to inform these five objectives: 1) describe sport-related concussion (SRC) epidemiology, 2) classify prevention strategies, 3) define objective, diagnostic tests, 4) identify treatment, and 5) integrate science and clinical care into prioritized action plans and policy. Our action plan evolved from 40 scientific presentations. The 155 attendees (physicians, athletic trainers, physical therapists, nurses, neuropsychologists, scientists, engineers, coaches, and officials) voted to prioritize these action items in the final Summit session. 1) Establish a national and international hockey data base for SRC at all levels, 2) eliminate body checking in Bantam youth hockey games, 3) expand a behavior modification program (Fair Play) to all youth hockey levels, 4) enforce game ejection penalties for fighting in Junior A and professional hockey leagues, 5) establish objective tests to diagnose concussion at point of care (POC), and 6) mandate baseline testing to improve concussion diagnosis for all age groups. Expedient implementation of the Summit III prioritized action items is necessary to reduce the risk, severity, and consequences of concussion in the sport of ice hockey.

Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic migraine.

Objective The main objective of this pilot study was to investigate the safety of administering onabotulinumtoxinA towards the sphenopalatine ganglion in 10 patients with intractable chronic migraine with an open, uncontrolled design. We also collected efficacy data to provide an indication as to whether future placebo-controlled studies should be performed. Method In a prospective, open-label, uncontrolled study after one-month baseline, we performed bilateral injections of 25 IU onabotulinumtoxinA (total dose 50 IU) toward the sphenopalatine ganglion in a single outpatient session in 10 patients with intractable migraine with a follow-up of 12 weeks. The primary outcome was adverse events and the main efficacy outcome was frequency of moderate and severe headache days in month 2 post-treatment compared to baseline. Results All 10 patients experienced a total of 25 adverse events. The majority of these were different types of local discomfort in the face and jaw, and none were classified as serious. In an intention-to-treat analysis of the main efficacy outcome, a statistically significant reduction of moderate and severe headache days in baseline versus month 2 was observed (16.3 ± 6.2 days baseline versus 7.6 ± 7.6 days month 2, p = 0.009). Eight out of 10 patients experienced an at least 50% reduction of moderate and severe headache days compared to baseline. Conclusion The result warrants randomised, placebo-controlled studies to establish both safety and efficacy of this potential novel treatment of chronic migraine.

Concussion in Ice Hockey: Current Gaps and Future Directions in an Objective Diagnosis.

OBJECTIVE: This review provides an update on sport-related concussion (SRC) in ice hockey and makes a case for changes in clinical concussion evaluation. Standard practice should require that concussions be objectively diagnosed and provide quantitative measures of the concussion injury that will serve as a platform for future evidence-based treatment. METHODS: The literature was surveyed to address several concussion-related topics: research in ice hockey-related head trauma, current subjective diagnosis, promising components of an objective diagnosis, and current and potential treatments. MAIN RESULTS: Sport-related head trauma has marked physiologic, pathologic, and psychological consequences for athletes. Although animal models have been used to simulate head trauma for pharmacologic testing, the current diagnosis and subsequent treatment in athletes still rely on an athlete's motivation to report or deny symptoms. Bias-free, objective diagnostic measures are needed to guide quantification of concussion severity and assessment of treatment effects. Most of the knowledge and management guidelines of concussion in ice hockey are generalizable to other contact sports. CONCLUSIONS: There is a need for an objective diagnosis of SRC that will quantify severity, establish a prognosis, and provide effective evidence-based treatment. Potential methods to improve concussion diagnosis by health care providers include a standardized concussion survey, the King-Devick test, a quantified electroencephalogram, and blood analysis for brain cell-specific biomarkers.

Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs.

OBJECTIVE: The primary objective of this study was to compare the efficacy and tolerability of topiramate and amitriptyline in the prophylaxis of episodic migraine headache. METHODS: This was a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority study. Adults with 3 to 12 migraines per month were randomized in a 1:1 ratio to receive an initial dose of 25 mg/d of either topiramate or amitriptyline, subsequently titrated to a maximum of 100 mg/d (or the maximum tolerated dose). The primary efficacy outcome was the change from prospective baseline in the mean monthly number of migraine episodes. Secondary efficacy variables included changes from the prospective baseline phase to the end of the double-blind phase in the mean monthly (28-day) rate of days with migraine, mean monthly rate of days with headache (migraine and nonmigraine), mean monthly rate of acute abortive medication use, mean monthly migraine duration, and mean monthly migraine severity. Additional secondary efficacy variables included changes in the mean monthly severity of migraine-associated symptoms (photophobia, phonophobia, and nausea), change in the mean monthly frequency f migraine-associated vomiting, and response rates (based on monthly migraine days and total headache days). The Migraine-Specific Quality of Life Questionnaire (MSQ) and the Weight Satisfaction Scale Questionnaire, which measures subjective satisfaction with current weight, were administered. Treatment-emergent adverse events (TEAEs) were monitored through the end of double-blind treatment. RESULTS: The intent-to-treat population included 331 subjects (172 topiramate, 159 amitriptyline; 84.9% female; 84.6% white; mean [SD] age, 38.8 [11.0] years; mean weight, 77.1 [20.1] kg) who provided at least 1 efficacy assessment. The least squares mean (LSM) change from baseline in the mean monthly number of migraine episodes was not significantly different between the topiramate and amitriptyline groups (-2.6 and -2.7, respectively; 95% CI, -0.6 to 0.7). There were no significant differences between treatment groups in any of the prespecified secondary outcome measures. Subjects receiving topiramate had a significantly greater improvement in mean functional disability scores during migraine attacks compared with amitriptyline (LSM change: -0.33 vs -0.19; 95% CI, -0.3 to 0.0; P = 0.040) and in the role function-restrictive, role function-preventive, and emotional function domains of the MSQ (P = 0.012, P = 0.014, and P = 0.029, respectively). Subjects receiving topiramate had a mean weight loss of 2.4 kg, compared with a mean weight gain of 2.4 kg in subjects receiving amitriptyline. Subjects in the topiramate group reported an overall improvement from baseline in weight satisfaction, whereas the amitriptyline group reported an overall deterioration in weight satisfaction (P < 0.001, topiramate vs amitriptyline). TEAEs of mild or moderate severity were reported in 118 subjects (66.7%) in the topiramate group and 112 subjects (66.3%) in the amitriptyline group. Among the most common TEAEs (reported in +/-5% of subjects during the double-blind phase) in the topiramate group were paresthesia (29.9%), fatigue (16.9%), somnolence (11.9%), hypoesthesia (10.7%), and nausea (10.2%). The most commonly reported TEAEs in the amitriptyline group were dry mouth (35.5%), fatigue (24.3%), somnolence (17.8%), weight increase (13.6%), dizziness (10.7%), and sinusitis (10.7%). CONCLUSIONS: In this noninferiority study, topiramate was at least as effective as amitriptyline in terms of reducing the rate of mean monthly migraine episodes and all prespecified secondary efficacy end points. Topiramate was associated with improvement in some quality-of-life indicators compared with amitriptyline and was associated with weight loss and improved weight satisfaction.

Facial pain.

Facial pain is a common symptom that may be a feature of a primary headache disorder or a secondary feature of organic disease. A thorough clinical history and physical examination may reveal the characteristic clinical features and assist in diagnosis. However, in some cases, the etiology may remain indeterminate.

Comprehensive management of patients presenting to the otolaryngologist for sinus pressure, pain, or headache.

OBJECTIVES/HYPOTHESIS: To study differential diagnosis and efficacy of management strategies in patients presenting to an otolaryngologist for sinus pressure, pain, or headache. STUDY DESIGN: Retrospective analysis at an academic medical center. METHODS: Patients were seen in the clinic (2010-2012) for sinus-related headache, pressure, pain or fullness (study symptoms) by a rhinologist. A retrospective chart review of patients with study symptoms was conducted. RESULTS: Of 211 patients with study symptoms, 70.62% met American Academy of Otolaryngology-Head and Neck Surgery criteria for sinusitis or had rhinologic disease. Otolaryngic therapy alone (medical or surgical) relieved study symptoms in 51.66%; combined neurology intervention helped another 15.17%. Nearly half of the patients (48.82%) were diagnosed with primary headache disorders. Comorbid rhinologic-neurologic disease was present in 27.96% and odontogenic disease in 7%. Initial otolaryngology referral was likely unnecessary for 36.49% of the study patients. Sinus computed tomography (CT) was available for 91% of 211 patients, and 80% of scans were positive. Endoscopic sinus surgery (ESS) was used in only 80/211 patients (37.69%) and was effective in 66/211 (31.28%). ESS was most successful in patients receiving concurrent neurological intervention. The Lund-Mackay CT score did not predict outcomes from ESS. Interdisciplinary otolaryngology-neurology efforts resulted in a positive outcome for 92.4% of patients. CONCLUSIONS: We present the first series detailing management of patients with sinus-headache pain in an otolaryngology practice. Such symptoms have multifactorial etiologies. Positive sinus CT results require cautious interpretation. ESS should be judiciously used. Interdisciplinary care is critical for success: approximately 50% of patients benefited from otolaryngic management, 50% needed neurological treatment, and 7% required dental disease management. LEVEL OF EVIDENCE: 4.

Occipital nerve stimulation with the Bion® microstimulator for the treatment of medically refractory chronic cluster headache.

BACKGROUND: Chronic cluster headache is a severely disabling neurological disorder. Evidence from open-label case series suggest that occipital nerve stimulation may be effective for the treatment of chronic cluster headache. OBJECTIVE: To evaluate the effectiveness of a microstimulator for chronic cluster headache. STUDY DESIGN: Prospective, observational feasibility study plus medical record review. SETTINGS: Academic medical center. METHODS: Four patients with medically refractory chronic cluster headache underwent implantation of a unilateral bion microstimulator. In-person follow-up was conducted for 12 months after implantation, and a prospective follow-up chart review was carried out to assess long term outcome. RESULTS: Three of the participants returned their headache diaries for evaluation. The mean duration of chronic cluster headache was 14.3 years (range 3 to 29 years). Pain was predominantly or exclusively retroocular/periocular. One participant demonstrated a positive response (> 50% reduction in cluster headache frequency) at 3 months post-implant, while there were 2 responders at 6 months. At least one of the participants continued to show > 60% reduction in headache frequency at 12 months. A chart review showed that at 58-67 months post-implant, all 3 participants reported continued use and benefit from stimulation. No side-shift in attacks was noted in any participant. Adverse events were limited to 2 participants with neck pain and/or cramping with stimulation at high amplitudes; one required revision for a faulty battery. LIMITATIONS: Small patient population without control group. Not blinded or randomized. CONCLUSION: Unilateral occipital nerve stimulation, using a minimally invasive microstimulator, may be effective for the treatment of medically refractory chronic cluster headache. This benefit may occur immediately after implantation, remain sustained up to 5 years after implantation, and occur despite the anterior location of the pain. Prospective, randomized controlled trials of occipital nerve stimulation in chronic cluster headache should proceed.