Dodick, David W.

Aim Migraine pain is thought to result from activation of meningeal nociceptors that might involve dural mast cell degranulation and release of proteases and pronociceptive mediators. Tryptase, the most abundant dural mast cell protease, has been demonstrated to stimulate dural mast cells, as well as trigeminal nociceptors by activating the protease activated receptor 2. Mast cell or neuronal protease activated receptors 2 may therefore represent a novel target for migraine treatment. In this study, we characterized and evaluated a novel protease activated receptor 2 monoclonal antibody as a preventive anti-migraine pain therapy in preclinical models. Methods Flow cytometry, immunocytochemistry, calcium imaging, Homogeneous Time Resolved Technology (HTRF) epitope competition assay and serum pharmacokinetic (PK) assay in rats were performed to confirm the activity, specificity and in vivo stability of PAR650097, a novel anti- protease activated receptor 2 monoclonal antibody. In vivo assessment was performed in female C57BL/6J mice by evaluation of PAR650097 in preventing cutaneous allodynia elicited by (a) supradural injection of the protease activated receptor 2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-amide trifluoroacetate (SLIGRL), or calcitonin gene-related (CGRP) peptide, and (b) induction of latent sensitization by priming with three daily episodes of restraint stress followed by challenge with a subthreshold inhalational exposure to umbellulone (UMB), a transient receptor potential ankyrin 1 (TRPA1) agonist. PAR650097 was administered as a pretreatment prior to the first restraint stress, umbellulone exposure, SLIGRL or calcitonin gene-related peptide injection. Additionally, fremanezumab, a calcitonin gene-related peptide antibody was administered as pre-treatment prior to supradural administration of calcitonin gene-related peptide or SLIGRL. Results In vitro, PAR650097 demonstrated rapid interaction with protease activated receptor 2, enabling it to fully inhibit protease-induced protease activated receptor 2 activation, in human and mouse cells, with high potency. Furthermore, PAR650097 was highly selective for protease activated receptor 2, demonstrating no affinity for protease activated receptor 1 protein and no functional effect on the activation of cellular protease activated receptor 1 with thrombin. In addition, PAR650097 had an acceptable PK profile, compatible with testing the effects of selective protease activated receptor 2 inhibition in vivo. In vivo, PAR650097 blocked cutaneous allodynia induced by either supradural SLIGRL or calcitonin gene-related peptide. Fremanezumab abolished cutaneous allodynia induced by supradural CGRP, and partially attenuated cutaneous allodynia induced by SLIGRL. Administration of PAR650097, before the first restraint stress episode, did not prevent the acute stress-induced cutaneous allodynia or restraint stress priming revealed by cutaneous allodynia induced by inhalational umbellulone. In contrast, PAR650097 prevented expression of cutaneous allodynia when given before the umbellulone challenge in restraint stress-primed animals. Conclusion PAR650097 specifically inhibits endogenously expressed protease activated receptor 2 in human and mouse cells with high potency. This antibody has an acceptable PK profile in rodents and effectively blocked SLIGR-induced cutaneous allodynia. PAR650097 additionally prevented cutaneous allodynia induced by supradural calcitonin gene-related peptide, indicating that the protease activated receptor 2 receptor is a downstream consequence of calcitonin gene-related peptide actions. Fremanezumab effectively blocked calcitonin gene-related peptide-induced cutaneous allodynia and only partially reduced cutaneous allodynia induced by a protease activated receptor 2 activator, suggesting both calcitonin gene-related peptide-dependent and -independent mechanisms in promoting migraine pain. While PAR650097 did not prevent stress-induced cutaneous allodynia or priming, it effectively prevented cutaneous allodynia induced by a TRPA1 agonist in animals with latent sensitization. Activation of protease activated receptor 2, therefore, contributes to both calcitonin gene-related peptide-dependent and -independent mechanisms in promoting migraine-like pain. Therapeutic targeting of protease activated receptor 2 receptors may represent an anti-migraine pain strategy with a potentially broad efficacy profile.

Introduction: Triptans, the most commonly prescribed acute treatments for migraine attacks are, per FDA labeling, contraindicated in cardiovascular (CV) disease patients and have warnings and precautions for those with CV risk factors. Methods: Headache specialists, cardiologists, and health economics and outcomes researchers convened to identify diagnostic codes for: (1) CV diseases contraindicating triptans based on FDA labeling; (2) conditions comprising “other significant underlying CV disease”; and (3) CV risk factors included as warnings and precautions for triptans. A retrospective, cross-sectional analysis of commercially insured adult US migraine patients in the 2017 Optum ® Clinformatics ® Data Mart (CDM) and the 2017 IBM ® Watson Health MarketScan ® Commercial Claims database was used to estimate the proportion of migraine patients with CV contraindications and warnings and precautions to triptans. Results: Of the 56,662 migraine patients analyzed from Optum CDM, 13.5% had ≥1 CV disease as specified in triptan labeling and an additional 8.5% had ≥1 “other CV disease” judged by the panel to constitute a “significant underlying CV disease” (total: 22.0% migraine patients). Of 176 724 migraine patients analyzed from MarketScan, 12.2% had ≥1 CV disease as specified in the labeling and an additional 8.0% had ≥1 “other significant underlying CV disease” (total: 20.2% of migraine patients). An additional 25.4% and 25.1% of migraine patients had ≥2 CV risk factors in Optum CDM and MarketScan. In total, 47.4% and 45.3% of migraine patients in both databases had a CV disease specified as a contraindication, an “other CV disease” endorsed as significant, or ≥2 CV risk factors identified as warnings and precautions to triptans. Conclusions: Analyses of more than 230,000 people with migraine showed that ≥20% of commercially insured US migraine patients have a CV condition that specifically contraindicates triptan treatment, and an additional 25% have ≥2 CV risk factors identified as warnings and precautions to triptans.

Aim Development and characterization of a novel injury-free preclinical model of migraine-like pain allowing mechanistic assessment of both acute and preventive treatments. Methods A “two-hit” hyperalgesic priming strategy was used to induce vulnerability to a normally subthreshold challenge with umbellulone, a transient receptor potential ankyrin 1 (TRPA1) activator, in uninjured female and male C57BL/6 mice. Priming (i.e. the first hit) was induced by three consecutive daily episodes of restraint stress; repeated umbellulone was also evaluated for potential priming effects. Sixteen days after the first restraint stress, mice received inhalational umbellulone (i.e. the second hit) to elicit migraine-like pain. Medications currently used for acute or preventive migraine therapy including propranolol (a beta blocker) and sumatriptan (5HT1 B/D agonist), as well as olcegepant, an experimental calcitonin gene related peptide (CGRP) receptor antagonist and nor-Binaltorphimine (nor-BNI), an experimental long-acting kappa opioid receptor (KOR) antagonist, were investigated for their efficacy to block priming and prevent or reverse umbellulone-induced allodynia in primed animals. To assess migraine-like pain, cutaneous allodynia was determined by responses to periorbital or hindpaw probing with von Frey filaments. Results Repeated restraint stress, but not umbellulone exposure, produced transient cutaneous allodynia that resolved within 16 d. Restraint stress produced long-lasting priming that persisted beyond 16 d, as demonstrated by reinstatement of cutaneous allodynia following inhalational umbellulone challenge. Pretreatment with propranolol or nor-BNI prior to restraint stress prevented both transient cutaneous allodynia and priming, demonstrated by a lack of umbellulone-induced cutaneous allodynia. Following establishment of restraint stress priming, olcegepant, but not propranolol or nor-BNI, prevented umbellulone-induced cutaneous allodynia. When administered 1 h after umbellulone, sumatriptan, but not olcegepant, reversed umbellulone-induced cutaneous allodynia in restraint stress-primed rats. Conclusion We have developed a novel injury-free model with translational relevance that can be used to study mechanisms relevant to migraine-like pain and to evaluate novel acute or preventive treatments. Restraint stress priming induced a state of vulnerability to a subthreshold stimulus that has been referred to as “latent sensitization”. The development of latent sensitization could be prevented by blockade of stress pathways with propranolol or with a kappa opioid receptor antagonist. Following establishment of latent sensitization, subthreshold stimulation with umbellulone reinstated cutaneous allodynia, likely from activation of meningeal TRPA1-expressing nociceptors. Accordingly, in restraint stress-primed animals, sumatriptan reversed umbellulone-induced cutaneous allodynia, supporting peripheral sites of action, while propranolol and nor-BNI were not effective. Surprisingly, olcegepant was effective in mice with latent sensitization when given prior to, but not after, umbellulone challenge, suggesting time-dependent contributions of calcitonin gene-related peptide receptor signaling in promoting migraine-like pain in this model. Activation of the calcitonin gene-related peptide receptor participates in initiating, but has a more limited role in maintaining, pain responses, supporting the efficacy of small molecule calcitonin gene-related peptide antagonists as preventive medications. Additionally, the effectiveness of sumatriptan in reversal of established pain thus suggests modulation of additional, non-calcitonin gene-related peptide receptor-mediated nociceptive mechanisms. Kappa opioid receptor antagonists may represent a novel preventive therapy for stress-related migraine.

Objective To assess the efficacy of erenumab at the ≥50%, ≥75%, and 100% reduction in monthly migraine days (MMD) response thresholds, using data from the 6‐month double‐blind treatment phase (DBTP) of the Study to Evaluate the Efficacy and Safety of Erenumab in Migraine Prevention (STRIVE) pivotal clinical trial. Methods Enrolled patients with episodic migraine (EM; ≥4 MMD and <15 monthly headache days) were randomized (1:1:1) to erenumab 70 mg (n = 312), erenumab 140 mg (n = 318), or placebo (n = 316) once monthly. We determined the proportions of patients with ≥50%, ≥75% and 100% reduction in MMD over the last 3 months of the STRIVE DBTP (months 4 through 6) and conducted post hoc analyses to contextualize the treatment benefit in patient subgroups achieving, and not achieving, these response thresholds. Outcome measures included changes in MMD, acute migraine‐specific medication days (MSMD), and patient‐reported outcomes. Results The proportions of patients with a reduction in MMD from baseline were greater for erenumab than for placebo at all response thresholds. As previously reported for the ≥50% response threshold, 135/312 (43.3%) of patients on erenumab 70 mg and 159/318 (50.0%) on erenumab 140 mg responded, vs 84/316 (26.6%) for placebo. At months 4 through 6, 65/312 (20.8%) and 70/318 (22.0%) of those on erenumab 70 mg and erenumab 140 mg, respectively, achieved ≥75% reductions vs 25/316 (7.9%) on placebo. A reduction of 100% response, which required no migraine days over 3 consecutive months based on observed data, was achieved by 10/312 (3.2%) of patients treated with erenumab 70 mg and 16/318 (5.0%) for erenumab 140 mg, vs 9/316 (2.8%) for placebo. At all response thresholds, responders achieved numerically greater reductions in mean MMD and MSMD, and greater improvements in disability than did the overall population; importantly, these remarkable responses were noted early. Meanwhile, 60/312 (19.2%) and 53/318 (16.7%) patients on erenumab 70 and 140 mg, respectively, had no reduction in MMD from baseline in months 4 through 6, compared with 104/316 (32.9%) patients on placebo. Conclusions The responses at the ≥50%, ≥75%, and 100% thresholds provide context for establishing realistic patient and physician expectations regarding the magnitude of treatment benefit that may be achieved by patients with EM responding to erenumab (STRIVE, NCT02456740).

Background Visual snow syndrome (VSS) is a neurological condition characterized by persistent flickering dots in the visual fields, palinopsia, enhanced entoptic phenomenon, photophobia, and nyctalopia. Neuroimaging evidence supports the role of the visual association cortex in visual snow syndrome. Case series: We provided clinical care to three patients with visual snow syndrome, in whom [ 123 I]-IMP single-photon emission computed tomography (SPECT) imaging was performed. Case 1 was a 21-year-old male with a past history of migraine with aura who exhibited visual snow and entoptic phenomenon. In this patient, [ 123 I]-IMP SPECT imaging revealed right occipital and temporal hypoperfusion with a distribution matching the ventral visual stream. [ 123 I]-IMP SPECT imaging detected only mild bilateral frontal hypoperfusion in Case 2 and no overt abnormalities in Case 3. Conclusion Although visual snow syndrome seems to be a heterogenous condition, our observations indicate that abnormal visual processing within the ventral visual stream may play a role in the pathogenesis of this condition.

Background and Objectives The association between migraine, depression, and anxiety has been established, but the impact of these psychiatric comorbidities on functional impairment in people with migraine has been under‐investigated. The purpose of this cross‐sectional observational study was to investigate the relationship between anxiety and depression symptoms on migraine‐related disability, pain interference, work interference, and career success in a cohort of patients with migraine. Methods This analysis included 567 migraine patients who had been enrolled into the American Registry for Migraine Research (ARMR) between February 2016 and June 2019. Patients completed the Generalized Anxiety Disorder‐7 (GAD‐7) and Patient Health Questionnaire‐2 (PHQ‐2) to measure symptoms of anxiety and depression, respectively. Patients completed the Migraine Disability Assessment Scale (MIDAS), Pain Interference (PROMIS pain short) questionnaire, and Work Productivity and Activity Interference (WPAI) questionnaire to measure levels of functional impairment at work and in daily activities. In addition, patients answered questions designed for ARMR regarding education and career interference. Models were created to describe the relationship between severity of psychiatric symptoms (anxiety and depression), and each outcome of interest (WPAI, MIDAS, pain interference, reporting that migraine had interfered with career success). Each model was controlled for age, sex, headache frequency, years with migraine, and average headache intensity. Results Among the 567 patients with migraine, mean (SD) age was 47.1 (13.7), 87.3% were female, and average headache frequency was 19.1 (9.3) days/month. PHQ‐2 scores were positively associated with scores on MIDAS ( b = 0.06, SE = 0.01, P ≤ .001), pain interference ( b = 1.4, SE = 0.2, P < .001), and WPAI including absenteeism ( b = 0.16, SE = 0.04, P = .007), presenteeism ( b = 2.7, SE = 1.1, P = .012), overall work productivity impairment ( b = 3.7, SE = 1.2, P = .001), and activity impairment ( b = 3.0, SE = 1.2, P = .009). PHQ‐2 scores were also associated with reporting that migraine interfered with career success ( b = 0.34, SE = 0.08, P ≤ .001). GAD‐7 scores were not associated with MIDAS, pain interference, WPAI, or reduced career success. Conclusions Severity of depression symptoms in patients with migraine is associated with migraine‐related disability, work interference, pain interference, and reduced career success. Patients with more severe symptoms of depression are more likely to have greater functional impairment. A management approach that addresses depression in those with migraine may lead to improvements in patient functioning.

Introduction YouTube is the most widely used video hosting website in the world; however, the quality and reliability of information is unknown. The aim of this study is to evaluate the content and distribution of the most popular videos on YouTube about migraine. Methods We searched for migraine-related videos on the online video hosting resource YouTube ( http://youtube.com/ ). Two authors screened the titles and video descriptions independently for all videos with a view count of ≥ 10,000 views. For each video we recorded descriptive data, the source/author and the primary purpose/content. Results We identified 351 eligible videos. In total, there was more than 3 days of content viewed more than 163 million times. Only 9% of these videos were authored by healthcare professionals. The majority (44%) of videos focused on complementary and alternative medicine. Discussion YouTube provides a wide array of easily accessible information on migraine, ranging from authoritative sources to potentially questionable content. If used uncritically, this may result in inadequate clinical management. Peer-reviewed information on migraine mechanisms and treatment is needed to provide the best available evidence for the public and patients. Ideally, a professional society or foundation such as the International Headache Society would develop, curate, and distribute content.

Introduction Health information is one of the most frequently searched topics on the internet. In this observational cross-sectional study, we evaluated the content of the highest indexed Google search results related to migraine management. Methods We identified the five most used search terms related to migraine management via Google Trends in the time period 1 January 2004 to 2 October 2019. We entered each search term into Google’s search engine and retrieved the search results from the first three pages from each search query. We stratified the recommended treatment options and evaluated the websites using the DISCERN tool. Results In total, 73 unique websites recommended a total of 77 different migraine treatment options, consisting of 35 (45%) acute and 42 (55%) preventive treatments. For acute treatments, pharmacological options were more frequently recommended (88% of websites), whereas non-pharmacological options were more frequent among preventive treatments (67%). Evaluation of the consumer health information using the DISCERN tool showed that non-governmental organizations had the highest mean total score with 3.8 (±0.19). Conclusions Googling when looking for migraine treatments reveals a multitude of management proposals of varying quality. Non-governmental organizations provide the overall highest quality of written consumer health information on migraine treatments among search results. We encourage stakeholders to optimize and distribute high-quality and peer-reviewed information on migraine management.

Clinical trials are a key component of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. Advances in drugs, devices, and biologicals, as well as novel trial designs, have prompted several updates over the nearly 30 years since, including most recently the Guidelines for controlled trials of preventive treatment of chronic migraine (2018), the Guidelines for controlled trials of acute treatment of migraine attacks in adults (2019), and Guidelines for controlled trials of preventive treatment of migraine in children and adolescents (2019). The present update incorporates findings from new research and is intended to optimize the design of controlled trials of preventive pharmacological treatment of episodic migraine in adults. A guideline for clinical trials with devices will be published separately.