Brin, Mitchell F.

Abstract Objective To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. Background Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. Methods The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health‐care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period. Results Twenty‐five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non‐pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods. Conclusions These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise.

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 patients and none had regulatory approval. The terminology and recognition of CM evolved in parallel with the onabotulinumtoxinA clinical development program. Because there were no globally accepted classification criteria for CM when onabotulinumtoxinA was in development, the patient populations for the trials conducted by Allergan were determined by the Allergan migraine team in collaboration with headache scientists and clinicians. These trials and collaborations ultimately led to improvements in CM classifications. In 2010, onabotulinumtoxinA became the first medication and first biologic approved specifically to prevent headaches in patients with CM. Approval was based on 2 similarly designed phase 3, double-blind, randomized, placebo-controlled, multicenter clinical studies. Both studies showed significantly greater improvements in mean change from baseline in headache-day frequency in patients with CM receiving onabotulinumtoxinA compared with those receiving placebo. The safety and effectiveness of onabotulinumtoxinA have been established globally in >5000 patients with CM with or without medication overuse treated in clinical and observational studies. Benefits also include improvements in quality of life, fewer psychiatric comorbidities, and reduced healthcare resource utilization. Across studies, onabotulinumtoxinA was well tolerated; adverse events tended to be mild or moderate in severity and to decline over subsequent treatment cycles.

Objective Investigation of onabotulinumtoxinA in a murine model of acute and persistent post-traumatic headache. Methods Mild traumatic brain injury was induced with a weight drop method. Periorbital and hindpaw cutaneous allodynia were measured for 14 days. Mice were then exposed to bright light stress and allodynia was reassessed. OnabotulinumtoxinA (0.5 U) was injected subcutaneously over the cranial sutures at different post-injury time points. Results After milt traumatic brain injury, mice exhibited periorbital and hindpaw allodynia that lasted for approximately 14 days. Allodynia could be reinstated on days 14–67 by exposure to stress only in previously injured mice. OnabotulinumtoxinA administration at 2 h after mild traumatic brain injury fully blocked both transient acute and stress-induced allodynia up to day 67. When administered 72 h post-mild traumatic brain injury, onabotulinumtoxinA reversed acute allodynia, but only partially prevented stress-induced allodynia. OnabotulinumtoxinA administration at day 12, when initial allodynia was largely resolved, produced incomplete and transient prevention of stress-induced allodynia. The degree of acute allodynia correlated positively with subsequent stress-induced allodynia. Conclusion Mild traumatic brain injury induced transient headache-like pain followed by long lasting sensitization and persistent vulnerability to a normally innocuous stress stimulus, respectively modeling acute and persistent post-traumatic headache.. Administration of onabotulinumtoxinA following the resolution of acute post-traumatic headache diminished persistent post-traumatic headache but the effects were transient, suggesting that underlying persistent mild traumatic brain injury-induced maladaptations were not reversed. In contrast, early onabotulinumtoxinA administration fully blocked both acute post-traumatic headache as well as the transition to persistent post-traumatic headache suggesting prevention of neural adaptations that promote vulnerability to headache-like pain. Additionally, the degree of acute post-traumatic headache was predictive of risk of persistent post-traumatic headache.

Objective To provide clinically relevant insights on the identification of the muscles and techniques involved in the safe and effective use of onabotulinumtoxinA for chronic migraine prophylaxis. Background Although guidance on the use of onabotulinumtoxinA for chronic migraine is available, based on the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program, clinical experience has shown that insufficient understanding of the anatomy and function of the head and neck muscles may lead to undesirable outcomes and suboptimal efficacy. Design/Methods Each muscle involved in the standardized PREEMPT injection paradigm is reviewed with a thorough description of each muscle's anatomy (ie, muscle description and location, innervation, vascular supply) and function. Key insights based on clinical experience are also provided to help improve outcomes. Results The identification of the muscles in the PREEMPT injection paradigm should be based on each patient's unique anatomy and injections should be administered using the advised techniques. A thorough examination of the patient prior to treatment is also critical to determine if any preexisting conditions may increase the risk for unwanted outcomes and appropriate expectations should be communicated. Conclusions Thorough knowledge of the functional anatomy of the muscles involved in the standardized PREEMPT injection paradigm is critical to achieve the efficacy and safety observed in clinical trials. In addition, it is important to assess a patient's baseline condition to anticipate the risk for unwanted outcomes that may result from treatment.

Abstract Background Cervical dystonia is thought to result in high disease burden, but limited information exists on its impact on employment and work productivity. We utilized data from the Cervical Dystonia Patient Registry for the Observation of OnabotulinumtoxinA Efficacy (ClinicalTrials.gov identifier: NCT 00836017) to assess the impact of cervical dystonia on employment and work productivity and examine the effect of onabotulinumtoxinA treatments on work productivity. Methods Subjects completed a questionnaire on employment status and work productivity at baseline and final visit. Baseline data were examined by severity of cervical dystonia, predominant subtype, presence of pain, prior exposure to botulinum toxin, and/or utility of a sensory trick. Work productivity results at baseline and final visit were compared in subjects who were toxin‐naïve at baseline and received three onabotulinumtoxinA treatments. Results Of 1,038 subjects, 42.8% were employed full‐ or part‐time, 6.1% unemployed, 32.7% retired, and 11.8% disabled. Of those currently employed, cervical dystonia affected work status of 26.0%, caused 29.8% to miss work in the past month (mean, 5.1 ± 6.4 days), and 57.8% reported decreased productivity. Half of those unemployed were employed when symptoms began, and 38.5% attributed lost employment to cervical dystonia. Pain, increasing severity, and anterocollis/retrocollis had the largest effects on work status/productivity. Preliminary analyses showed that absenteeism and presenteeism were significantly decreased following onabotulinumtoxinA treatments in the subpopulation that was toxin‐naïve at baseline. Conclusions This analysis confirms the substantial negative impact of cervical dystonia on employment, with cervical dystonia‐associated pain being a particularly important driver. OnabotulinumtoxinA treatment appears to improve work productivity.