Balance alterations are associated with neck pain and neck muscle endurance in migraine.

BACKGROUND: Migraine patients may present with both cervical and balance dysfunctions. The neck plays an important role in balance by providing substantial proprioceptive input, which is integrated in the central nervous system and influences the balance control systems. Whether balance and neck dysfunctions are associated in patients with migraine is still to be explored. OBJECTIVES: This study aimed to assess the association between the sensory organization test of balance with neck pain features, cervical strength, endurance, and range of motion in patients with migraine. METHODS: Sixty-five patients with migraine underwent the sensory organization test assessed with the Equitest-Neurocom® device. Maximum voluntary isometric contraction, cervical flexion and extension range of motion, and cervical flexor and extensor endurance were assessed. In addition, the features of migraine and neck pain were collected. Patients were dichotomized according to cut-off scores of balance performance and the association between outcomes were explored. RESULTS: Patients with reduced balance performance presented a higher frequency of migraine (p = 0.035), a higher frequency of aura (p = 0.002), greater neck pain intensity (p = 0.013), and decreased endurance of cervical flexors (p = 0.010) and extensors (p < 0.0001). The total balance score was correlated with age (r = -0.33; p = 0.007), migraine frequency (r = -0.29; p = 0.021), neck pain intensity (r = -0.26; p = 0.038), and endurance of the cervical flexors (r = 0.39; p = 0.001) and extensors (r = 0.36; p = 0.001). Migraine frequency, neck pain intensity, and endurance of the cervical flexors can predict 21% of the sensory organization test variability. CONCLUSION: Neck pain features and endurance of the cervical muscles are related to reduced balance performance in patients with migraine. These results shed light to a better understanding of balance alterations in migraine patients.

White Matter Lesions Identified by Magnetic Resonance in Women with Migraine: A Volumetric Analysis and Clinical Correlations.

BACKGROUND: Repeated migraine attacks and aura could independently cause structural changes in the central nervous system. Our research aims to study the correlation of migraine type, attack frequency, and other clinical variables with the presence, volume and localization of white matter lesions (WML), in a controlled study. METHODS: Sixty volunteers from a tertiary headache center were selected and divided equally into four groups: episodic migraine without aura (MoA), episodic migraine with aura (MA), chronic migraine (CM) and controls (CG). Voxel-based morphometry techniques were used to analyze WML. RESULTS: There were no differences in WML variables between groups. There was a positive correlation between age and the number and total volume of WMLs, which persisted in the comparison categorized by size and brain lobe. Disease duration was positively correlated with the number and total volume of WML, and when controlled by age, the correlation maintained significance only for the insular lobe. Aura frequency was associated with frontal and temporal lobe WMLs. There was no statistically significant correlation between WML and other clinical variables. CONCLUSION: Migraine overall is not a risk factor for WML. Aura frequency is, however, associated with temporal WML. Disease duration, in adjusted analyses that account for age, is associated with insular WML.

Migraine and balance impairment: Influence of subdiagnosis, otoneurological function, falls, and psychosocial factors.

OBJECTIVE: To assess the balance sensory organization among patients with migraine, considering the influence of migraine subdiagnosis, otoneurological function, falls, and psychosocial factors. BACKGROUND: Migraine has been associated with vestibular symptoms and balance dysfunction; however, neither comprehensive balance assessment nor associated factors for greater impairment have been addressed thus far. METHODS: Patients from a tertiary headache clinic with a diagnosis of episodic migraine with aura (MWA), without aura (MWoA), and chronic migraine (CM) were included for this cross-sectional study (30 patients per group). Thirty headache-free controls (CG) were recruited. Participants underwent a comprehensive evaluation protocol, including the Sensory Organization Test (SOT) and otoneurological examination. Questionnaires about fear of falls, dizziness disability, and kinesiophobia were administered. RESULTS: All migraine groups presented lower composite SOT scores than controls (CG: 82.4 [95% confidence interval (CI): 79.5-85.3], MWoA: 76.5 [95% CI: 73.6-79.3], MWA: 66.5 [95% CI: 63.6-69.3], CM: 69.1 [95% CI: 66.3-72.0]; p < 0.0001). Compared to controls and to MWoA, MWA and CM groups exhibited greater vestibular (CG: 75.9 [95% CI: 71.3-80.4], MWoA: 67.3 [95% CI: 62.7-71.8], MWA: 55.7 [95% CI: 51.2-60.3], CM: 58.4 [95% CI: 53.8-63.0]; p < 0.0001) and visual functional impairment (CG: 89.6 [95% CI: 84.2-94.9], MWoA: 83.2 [95% CI: 77.9-88.6], MWA: 68.6 [95% CI: 63.3-74.0], CM: 71.9 [95% CI: 66.5-77.2], p < 0.0001). Fall events during the assessment were documented more often among patients with migraine (CG: 0.0, interquartile range [IQR], 0.0, 0.0); MWoA: 1.0 [IQR: 1.0, 1.0], MWA: 2.0 [IQR: 1.8, 4.3], CM: 1.0 [IQR: 1.0, 2.0]; p = 0.001). The SOT scores correlated with fear of falls (r = -0.44), dizziness disability (r = -0.37), kinesiophobia (r = -0.38), and migraine frequency (r = -0.38). There was no significant influence of the vestibular migraine diagnosis in the study outcomes when used as a covariate in the analysis (composite score [F = 3.33, p = 0.070], visual score [F = 2.11, p = 0.149], vestibular score [F = 1.88, p = 0.172], somatosensory score [F = 0.00, p = 0.993]). CONCLUSIONS: Aura and greater migraine frequency were related to falls and balance impairment with sensory input manipulation, although no otoneurological alterations were detected. The diagnosis of vestibular migraine does not influence the balance performance. The vestibular/visual systems should be considered in the clinical examination and treatment of patients with migraine.

Associated Factors of Attention-Deficit/Hyperactivity Disorder Diagnosis and Psychostimulant Use: A Nationwide Representative Study.

BACKGROUND: Connections between epidemiological findings and children's and adolescents' mental health policies have not been properly made in Brazil, and such nationwide studies are scarce. This epidemiological study (1) estimated the prevalence and predictors of parent-reported attention-deficit/hyperactivity disorder (ADHD) (ADHD-report), (2) estimated the probable diagnosis and risk of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 5th edition, criteria (ADHD-probable), and (3) estimated current psychostimulant use (ADHD-pst) in a representative nationwide sample of Brazilian school-aged children and adolescents. METHODS: Data were obtained from 7114 school-aged children (49.9% boys) from 87 cities in 18 Brazilian states. Parents and teachers were interviewed using psychometrically sound questionnaires. Data and codes are available. RESULTS: The prevalence of ADHD-report, ADHD-probable, and ADHD-pst were 7.1%, 3.9%, and 1.9%, respectively. The agreement was low between ADHD-probable and ADHD-report (22.6%) and between ADHD-report and ADHD-pst (15.6%). Logistic regression revealed that predictors of all three categories were male gender (odds ratio [OR] = 1.71, 2.32, and 1.96, respectively), divorced parents (OR = 1.47, 1.65, and 1.68, respectively), and below-expectation school performance (OR = 3.1, 13.74, and 3.95, respectively). Socioeconomic status was a significant predictor of ADHD-report, and participants from lower classes were less frequently diagnosed with ADHD than their peers from upper classes (OR = 0.57, 95% confidence interval = 0.37-0.88, P = 0.012). CONCLUSIONS: The present findings provide an accurate description of ADHD in Brazil. We suggest disparities in agreement between report, risk, and psychostimulant use among children and adolescents and discrepancies between socioeconomic classes concerning the prevalence of an ADHD diagnosis.

Is kinesiophobia related to fear of falling, dizziness disability, and migraine disability in patients with migraine?

INTRODUCTION: Kinesiophobia is a common symptom associated with high disability, and has been observed in patients with migraine. However, the association between kinesiophobia and clinical factors in this population is unknown. OBJECTIVE: To assess the fear of falling, dizziness disability, and migraine disability in patients with migraine, considering the presence of kinesiophobia. METHODS: Eighty patients with migraine completed the Tampa Scale for Kinesiophobia and were divided into two groups according to the questionnaire cutoff point: migraine without kinesiophobia (MoK, n = 39) and migraine with kinesiophobia (MK, n = 41). Fear of falling, dizziness disability, and migraine disability were assessed in both groups using validated questionnaires. RESULTS: The MK group presented higher scores on dizziness disability, fear of falling, and migraine disability compared to the MoK (p < .05). Kinesiophobia can explain 29% of the variance in dizziness disability and 18% of migraine disability. Both kinesiophobia and the presence of dizziness can explain 14% of fear of falling variability. Also, kinesiophobia is associated with the risk of presenting fear of falling (Prevalence Ratio = 2.4, p = .012), and migraine disability (Prevalence Ratio = 2.6, p = .01). CONCLUSION: The presence of kinesiophobia should be considered in clinical practice when evaluating migraine, as it is associated with increased levels of fear of falling, dizziness disability, and migraine disability.

Migraine With Aura Is Related to Delayed Motor Control Reaction and Imbalance Following External Perturbations.

Background: It is evidenced that migraineurs present balance deficits. However, the balance recovery following unexpected ground perturbations, which reflect conditions of everyday activities, has not been investigated in this population. Aim: We aimed to assess the reactive postural responses among patients with migraine with and without aura, chronic migraine, and controls. We further aimed to assess the factors associated with greater self-report of falls. Methods: Ninety patients diagnosed by headache specialists were equally classified into three migraine subgroups according to the presence of aura and chronic migraine. Thirty controls were also recruited. All participants underwent the motor control test (MCT) and adaptation test (ADT) protocols of dynamic posturography tests (EquiTest®, NeuroCom, USA). Clinical and headache features and information on falls in the previous year, fear of falling, and vestibular symptoms were also assessed. Results: Patients with aura presented a greater sway area in most of the MCT conditions than the other three groups (p = 0.001). The aura group also presented delayed latency responses after perturbations compared with controls and patients without aura (p < 0.03). In the ADT, a greater sway area was observed in patients with aura than in groups without aura, chronic migraine, and controls (p < 0.0001). The MCT and ADT sway area, the frequency of aura, and the fear of falling explained 46% of the falls in the previous 12 months. Conclusion: Patients with aura exhibited greater delay and sway area after unexpected ground perturbations than controls and other migraine subgroups, which are related to the reported number of falls.

Effects of fremanezumab in patients with chronic migraine and comorbid depression: Subgroup analysis of the randomized HALO CM study.

OBJECTIVE: To evaluate the efficacy of fremanezumab in patients with chronic migraine (CM) and moderate to severe depression. BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has been approved for the preventive treatment of migraine in adults. CM and depression are highly comorbid. METHODS: The 12-week, Phase 3 HALO trial randomized patients with CM to fremanezumab quarterly (675 mg/placebo/placebo), fremanezumab monthly (675/225/225 mg), or placebo. Post hoc analyses evaluated the effects of fremanezumab in patients with moderate to severe depression (baseline 9-item Patient Health Questionnaire sum score ≥10) on monthly number of headache days of at least moderate severity; monthly migraine days; Patient Global Impression of Change (PGIC); 6-item Headache Impact Test (HIT-6) scores; and depression. RESULTS: For the 219/1121 (19.5%) patients with moderate to severe depression at baseline, fremanezumab was associated with a significant reduction in monthly number of headache days of at least moderate severity for active treatment versus placebo (least-squares mean change ± standard error for quarterly dosing: -5.3 ± 0.77; for monthly dosing: -5.5 ± 0.72; and for placebo: -2.2 ± 0.81; both p < 0.001). More patients achieved a ≥50% reduction in headache days of at least moderate severity with fremanezumab (quarterly: 31/78 [39.7%]; monthly: 39/96 [40.6%]) than placebo (9/67 [13.4%]; both p < 0.001). Compared with placebo, fremanezumab improved PGIC and HIT-6 scores. CONCLUSIONS: Fremanezumab demonstrated efficacy in the preventive treatment of CM and reduced headache impact in patients with comorbid depression.

Resilience and vulnerability in adolescents with primary headaches: A cross-sectional population-based study.

BACKGROUND: A scarcity of studies on the role of resilience resources (RRs) and vulnerability risk (VR) in children and adolescents with primary headache hampers the development of a risk-resilience model for pediatric headaches. OBJECTIVE: To examine the extent to which headache frequency and diagnosis are associated with RRs and VR and explore possible predictors of low RRs and high VR in a cross-sectional population-based study in adolescents. METHODS: This is a cross-sectional population study conducted in a small city in Brazil (Delfinópolis). Consents and analyzable data were obtained from 339/378 adolescents (89.7%). RRs and VR were assessed using the validated Brazilian version of the Resiliency Scales for Children and Adolescents, completed by the adolescents. Parents filled a structured questionnaire assessing sociodemographic and headache characteristics, as well as the Brazilian-validated version of the Strengths and Difficulties Questionnaire added to the impact supplement to evaluate the adolescent's psychosocial adjustment skills. Teachers completed a structured questionnaire about the students' school performance. RESULTS: A higher frequency of headache was associated with lower RRs (F3,335  = 2.99, p = 0.031) and higher VR (F3,335  = 4.05, p = 0.007). Headache diagnosis did not significantly influence the risk of having lower RRs or higher VR. In the exploratory analyses, females (OR 3.07; 95% CI: 1.16-9.3) and individuals with psychosocial adjustment problems (OR 7.5; 95% CI: 2.51-22.4) were predictors of low RRs, and prenatal exposure to tobacco (OR 5.6; 95% CI: 1.57-20.9) was a predictor of high VR in adolescents with primary headache. CONCLUSIONS: The risk of low RRs and high VR was associated with a higher headache frequency, but not with headache diagnosis. These findings may contribute to the development of a risk-resilience model of headaches in the pediatric population and help identify novel targets and develop effective resources for successful interventions.

The Influence of Photophobia on Postural Control in Patients With Migraine.

BACKGROUND: People with migraine exhibit postural control impairments. These patients also have an increased light sensitivity due to the disease, and it remains during the headache-free period. It is currently unknown if increased lighting levels can alter the balance control, especially in individuals with visual hypersensitivity, such as migraineurs. This study aimed to assess the balance and photophobia of women with migraine and non-headache controls under different light conditions. METHODS: This cross-sectional study consisted of 14 women with migraine (mean ± SD 30.6 ± 8.1 years old) and 14 women without any kind of headache (mean ± SD 27.2 ± 2.8 years old) screened from a tertiary headache clinical hospital and the local community. Quiet standing balance was evaluated during bipodal and unipodal support, under 3 light conditions: ambient (AMB) - 270 lx, visual discomfort threshold (VDT) - 400 lx, and intense visual discomfort (IVD) - 2000 lx. Sway area of the center of pressure was processed and compared between groups. The association of migraine with the risk of presenting a greater imbalance in the discomfort lighting conditions was verified. RESULTS: Compared to the non-headache controls, the migraine group presented greater sway area in bipodal stance under the 3 light conditions (mean difference (95% CI)): AMB 0.81 cm2 (0.19 to 1.43), P = .011; VDT 3.17 cm2 (0.74 to 5.60), P = .001; IVD 5.56 cm2 (2.75 to 8.37), P < .0001. Within-subject analysis showed increased sway area in bipodal stance among all lighting conditions for the migraine group only (mean difference (95% CI)): VDT-AMB 2.20 cm2 (0.23 to 4.18), P = .024; IVD-AMB 4.50 cm2 (2.38 to 6.62), P < .0001, IVD-VDT 2.29 cm2 (0.57 to 4.01), P = .005. The Prevalence Ratio (PR) analysis showed that migraine was associated with the risk of presenting greater imbalance in both bipodal and unipodal standing conditions for both VDT (PR value (95% CI) - bipodal: PR = 4.00 (1.02 to 15.59), P = .045; unipodal: PR = 4.00 (1.43 to 11.15), P = .008), and the IVD (bipodal: PR = 3.33 (1.13 to 9.58), P = .025; unipodal: PR = 5.50 (1.48 to 20.42), P = .010) lighting conditions. CONCLUSION: Photophobia might be a disturbing factor that worsens the balance of patients with migraine during the quiet standing posture.

ADHD Is Comorbid to Migraine in Childhood: A Population-Based Study.

Objective: Recurrent headaches and ADHD are prevalent in the pediatric population. Herein, we assess if ADHD is comorbid to headaches overall, to headache subtypes (e.g., migraine), and to headache frequency. Method: Informed consent and analyzable data were obtained for 5,671 children aged 5 to 12 years (65.9% of the target sample). Parents and teachers were interviewed using validated questionnaires based on the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5). Relative risks were modeled using univariate and multivariate analyses. Results: As contrasted to nonheadache controls, the prevalence of ADHD was significantly higher in children with migraine (p < .001) but not in those with tension-type headaches. In children with migraine, risk of ADHD increased as a function of headache frequency (p < .05). Conclusion: Migraine and frequent migraine are comorbid to ADHD. Future studies should focus on the impact of the association on the burden to the children and their families.

Impact of chronic migraine attacks and their severity on the endogenous µ-opioid neurotransmission in the limbic system.

OBJECTIVE: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous µ-opioid neurotransmission. BACKGROUND: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. METHODS: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the µ-opioid receptor availability and the clinical data. RESULTS: µOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower µOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower µOR BPND values indicate either a decrease in µOR concentration or an increase in endogenous µ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in µOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). CONCLUSIONS: Increased endogenous µ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous µ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

Fremanezumab as a preventive treatment for episodic and chronic migraine.

Introduction: The importance of calcitonin gene-related peptide (CGRP) in migraine pathogenesis is well established. Fremanezumab is a humanized IgG2a monoclonal antibody that binds to CGRP. Areas covered: In this paper, we review the development of fremanezumab, from early development into approval. The authors focus on the efficacy and safety of fremanezumab in both migraine stages. The authors highlight studies conducted in special populations and focus on unique aspects of its development, as well as on clinical pearls supported by the data. Expert opinion: Fremanezumab was shown to be effective in episodic and chronic migraine, with a monthly and quarterly dose of administration, as monotherapy and add-on therapy. As with other monoclonal antibodies, the anti-CGRP onset of action was remarkably quick, and the effect seems to be maintained over time. No overt safety concerns emerged from the clinical studies, although long-term surveillance is necessary.

Painful Temporomandibular Disorder Is Associated With Migraine in Adolescents: A Case-Control Study.

Some types of primary headaches and temporomandibular disorders (TMD) are comorbid in adults and highly prevalent in adolescents. Herein, we investigated the association of painful TMD with specific headache diagnoses (migraine, tension-type headache) and with headache frequency in adolescents. We also explored the association of headache diagnosis with the number of painful sites in the trigeminal area. Painful TMD was assessed using the Research Diagnostic Criteria for TMD. We conducted a case-control study of adolescents from 13 to 15 years old who were recruited among participants in a previous epidemiologic study conducted in Araraquara, SP, Brazil. Headaches were classified according to the second edition of the International Classification for Headache Disorders. Logistic, multinomial logistic and linear regression models were used to test associations. Of 149 individuals, 55.7% presented painful TMD. Adolescents with painful TMD (cases) were more likely to have migraine compared with those without TMD (controls; odds ratio = 3.0, 95% confidence interval = 1.47-6.19, P = .033). Significant differences were not observed for probable tension-type headache (P = .307) or tension-type headache (P = .834). Painful TMD was also associated with an increase in headache frequency (linear-by-linear association = 8.051; P = .005). Only migraine was associated with a greater number of painful sites on palpation in the trigeminal area (P = .001). Migraine and frequency of headache were associated with painful TMD in adolescents. PERSPECTIVE: Migraine and headache frequency were strongly associated with painful TMD in adolescents, and causality must be determined. For now, the presence of 1 condition should raise suspicion of the other and warrants collaboration between orofacial pain specialists and neurologists.

The Effect of Beginning Treatment With Fremanezumab on Headache and Associated Symptoms in the Randomized Phase 2 Study of High Frequency Episodic Migraine: Post-Hoc Analyses on the First 3 Weeks of Treatment.

BACKGROUND: Migraine has a substantial impact on daily living, affecting productivity and quality of life for patients and their families. Patients frequently discontinue preventive medications in part because of a delay in headache and symptom relief due to the long dose titration procedures necessary for some migraine preventives. OBJECTIVE: To evaluate the efficacy of fremanezumab, a selective monoclonal CGRP ligand antibody, during the first 3 weeks of therapy in patients with high-frequency episodic migraine (HFEM) to relieve migraine headaches and associated symptoms and to reduce use of acute migraine medications. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, phase 2 study, patients with HFEM who met inclusion criteria and were 80% compliant with daily headache diary entry were randomized and treated once every 28 days for 3 months with either placebo or fremanezumab 225 or 675 mg. Compared to placebo, both doses of fremanezumab significantly reduced the primary endpoint of the HFEM study, change in the number of migraine days in month 3 relative to baseline. Herein, we performed post-hoc analyses to assess the efficacy of each dose during the first 3 weeks of treatment to reduce migraine headache parameters, associated migraine symptoms, and the consumption of acute migraine medications. RESULTS: The sample consisted of 297 study participants. Compared to placebo, decreases in migraine days were seen during the first week of therapy for both fremanezumab doses with least square mean (LSM) differences between fremanezumab 225 mg and placebo of -0.93 (95% CI: -1.36, -0.49) and between 675 mg dose and placebo of -1.02 (95% CI: -1.46, -0.58), both P < .0001. This benefit was maintained through the second week of therapy for the 225 and 675 mg doses, respectively, (-0.76 (95% CI: -1.11, -0.40) P < .0001, -.79 (95% CI: -1.15, -0.44) P < .0001) and the third week of therapy (-0.64 (95% CI: -0.97, -0.30) P = .0003 and -0.64 (95% CI: -0.98, -0.30) P = .0003). Likewise in the first week, patients recorded reductions in associated migraine symptoms such as nausea, vomiting, photophobia, and phonophobia, which continued through weeks 2 and 3. There were also reductions in days with acute medication use to treat migraine for the 225 and 675 mg fremanezumab doses compared to placebo. In the first week, LSM differences between 225 mg and placebo were -1.02 (95% CI: -1.39, -0.64) and between 675 mg and placebo were -1.06 (95% CI: -1.39, -0.64) P < .0001); for the second and third weeks (-1.01 (95% CI: -1.14, -0.55) P < .0001; -.90 (95% CI: -1.04, -0.44) P < .0001; -.91 (95% CI: -0.92, -0.34) P < .0001; and -.83 (95% CI: -0.84, -0.26) P = .0002), respectively. CONCLUSION: Fremanezumab treatment resulted in a rapid preventive response in patients with HFEM, with reductions seen in several headache parameters and migraine symptoms within the first week after therapy initiation and continuing during the second and third weeks. Patients also were able to rapidly reduce their use of acute medications to treat migraine attacks. The trial is registered at Clinicaltrials.gov as NCT02025556.

Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials.

BACKGROUND: In phase 2 and 3 studies, fremanezumab, a monoclonal CGRP antibody, was an effective preventive treatment for high-frequency episodic migraine (HFEM) and chronic migraine (CM). OBJECTIVE: Post-hoc analyses evaluated population-wise 50%, 75% and 100% responder rates, and the extent to which individual responders sustained a 50%, 75% and 100% reduction in migraine days, moderate-to-severe (M/S) headache days and days of acute medication use during all three treatment months of the fremanezumab phase 2 studies. DESIGN/METHODS: HFEM patients received either placebo or three once-monthly injections of 225 mg or 675 mg. CM patients received either placebo or three once-monthly injections of 900 mg, or an initial loading dose of 675 mg and subsequent injections of 225 mg. Patients reported headache-related data daily using an electronic diary. RESULTS: In the HFEM study, the percent of patients on fremanezumab doses 225 mg and 675 mg were greater compared to the percent of placebo patients with sustained 50% reduction in migraine days (39% and 35% vs. 10% for placebo, both p < 0.0001), M/S headache days (36% and 38% vs. 16% placebo, p = 0.0017 and p = 0.0007 respectively), and acute medication use days (36% and 27% vs. 8% placebo, p < 0.0001 and p = 0.0003). Likewise, although there were fewer patients with sustained 75% reduction, there were increases in the percent of patients on fremanezumab 225 mg and 675 mg in the HFEM study relative to placebo patients in migraine days (19% and 11% vs. 3% placebo, p = 0.0002 and p = 0.0176), M/S headache days (19% and 15% vs. 2% placebo, p = 0.0001 and p = 0.0011) and days of acute medication use (16% and 8% vs. 2% placebo, p = 0.0005 and p = 0.0377). In the CM study, there were increases in the percent of patients on fremanezumab 675/225 mg and 900 mg with 50% sustained reduction in M/S headache days (32% and 40% vs. 15% placebo, p = 0.0058 and p = 0.0002) and days of acute medication use (26% and 22% vs. 11% placebo, p = 0.0098 and p = 0.0492). There were also increases in the percent of patients on fremanezumab 675/225 mg and 900 mg compared to patients on placebo with 75% sustained reduction in M/S headache days (10% and 13% vs. 3%, p = 0.0665 and p = 0.0203). Few patients had 100% sustained reductions in these parameters in either study. CONCLUSIONS: Post-hoc results must be interpreted with caution; nonetheless, a statistically significant percentage of patients who initially responded to fremanezumab within 1 month sustained this response over the subsequent 2 months. Sustained reduction in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments. Trials are registered as http://clinical trials.gov as NCT02025556 and NCT02021773.

Presence of vestibular symptoms and related disability in migraine with and without aura and chronic migraine.

OBJECTIVE: To assess the presence and handicap due to vestibular symptoms in three subgroups of patients with migraine and controls. METHODS: Women between 18-55 years old were diagnosed by headache specialists and stratified as migraine with aura (n = 60), migraine without aura (n = 60), chronic migraine (n = 60) and controls (n = 60). Information regarding demographics, headache and vestibular symptoms were collected in this cross-sectional study. The self-perceived handicap related to vestibular symptoms was assessed through the Dizziness Handicap Inventory questionnaire. RESULTS: A total of 85% of women with migraine with aura and chronic migraine had vestibular symptoms contrasted to 70% of the migraine without aura group ( p < 0.05), and 12% of the control group reported symptoms ( p < 0.0001). Patients with migraine exhibited greater Dizziness Handicap Inventory scores than controls ( p < 0.001); and migraine with aura and chronic migraine groups reached greater scores than migraine without aura ( p < 0.01). Presence of migraine is associated with a greater risk of vestibular symptoms (migraine without aura: 5.20, migraine with aura: 6.60, chronic migraine:6.20, p < 0.0003) and with a greater risk of moderate-to-severe handicap (migraine without aura: 20.0, migraine with aura: 40.0, chronic migraine: 40.0, p < 0.0003). The presence of aura and greater migraine frequency adds to the risk of any handicap (migraine with aura: 1.9, chronic migraine: 1.7, p < 0.04) and to the risk of moderate-to-severe handicap (migraine with aura: 2.0, chronic migraine: 2.0, p < 0.0003). Migraine aura, intensity and frequency predict 36% of the dizziness handicap. CONCLUSION: The prevalence of vestibular symptoms is increased in migraine during and between headache attacks, particularly in migraine with aura and chronic migraine along with an increased handicap due to those symptoms. Vestibular symptoms among subgroups of migraine should be considered when evaluating the functional impact of migraine.

From LBR-101 to Fremanezumab for Migraine.

Calcitonin gene-related peptide (CGRP) is a neuropeptide of importance in migraine pathogenesis. Its central role in migraine was proven pharmacologically by the development of CGRP receptor antagonists. Monoclonal antibodies targeting CGRP or its receptor are effective in the preventive treatment of episodic and chronic migraine and are considered potential breakthroughs in their treatment. Fremanezumab (previously known as TEV-48125, LBR-101, or RN-307) is a humanized IgG2a monoclonal antibody that binds to CGRP. The development of this antibody validated the role of CGRP in chronic migraine and the drug has been recently approved in the US by the FDA, while it continues to be reviewed by other regulatory agencies. Herein we provide an in-depth review of its development. We start by summarizing its in vitro and in vivo pharmacology, and the phase I studies. We then review the late-stage clinical development, with a focus on its efficacy, safety, similarities, and uniqueness relative to other CGRP antibodies. We close by discussing lessons learned on the mechanisms of migraine and areas for future development and exploration.

Fremanezumab for preventive treatment of migraine: Functional status on headache-free days.

OBJECTIVE: To evaluate the effect of fremanezumab on the functional status on headache-free days in phase 2 episodic migraine (EM) and chronic migraine (CM) studies. METHODS: Functional status data were collected prospectively via the electronic headache diary on all headache-free days by patients answering questions regarding work/school/household chore performance, speed of work completion, concentration, and feeling of fatigue. Individuals with EM receiving monthly doses of fremanezumab 225 mg (n = 96) or 675 mg (n = 97) or placebo (n = 104) were compared. Individuals with CM receiving fremanezumab 675 mg followed by monthly 225 mg (n = 88) and 900 mg (n = 86) were also independently compared to those receiving placebo (n = 89). RESULTS: In patients with EM, compared to patients receiving placebo, those receiving fremanezumab experienced an increased number of headache-free days with normal function in work/school/household chore performance and concentration/mental fatigue measures compared to their baseline over the entire treatment period (all p < 0.005). An increased number of headache-free days with normal functional performance for some measures was also found in the CM group in those treated with fremanezumab. CONCLUSION: There was an increased number of headache-free days with normal functional performance on all measures for the patients with EM and some measures for patients with CM in the fremanezumab-treated groups. Further research is required to confirm these findings in a prospective study and to clarify the underlying mechanism(s). CLINICALTRIALSGOV IDENTIFIER: NCT02025556 and NCT02021773. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with migraine, fremanezumab increases normal functional performance on headache-free days.