Effects of OnabotulinumtoxinA on Allodynia and Interictal Burden of Patients with Chronic Migraine

Objectives To investigate pain, quality of life, sleep, and functional outcomes between chronic migraine (CM) patients with temporomandibular disorder (TMD) and patients with CM alone. Methods Thirty one patients with CM and thirty one patients with CM+TMD were recruited in the study. All patients had not been on preventive treatment for CM or TMD in the previous three months. TMD was examined by physical examination, guided by the subdomains of the Helkimo Clinical Dysfunction Index (HCDI). All patients were evaluated for allodynia using the Allodynia Symptom Checklist (ASC-12), quality of life using the 36-item Short Form Health Survey (SF-36), headache-related disability using the Migraine Disability Assessment Scale (MIDAS) and the Headache Impact Test (HIT-6), and sleep quality using the Pittsburgh Sleep Quality Index (PSQI). Results The average pain intensity was higher in patients with CM+TMD (p < 0.001). The number of patients with a migraine attack duration of more than 3 days were significantly higher in the same group (p = 0.001). ASC-12 scores were significantly elevated in patients with CM+TMD (p < 0.001). MIDAS and HIT-6 scores were significantly higher in the CM+TMD patient group (p = 0.010, p < 0.001, respectively). HCDI score was significantly positively correlated with age, BMI, average number of headache days in a month, ASC-12 score, PSQI sleep disturbance domain score, and PSQI total score (r = 0.625, 0.406, 0.417, 0.484, 0.499, and 0.487, respectively). Conclusion In patients with CM, TMD comorbidity significantly associated with high average pain intensity, migraine attack duration, and allodynia. Physicians managing headaches should not overlook TMD symptoms in CM and should benefit from collaborating with TMD specialists to address TMD symptoms effectively.

BackgroundCentral sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an analogous spatial distribution of cutaneous allodynia with cephalic and extracephalic symptoms. We investigated whether allodynia, and its subtypes based on spatial distribution and type of stimulus, predict response to treatment in chronic migraine patients.MethodsThis study was conducted as part of the CHARM study (NTR3440), a randomized, double-blind, placebo-controlled trial in chronic migraine patients with medication overuse. We included 173 patients. The presence of cutaneous allodynia at baseline was established with the Allodynia Symptom Checklist. Primary endpoint was reversion from chronic to episodic migraine.ResultsOf all patients, 74.6% reported cutaneous allodynia. Absence of allodynia compared to presence of allodynia was predictive for reversion from chronic to episodic migraine, odds ratio (OR): 2.45 (95% CI: 1.03–5.84), p = 0.042. The predictive value was more pronounced when subdivided for spatial distribution, for participants without allodynia versus cephalic (OR: 4.16 (95% CI: 1.21–14.30), p = 0.024) and extracephalic (OR: 7.32 (95% CI: 1.98- 27.11), p = 0.003) allodynia. Mechanical, but not thermal, allodynia, was associated with outcome.ConclusionsCutaneous allodynia, an important marker for central sensitization, likely has predictive value for treatment response in chronic migraine.Graphical

Pre-emptive/early intervention with triptans in migraine: hope, hype and hazard

Background: There is a need for effective, well tolerated and affordable drug for chronic migraine prophylaxis in low socioeconomic countries.&#x0D; Objective: To study the efficacy and safety of propranolol and sodium valproate (a food and drug administration approved and widely used treatment for prevention of migraine) as a prophylactic treatment in chronic migraine (CM) patients and to compare their efficacy and safety to each other.&#x0D; Methods: In this single center, open labeled clinical trial, 40 patients with CM were subdivided into two group: group 1 (n=20) treated with propranolol and group 2 (n=20) treated with sodium valproate. Patients maintained headache diaries over a 1-month baseline period and a 6- month active study period. The evaluation of the treatment was done after 3 and 6 months of the initiation of the treatment. The efficacy measures were evaluation of monthly attacks frequency and attacks severity using VAS of pain (visual analogue scale. Disability and impact of migraine were evaluated using Migraine assessment disability scale (MIDAS) and Headache Impact Test (HIT-6). Throughout the study, patients were monitored for any symptoms or signs of adverse effects.&#x0D; Results: Of 40 patients participated in this study (mean age, 33.48; females 72.5%). At the 6th month, the study was completed by 27 patients (propranolol; n=14 and sodium valproate; n=13). Between 55 and 62% of both groups reported more than 50% reduction in monthly attacks frequency. In both groups, there was significant reduction of VAS of pain scores. Both groups showed significant improvement of HIT-6 and MIDAS scores. Before the start of treatment, 85% to 100% of patients in both groups had severe MIDAS and HIT-6 scores. At the end of the study, only 35.7% of propranolol group and 30.8 of sodium valproate group showed severe MIDAS scores and 50% of propranolol group and 40% of sodium valproate group reported severe HIT-6 scores. 55% (n=11) of patients in propranolol reported AEs related to treatment compared to 75% (n=15) in the sodium valproate group. A higher proportion of patients discontinued the treatment because of AEs in Na valproate group compared to sodium valproate group with no statistically significant difference in between (20% vs. 5%, respectively).&#x0D; Conclusions: Propranolol and sodium valproate demonstrated similar efficacy and tolerability in the prophylactic treatment of CM.

ObjectiveTo examine changes in the occurrence, severity, and symptoms of headache episodes in patients with chronic migraine following eptinezumab treatment.MethodsPROMISE-2 was a double-blind, placebo-controlled, parallel-group trial that randomized adults with chronic migraine to eptinezumab 100 mg, 300 mg, or placebo IV every 12 weeks for up to 24 weeks (2 infusions). Headache episodes (migraine and non-migraine) and their characteristics were reported in daily electronic diaries during the 28-day baseline and throughout the 24-week treatment period.ResultsA total of 1072 patients were included in this post hoc analysis. Mean monthly headache days decreased by 8.9 (100 mg) and 9.7 (300 mg) compared to a 7.3 decrease in placebo over the first 4-week interval post initial dose and reductions were maintained throughout the 24-week treatment period. Mean monthly headache episodes also decreased by 8.4 (100 mg) and 9.0 (300 mg) compared to a decrease of 7.1 with placebo. The proportion of headache episodes that were migraine attacks decreased by 11.2% (100 mg), 12.4% (300 mg), and 3.9% (placebo), and among remaining headaches decreases in severe pain, nausea, phonophobia, photophobia, and physical activity limitations were numerically greater than placebo.ConclusionsPatients with chronic migraine treated with eptinezumab decreased the monthly severity and frequency of headache days and episodes more than placebo. Beyond decreased headache frequency, patients treated with eptinezumab reported a reduction in the percent of remaining headache episodes that were migraine attacks, as well as a decrease in burdensome symptoms of headache episodes, indicating additional decreased headache severity after eptinezumab treatment.Trial registration: ClinicalTrials.gov Identifier: NCT02974153; registered November 23, 2016.

IntroductionErenumab has been studied in Randomised Controlled Trials (RCT), with stricter exclusion criteria than real world populations.Methods65 patients from two Australian headache centres on Erenumab had primary outcomes of ≥ 50% response in monthly migraine days (MMD) and monthly headache days (MHD), compared to their demographics, frequency, duration of Chronic Migraine (CM), failed prophylactic medications, severity scores and medication overuse headache (MOH).Results35% (23/65) had daily headaches, with ≥ 50% MHD and MMD reduction in this subgroup of 17% (4/23) and 65% (13/20), respectively. Duration of CM was &gt;10 years in 48% (29/61), with ≥ 50% MHD and MMD reduction in 28% (8/29) and 48% (13/27), respectively. 100% (64/64) had failed &gt; 3 prophylactic medications with ≥50% MHD and MMD reduction in 30% (19/64) and 47% (27/58), respectively, with reducing rates of ≥ 50%MMD reduction if &gt;5 (29%; 17/58) and &gt;10 (22%;2/9). 95% had high severity scores (HIT-6 score &gt;60), with a ≥ 50% MMD reduction in 43% (23/54). MOH occurred in 41% (24/58) for triptan and 29% (17/58) for codeine medications, with a ≥ 50% MMD reduction in 71% (17/24) and 41% (7/17), respectively (all groups p&gt;0.05).ConclusionThis real world cohort treated with Erenumab included patients that would be excluded from RCT analysis- including more chronic, frequent, severe and refractory migraine. Despite this, there were still ≥50% responders in more severe subgroups, particularly daily headache, high severity scores and triptan MOH. Measuring MMD may be more sensitive for assessing improvement than MHD.

Chronic migraine (CM) is the most prevalent headache-related disorder that affects 1% to 2% of the world's population. OnabotulinumtoxinA (BoNT-A) is a potent neurotoxin produced by Clostridium botulinum. In this study, we explored the health-related quality of life (HRQol) and the output of BoNT-A as a preventative therapy in CM patients. To assess the HRQol of the patients with CM on BoNT-A therapy by the headache impact test (HIT-6) score. Patients with CM (n = 51) were diagnosed and enrolled for the study. The impact of CM on Qol was assessed using the HIT-6 questionnaire at the beginning, 1 month and 3 months of the therapy. A significant reduction of HIT-6 score was observed 1 and 3 months post-BoNT-A therapy (P < 0.0001) as compared to pre-BoNT-A therapy. Our findings suggest that BoNT-A therapy can improve HRQol by reducing the incidence of migraine headaches. Thus, BoNT-A can be effective in the management of CM.

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). 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. 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. OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures.

Cephalic and extracephalic neurophysiological effects of botulinum toxin type A in chronic migraine

To describe differences in clinical and demographic characteristics between patients with episodic migraine (EM) or chronic migraine (CM) and determine the effect of migraine subtype on patient-reported outcome measures (PROM). Prior studies have characterized migraine in the general population. While this provides a basis for our understanding of migraine, we have less insight into the characteristics, comorbidities, and outcomes of migraine patients who present to subspecialty headache clinics. These patients represent a subset of the population that bears the greatest burden of migraine disability and are more representative of migraine patients who seek medical care. Valuable insights can be gained from a better understanding of CM and EM in this population. We conducted a retrospective observational cohort study of patients with CM or EM seen in the Cleveland Clinic Headache Center between January 2012 and June 2017. Demographics, clinical characteristics, and patient-reported outcome measures (3-Level European Quality of Life 5-Dimension [EQ-5D-3L], Headache Impact Test-6 [HIT-6], Patient Health Questionnaire-9 [PHQ-9]) were compared between groups. Eleven thousand thirty-seven patients who had 29,032 visits were included. More CM patients reported being on disability 517/3652 (14.2%) than EM patients 249/4881 (5.1%) and had significantly worse mean HIT-6 (67.3 ± 7.4 vs. 63.1 ± 7.4, p < 0.001) and median [interquartile range] EQ-5D-3L (0.77 [0.44-0.82] vs. 0.83 [0.77-1.00], p < 0.001), and PHQ-9 (10 [6-16] vs. 5 [2-10], p < 0.001). There are multiple differences in demographic characteristics and comorbid conditions between patients with CM and EM. After adjustment for these factors, CM patients had higher PHQ-9 scores, lower quality of life scores, greater disability, and greater work restrictions/unemployment.

Background Elderly migraine is a public health problem with prolonged life expectancy, and effective prophylactic treatment is needed. There were no reports on fremanezumab for the elderly. We described the real-world data of fremanezumab, calcitonin gene-related peptide-related monoclonal antibody (CGRP-mAB), for migraine in elderly over 70 years old. Methods We retrospectively investigated six elderly migraine patients over 70 years old treated with fremanezumab. Headache impact test-6 (HIT-6), monthly headache days (MHD), and monthly acute medication intake days (AMD) before one and three months after starting fremanezumab treatment were evaluated. Results Three women and three men (median age 78; range: 71-99) were included. One was chronic migraine (CM), three were CM and medication-overuse headache, and two were episodic migraine and tension-type headache. All six patients received monthly fremanezumab. The median MHD before, during one, and three months after treatment were 30 (4-30), 30 (4-30), and 29 (15-30, n=4). Those of AMD were 17 (0-30), 9.5 (0-30), and 1 (0-28). Those about HIT-6 were 64 (56-72), 59.5 (52-70), and 55.5 (48-64). Two (33.3%) of the six patients experienced therapeutic effectiveness. There were no side effects. Conclusion We described the six elderly migraine patients aged over 70 years old treated with fremanezumab. Two (33.3%) of the six patients experienced therapeutic effectiveness. This is the first report of fremanezumab for elderly migraine patients aged over 70 years old. Further evidence accumulation is needed about CGRP-mABs for the elderly.

Objectives: This case report aims to describe the effects of craniosacral therapy and acupuncture in a patient with chronic migraine.Methods: A 33-year-old man with chronic migraine was treated with 20 sessions of craniosacral therapy and acupuncture for 8 weeks. The number of migraine and headache days were monitored every month. The pain intensity of headache was measured on the visual analog scale (VAS). Korean Headache Impact Test-6 (HIT-6) and Migraine Specific Quality of Life (MSQoL) were also used.Results: The number of headache days per month reduced from 28 to 7 after 8 weeks of treatment and to 3 after 3 months of treatment. The pain intensity of headache based on VAS reduced from 7.5 to 3 after 8 weeks and further to &lt; 1 after 3 months of treatment. Furthermore, the patient’s HIT-6 and MSQoL scores improved during the treatment period, which was maintained or further improved at the 3 month follow-up. No side effects were observed during or after the treatment.Conclusion: This case indicates that craniosacral therapy and acupuncture could be effective treatments for chronic migraine. Further studies are required to validate the efficacy of craniosacral therapy for chronic migraine.

This study was performed to determine if there were a time of year that children were more likely to transition into a chronic daily headache. We retrospectively reviewed records of 103 patients with chronic migraine and 104 patients with new daily persistent headache. Of these, 56 chronic migraine and 92 new daily persistent headache patients were able to identify the specific month in which they began to experience daily headaches. Thirty-nine percent of new daily persistent headache patients had an onset of daily headache in either September or January, months traditionally associated with the start of the school semester in the United States. Only a single patient reported onset in May or June. Data for the transition from episodic to chronic migraine also showed higher rates in September and January, but did not reach statistical significance. These data demonstrate the higher rates of new daily persistent headache onset during school start months and question what factors may be responsible for this association.

IntroductionThe double-blind, phase 3 PREEMPT trials demonstrated the efficacy and tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis evaluated the effect of onabotulinumtoxinA on clinically meaningful changes in headache severity, headache-related impact, and quality of life.MethodsPooled, 24-week data were used to determine percentages of patients meeting responder criteria for the change in headache days (≥ 50% reduction in headache-day frequency), Headache Impact Test (HIT-6; ≥ 5-point improvement), MSQ Role Function-Restrictive (MSQ-RFR; ≥ 10.9-point improvement), and Average Daily Headache Severity (ADHS; ≥ 1-point improvement on a 4-point ordinal scale [0 = no pain, 3 = severe pain]).ResultsIn the pooled analysis population (N = 1384; onabotulinumtoxinA, n = 688; placebo, n = 696), significantly more patients treated with onabotulinumtoxinA compared with placebo were responders on HIT-6 (40.8 vs. 25.3%), MSQ-RFR (59.0 vs. 40.2%), and ADHS (35.5 vs. 22.4%) measures, and achieved traditional ≥ 50% reduction in headache days (44.8 vs. 34.2%; all P < 0.001). At least one responder criterion was met by 72.1% and 56.6% of onabotulinumtoxinA- and placebo-treated patients, respectively; all four were met by 20.4% and 8.6%, respectively (P < 0.001). Linear regression analysis showed that approximately 20% of the variance in HIT-6 and MSQ-RFR improvement was explained by improvement in headache days.ConclusionsTreatment with onabotulinumtoxinA for 24 weeks was associated with clinically meaningful benefits beyond reduction in headache days; including reductions in headache severity and headache-related impact, and improved quality of life. While 45% of patients met responder criteria for monthly headache days, over 70% had clinically meaningful improvements on at least one outcome measure.Trial RegistrationClinicalTrials.gov identifier, NCT00156910 (PREEMPT 1) and NCT00168428 (PREEMPT 2)

Chronic migraine (CM) is the ultimate and most burdensome form of the transformation from episodic migraine (EM), called chronification. The mechanism behind migraine chronification is poorly known and difficult to explore as CM has the same spectrum of pathogenesis as EM and the EM-CM transition is bidirectional. Central sensitization (CS) is a key phenomenon in migraine: its mechanisms include disturbed neural plasticity, which is the ability of the nervous system to adapt to endo- and exogenous changes. Cutaneous allodynia, a maker of central sensitization, may be an easy-to-determine marker of the EM-CM transition. Pituitary adenylate cyclase-activating peptide, a pro-inflammatory, vasodilatory and pain-producing neuropeptide, which has been proposed as an alternative to CGRP target in migraine, was shown to improve CS by regulating synaptic plasticity in the trigeminal nucleus caudalis in CM rats. Oxytocin and its receptor were found to influence CS through modulating synaptic plasticity in CM mice. Similar results were obtained for ephrin type-B receptor and its ligands. These and other studies suggest that neural plasticity may be important in CM pathogenesis. Still, its involvement in migraine chronification requires further studies which should include patients/animals with EM and CM. In this narrative/hypothesis paper, we review the current literature on the molecular mechanisms of CM pathogenesis and try to link them with neural plasticity and central sensitization to support the hypothesis that it is a key element in migraine chronification.