Evaluating patient and family preferences for acute and preventive pediatric headache treatment.

OBJECTIVE: To describe acute and preventive treatment preferences among youth with migraine and their parents/guardians, and to describe the degree of youth-parent/guardian preference agreement. BACKGROUND: Headache disorders are common in youth, but little is known about patient and family preferences for headache treatments and outcomes. METHODS: In this cross-sectional survey, a headache treatment preferences questionnaire was co-created with stakeholders, piloted, and distributed to consenting youth with migraine aged 9-18 years and parents/guardians at a tertiary care headache clinic in western Canada. Response data were summarized for youth and parents/guardians separately, and agreement rates within a youth-parent/guardian pair were compared to a hypothesized agreement rate of 80% for the primary questionnaire items. RESULTS: Seventy-two youth and n = 94 parents/guardians participated, with n = 63 in youth-parent/guardian pairs. Freedom from pain and rapid relief, and reducing pain severity and headache frequency were top acute and preventive treatment priorities, respectively. More than 90% (69/72) agreed that ≥ 50% reduction in headache frequency was a good target. For both acute and preventive interventions, swallowed pill-based options were most often selected as the preferred first-line treatment, with neuromodulation selected as the preferred second-line treatment. The level of agreement within youth-parent/guardian pairs on preferred treatment modalities was lower than hypothesized for acute (63% [40/63], 95% confidence interval [CI] = 52-75%, χ2 = 10.73, p = 0.001) but not for preventive treatment (73% [46/63], 95% CI = 62-84%, χ2 = 1.92, p = 0.166). Regarding which treatment modalities were perceived as most effective, youth-parent agreement was lower than hypothesized for both acute (48% [30/63], 95% CI = 35-60%, χ2 = 41.29, p < 0.001) and preventive treatment (46% [29/63], 95% CI = 34-58%, χ2 = 45.43, p < 0.001). CONCLUSION: Youth and family preferences aligned qualitatively, but sometimes diverged quantitatively, from typical clinical trial outcomes. The level of agreement within youth-parent/guardian pairs on treatment preferences and perceptions was low. Clinicians should consider both perspectives as they may be divergent.

Headache alleviation with nasal irrigation following endoscopic endonasal surgery for pituitary adenomas.

BACKGROUND: Headache is a common occurrence after endoscopic endonasal surgery (EES) for pituitary adenomas and significantly impacts the quality of life of patients. This study aims to investigate the effectiveness of nasal irrigation in relieving postoperative headache after EES. METHODS: A retrospective analysis was conducted on a cohort of 101 patients (Cohort I) who underwent EES for pituitary adenomas to explore the risk factors associated with postoperative headache. Another cohort of 72 patients (Cohort II) who received adjuvant nasal irrigation following surgery was enrolled for further analysis. The Headache Impact Test (HIT-6) was used to score the severity of headache, and patients with a HIT score > 55 were classified as having headache. RESULTS: In Cohort I, 21.78% of patients experienced headache one month after EES, which decreased to 5.94% at the three-month follow-up. Multivariate analysis revealed that postoperative nasal sinusitis (OR = 3.88, 95%CI 1.16-13.03, p = 0.028) and Hardy's grade C-D (OR = 10.53, 95%CI 1.02-109.19, p = 0.049) independently predicted the presence of postoperative headache at one month. At the three-month follow-up, patients with sinusitis had higher HIT-6 scores compared to those without sinusitis (44.43 ± 9.78 vs. 39.72 ± 5.25, p = 0.017). In Cohort II, the incidence of sinusitis at three months was significantly lower than that in Cohort I (p = 0.028). Importantly, both the incidence of headache and HIT-6 scores in Cohort II were significantly lower than those in Cohort I at the one- and three-month follow-ups. CONCLUSIONS: Postoperative sinusitis is an independent risk factor for the development of headache following EES for pituitary adenomas. Prophylactic nasal irrigation helps relieve postoperative headache, possibly by preventing the occurrence of sinusitis.

Can temporomandibular disorder symptoms and headaches be prevented in 13- to 15-year-old girls by information provided in a school setting?

OBJECTIVE: Temporomandibular disorders (TMD) may develop, especially among girls, during the adolescence period. The aim of this study was to study if information and advice in a school setting could prevent development of TMD symptoms and headaches during the early teenage period. METHODS: Thirteen-year-old girls, at 19 upper elementary schools were invited to participate in a study with structured information about the jaw system, TMD symptoms and risk factors, as well as advice how to manage risk factor and TMD. Six hundred and fifty-one girls enrolled, of which 507 girls were followed for 2-2.5 years. Half received information on three occasions (cases), and the other half served as controls. Included in the analysis of incidence of TMD symptoms were those without frequently occurring TMD symptoms (not including headaches) at baseline (n = 396) and included in the analysis of incidence of headaches were those without frequent headaches at baseline (n = 297). RESULT: The 2-year incidence of TMD symptoms was significantly lower in the information cohort (19%) compared to the controls (28%) (p = .03). The 2-year incidence of headaches was lower among those who were allocated to information (30%) compared to controls (40%), but the difference was not statistically significant (p = .099). Cases who had headaches at baseline reported a significantly lower prevalence at follow-up compared to controls (p = .03). CONCLUSION: Standardized information in school settings can prevent development of TMD symptoms and headaches among young girls.

[Non-medical Approaches to Headache Prevention: What is the Evidence?] / "Nicht-medikamentöse Verfahren in der Kopfschmerzprophylaxe, was ist die Evidenz?".

Primary headaches can be prevented by medication, exercise, behavioral therapy, or lifestyle changes. It is important to note that if medication is used for prophylaxis, non-drug approaches should also be recommended as a complement. Patients often wish to address their headaches without medication. Except for cognitive behavioral therapy and biofeedback, the evidence for nonmedication approaches to headache management has not been definitively established. This article reviews the current literature on the evidence for endurance exercise, relaxation exercises, physical therapy, lifestyle factors, and complementary procedures. For tension-type headache, there is an increasing number of studies reporting positive results from physical therapy; long-term follow-up, however, are still pending. Aerobic endurance exercise has the best evidence as a measure for prevention of migraine. However, other methods can also be used.

Effect of surgical mask and N95 respirator mask use on cerebrovascular reactivity.

Background and purpose:

Face masks are crucial parts of personal protective equipment (PPE) to reduce the risk of respiratory infections. The COVID-19 outbreak has increased healthcare workers’ use of face masks. This study aimed to evaluate changes in cerebrovascular response among healthcare workers using surgical and N95 respirator masks. 

90 healthcare workers: 30 wearing surgical masks, 30 wearing N95 respirators, and 30 without masks were included. After two-hour of face mask use, the baseline mean flow velocity (MFV) and the mean breath-holding index (BHI) of the bilateral middle cerebral arteries (MCAs) were evaluated with transcranial Doppler ultrasound. The presence of de-novo headache was recorded. BHI values ​​below 0.69 were evaluated as a sign of impaired cerebrovascular reactivity (CVR). 

The rate of de-novo headache was significantly higher in the N95 respirator mask group (p = 0.004). Compared to the control and surgical mask groups, the N95 respirator mask group had significantly lower values of the baseline MFV of the right MCA (p = 0.003 and p = 0.021, respectively) and mean BHI (p = 0.003 and p = 0.012, respectively). Still, only one N95 respirator mask user had a mean BHI value below 0.69.

Surgical masks did not signi­fi­cantly affect cerebral hemodynamics. Although N95 respirator mask use significantly decreased BHI values, the CVR is still within normal limits, and the development of de-novo headache is not directly associated with low CVR. 

The effect of local cold compresses for nitroglycerin-induced headache: An observational pretest-posttest study.

BACKGROUND: Nitroglycerin (NTG)-induced headache is the most common side effect of nitrate therapy and negatively affects the quality of life. AIMS: To assess the preventive and severity-reducing effect of cold compresses applied to the bilateral frontotemporal and occipital regions, where pain is most frequently experienced, for headache among individuals receiving intravenous NTG treatment. STUDY DESIGN: This research used an observational, two-group, pretest-posttest design and was completed from October 2020 to May 2021 in the coronary intensive care unit of a state hospital located in the north of Turkey. The first group in the research had cold compresses applied for 20 min with the aid of an applicator at the start of NTG infusion, while the second group had the same implementation when headache developed during infusion. RESULTS: Both groups were similar in terms of the demographic and clinical features of participants. In our study, more headache was observed in the group without local cold compresses at the start of infusion (53.3%) compared with the group with local cold compresses at the start of infusion (25.8%) (χ2  = 4.841, p = .028). In both groups, the heart rate, systolic and diastolic blood pressure values of patients significantly approached normal values after cold compresses. Patients with local cold compresses applied when headache developed had significantly different visual analog scale scores before (5.75) and after (2.00) the cold compresses application (z = 3.558, p = .000). CONCLUSION: At the beginning of the infusion, local cold compresses application may prevent NTG-induced headache in patients without headache, and local cold compresses applied when headache develops may reduce the severity of NTG-induced headache. RELEVANCE TO CLINICAL PRACTICE: Application of cold compresses immediately when treatment begins is recommended as a simple and effective practice with no side effects for patients receiving NTG treatment.

Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study).

BACKGROUND: Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM. METHODS: This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9-12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals. RESULTS: Sixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p < 0.05), MHDs (-9.4, p < 0.001), MAI (-5.7, p < 0.05; -11.1, p < 0.001), NRS (-3.1, p < 0.001; -2.5, p < 0.001), and MIDAS scores (-58.3, p < 0.05; -43.7; p < 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p < 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85-0.98, p = 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason. CONCLUSIONS: Fremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.

Reduction in the severity and duration of headache following fremanezumab treatment in patients with episodic and chronic migraine.

OBJECTIVE: To evaluate the impact of fremanezumab on the severity and duration of remaining migraine attacks in patients with chronic migraine (CM) or episodic migraine (EM). BACKGROUND: Fremanezumab is a fully humanized monoclonal antibody (IgGΔa) that selectively targets calcitonin gene-related peptide and is efficacious in reducing migraine frequency. METHODS: This exploratory post hoc analysis included data from three randomized, double-blind, 12-week, phase 3 studies (HALO CM, HALO EM, and FOCUS). In all three studies, patients with CM or EM were randomized 1:1:1 to receive subcutaneous quarterly fremanezumab (month 1/2/3: 675 mg/placebo/placebo), monthly fremanezumab (month 1/2/3: 675 mg [CM], 225 mg [EM]/225 mg/225 mg), or matched monthly placebo. Changes from baseline were evaluated in the proportion of headache days of at least moderate severity, peak severity of headache days, mean monthly headache hours (of any severity and at least moderate severity), and mean headache hours per headache day of any severity. RESULTS: A total of 2843 patients were randomized with 2823 patients included in the efficacy analyses across all studies (HALO CM, N = 1121; HALO EM, N = 865; FOCUS, N = 837). At study baseline, mean (standard deviation [SD]) monthly number of headache days rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 13.2 (5.5), 12.8 (5.8), and 13.3 (5.8) in HALO CM; 7.2 (3.1), 6.8 (2.9), and 6.9 (3.1) in HALO EM; and 12.4 (5.8), 12.7 (5.8), and 12.8 (5.9) in FOCUS. Patients experienced significant least-squares mean (LSM; 95% confidence interval) percent reductions from baseline in monthly number of headache days rated moderate or severe during the 12 weeks: HALO CM, quarterly fremanezumab, 34.5% (-39.8, -29.2) and monthly fremanezumab, 36.2% (-41.4, -31.0) vs. placebo, 19.6% (-20.0, -14.3); HALO EM, quarterly fremanezumab, 40.7% (-47.8, -33.5) and monthly fremanezumab, 43.4% (-50.4, -36.3) vs. placebo, 17.9% (-24.9, -11.0); and FOCUS, quarterly fremanezumab, 36.5% (-41.9, -31.1) and monthly fremanezumab, 38.6% (-44.0, -33.3) vs. placebo, 3.5% (-8.9, 1.8); all p < 0.0001. At study baseline, mean (SD) number of monthly headache hours rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 66.4 (58.8), 68.0 (53.9), and 68.5 (57.0) in HALO CM; 33.3 (25.4), 31.7 (23.7), and 31.6 (23.2) in HALO EM; and 59.2 (54.7), 64.3 (65.2), and 65.9 (70.2) in FOCUS. Significant reductions were observed in LSM (standard error) number of monthly headache hours of at least moderate severity: HALO CM, quarterly fremanezumab, 24.4 (2.5) and monthly fremanezumab, 26.4 (2.3) vs. placebo, 14.1 (2.5); HALO EM, quarterly fremanezumab, 14.5 (1.4) and monthly fremanezumab, 15.5 (1.3) vs. placebo, 8.1 (1.3); and FOCUS, quarterly fremanezumab, 16.8 (3.0) and monthly fremanezumab, 18.3 (3.0) vs. placebo, 2.3 (3.0); all p < 0.001. CONCLUSION: These analyses demonstrated that quarterly or monthly treatment with fremanezumab significantly reduced headache severity and duration in patients with CM or EM, including in patients with documented inadequate response to two to four prior migraine preventive medication classes.

Use of therapeutic caffeine in acute care postoperative and critical care settings: a scoping review.

BACKGROUND: Caffeine is the most utilised psychoactive drug worldwide. However, caffeine withdrawal and the therapeutic use of caffeine in intensive care and in the perioperative period have not been well summarised. Our objective was to conduct a scoping review of caffeine withdrawal and use in the intensive care unit (ICU) and postoperative patients. METHODS: PubMed, Embase, CINAHL Complete, Scopus and Web of Science were systematically searched for studies investigating the effects of caffeine withdrawal or administration in ICU patients and in the perioperative period. Areas of recent systematic review such as pain or post-dural puncture headache were not included in this review. Studies were limited to adults. RESULTS: Of 2268 articles screened, 26 were included and grouped into two themes of caffeine use in in the perioperative period and in the ICU. Caffeine withdrawal in the postoperative period increases the incidence of headache, which can be effectively treated prophylactically with perioperative caffeine. There were no studies investigating caffeine withdrawal or effect on sleep wake cycles, daytime somnolence, or delirium in the intensive care setting. Administration of caffeine results in faster emergence from sedation and anaesthesia, particularly in individuals who are at high risk of post-extubation complications. There has only been one study investigating caffeine administration to facilitate post-anaesthetic emergence in ICU. Caffeine administration appears to be safe in moderate doses in the perioperative period and in the intensive care setting. CONCLUSIONS: Although caffeine is widely used, there is a paucity of studies investigating withdrawal or therapeutic effects in patients admitted to ICU and further novel studies are a priority.

Prospective Double-Blinded Randomized Field-Based Clinical Trial of Metoclopramide and Ibuprofen for the Treatment of High Altitude Headache and Acute Mountain Sickness.

INTRODUCTION: High altitude headache (HAH) and acute mountain sickness (AMS) are common pathologies at high altitudes. There are similarities between AMS and migraine headaches, with nausea being a common symptom. Several studies have shown ibuprofen can be effective for AMS prophylaxis, but few have addressed treatment. Metoclopramide is commonly administered for migraine headaches but has not been evaluated for HAH or AMS. We aimed to evaluate metoclopramide and ibuprofen for treatment of HAH and AMS. METHODS: We performed a prospective, double-blinded, randomized, field-based clinical trial of metoclopramide and ibuprofen for the treatment of HAH and AMS in 47 adult subjects in the Mount Everest region of Nepal. Subjects received either 400 mg ibuprofen or 10 mg metoclopramide in a 1-time dose. Lake Louise Score (LLS) and visual analog scale of symptoms were measured before and at 30, 60, and 120 min after treatment. RESULTS: Subjects in both the metoclopramide and ibuprofen arms reported reduced headache severity and nausea compared to pretreatment values at 120 min. The ibuprofen group reported 22 mm reduction in headache and 6 mm reduction in nausea on a 100 mm visual analog scale at 120 min. The metoclopramide group reported 23 mm reduction in headache and 14 mm reduction in nausea. The ibuprofen group reported an average 3.5-point decrease on LLS, whereas the metoclopramide group reported an average 2.0-point decrease on LLS at 120 min. CONCLUSIONS: Metoclopramide and ibuprofen may be effective alternative treatment options in HAH and AMS, especially for those patients who additionally report nausea.

Empiric use of oxygen for acute atraumatic, unilateral, retro-orbital headaches.

This article describes a man who presented with a 2-week history of atraumatic, unilateral, retro-orbital cranio-facial pain, ipsilateral diaphoresis, and facial flushing. He was diagnosed with cluster headaches after a positive response to oxygen therapy. Early consideration for oxygen therapy in the acute setting should be considered in all patients with an acute, unilateral, retro-orbital headache.

Effect of the H1-antihistamine clemastine on PACAP38 induced migraine.

OBJECTIVE: To investigate the effect of the H1-antihistamine clemastine on the migraine-inducing abilities of pituitary adenylate cyclase activating peptide-38. METHODS: We conducted a double-blind, randomized, placebo controlled two-way cross-over study. Twenty migraine without aura patients were randomly allocated to receive bolus clemastine 2 mg (1 mg/ml) or bolus saline 2 ml intravenously over 2 min on two study days. Following each bolus injection, 10 pmol/kg/min of pituitary adenylate cyclase activating peptide-38 was administered intravenously over 20 min. We recorded migraine/headache characteristics every 10 min until 90 min after the start of infusion, and collected blood to investigate mast cell degranulation and the inflammation markers tryptase and tumor necrosis factor-alpha before and after infusion of pituitary adenylate cyclase activating peptide-38. RESULTS: After clemastine pretreatment, five out of 20 participants developed a migraine-like attack in response to a pituitary adenylate cyclase activating peptide-38 infusion compared to nine out of 20 after placebo pretreatment ( p = 0.288). Following clemastine pretreatment, 15 out of 20 participants reported headache in response to a pituitary adenylate cyclase activating peptide-38 infusion, whereas 19 out of 20 participants did so following placebo pretreatment ( p = 0.221). We found no difference in area under the curve 12 h for headache intensity between the two experimental days ( p = 0.481). We found no difference in area under the curve 180 min for tryptase ( p = 0.525) or tumor necrosis factor-alpha ( p = 0.487) between clemastine and placebo pretreatment days. CONCLUSION: H1-antihistamine, clemastine, failed to prevent migraine or headache after pituitary adenylate cyclase activating peptide-38 infusion, thus making a role for histamine release or mast cell degranulation in pituitary adenylate cyclase activating peptide-38-induced migraine less likely.

Hemodialysis-related headache and how to prevent it.

BACKGROUND AND PURPOSE: Hemodialysis (HD) may have some adverse effects on the nervous system. Headache is the most commonly reported neurological symptom amongst HD patients. Our aim was to determine the frequency, clinical characteristics and triggering factors of HD-related headache (HRH) and to evaluate preventive strategies for reducing HRH. METHOD: In all, 494 patients were included. Comparative controls (CC) were classified within the same patients without headache. Arterial systolic/diastolic blood pressure, blood urea nitrogen (BUN) and creatinine were correlated before/after one HD. The urea reduction ratio during the dialysis session was determined. RESULTS: A total of 175 patients (35.4%) with a mean age of 57.3 ± 15.7 years were diagnosed with HRH. HRH was more common in males (P < 0.001). Headache was started a mean of 2.90 ± 0.86 h after the HD. The common localization of pain was reported to be bifrontal in 41.7% (n = 73). The mean duration of headache was 6.22 ± 7.8 h, with a duration of ≤4 h reported by 64.0% of patients. The mean Visual Analog Scale score was 5.64 ± 2.05. The differences between pre/post-dialysis BUN values were 94.6 ± 31.1 in HRH patients and 86.8 ± 28.5 in the CC group (P = 0.006). The systolic blood pressure difference between the pre/post-dialysis measurements was 22.4 ± 16.5 mmHg in HRH patients and 12.8 ± 19.4 mmHg in CC(P < 0.001). Patients with HRH had significantly higher mean systolic and diastolic blood pressure pre-dialysis values (systolic, P = 0.002; diastolic, P < 0.001). The differences in systolic/diastolic blood pressure between pre/post-dialysis were higher in the HRH group (P < 0.001, P = 0.001, respectively). CONCLUSION: Regulating the frequency and timing of dialysis may provide better management in HRH with high BUN levels and high pre-dialysis blood pressure.

Non-Pharmacological Treatment for Primary Headaches Prevention and Lifestyle Changes in a Low-Income Community of Brazil: A Randomized Clinical Trial.

BACKGROUND: Primary headaches can be reduced by lifestyle changes, such as stress management and physical activity. However, access to programs focused on behavioral interventions is limited in underserved, poor communities. OBJECTIVES: We performed a randomized open-label clinical trial to test the therapeutic and behavioral effects of aerobic exercise, relaxation, or the combination of both, in individuals with primary headaches of a small, low-income community of the Brazilian Amazon. METHODS: Participants were screened from the riverine/rural population, and individuals with primary headache were included. We assessed clinical characteristics and physical activity levels. Interventions were delivery 3 times/week for 6 months. The primary outcome variable was changes in days with headache, while changes in duration of attacks, pain intensity, and physical activity levels were secondary outcomes variables. RESULTS: Seven hundred and ninety individuals were screened (15.3% of rural/riverine population). Seventy-four participants were randomly assigned to relaxation (n = 25), physical activity orientation program (n = 25), or both (n = 24) interventions. Intention to treat analyses showed all interventions as effective to reduce days with headaches and duration of attacks (both P < .01). Pain intensity was reduced only in relaxation and relaxation + physical activity groups (both P < .01). Physical activity levels increased only in the relaxation + physical activity group (P < .05). CONCLUSIONS: Non-pharmacological interventions such as physical activity and relaxation are effective for reducing headaches, while combining such interventions promote health behavior toward higher physical activity levels in low-income populations with primary headaches. CLINICAL TRIAL REGISTRATION NUMBER: SGPP 1544.

FORWARD Study: Evaluating the Comparative Effectiveness of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults With Chronic Migraine.

OBJECTIVE: To compare effectiveness of onabotulinumtoxinA and topiramate for chronic migraine (CM) prevention. BACKGROUND: The efficacy* of onabotulinumtoxinA and topiramate has been established in placebo-controlled randomized clinical trials (*defined as the benefit of treatment under ideal conditions). The effectiveness* of the 2 preventive treatments, however, has not been established (*the benefit of treatment under real-world conditions, representing a blend of efficacy and tolerability). METHODS: In this multicenter, randomized, parallel-group, post-authorization, open-label prospective study (FORWARD; ClinicalTrials.gov, NCT02191579), we randomized adults with CM (1:1) to onabotulinumtoxinA 155 U every 12 weeks for 3 cycles or topiramate "immediate release" 50-100 mg/day to week 36. Primary outcome measure was proportion of patients achieving ≥50% reduction in headache days (weeks 29-32). Missing values were imputed using baseline observation carried forward (BOCF) methodology. After 12 weeks, patients initially randomized to topiramate could cross over to onabotulinumtoxinA treatment. We monitored and recorded all adverse events (AEs). RESULTS: We enrolled 282 patients (onabotulinumtoxinA, n = 140; topiramate, n = 142) and 148 patients completed randomized treatment (onabotulinumtoxinA, n = 120 [86%]; topiramate, n = 28 [20%]). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, n = 7 [5%]; topiramate, n = 27 [19%]) and AEs (onabotulinumtoxinA, n = 5 [4%]; topiramate, n = 72 [51%]). Eighty topiramate patients crossed over to onabotulinumtoxinA. In the BOCF analysis, a significantly higher proportion of patients randomized to onabotulinumtoxinA experienced ≥50% reduction in headache frequency compared with those randomized to topiramate (40% [56/140] vs 12% [17/142], respectively; adjusted OR, 4.9 [95% CI, 2.7-9.1]; P < .001). OnabotulinumtoxinA was superior to topiramate in meeting secondary endpoints. In a post hoc analysis using observed data, the 50% responder rates at week 12 were 45.6% for onabotulinumtoxinA (n = 125) and 29.4% for topiramate (n = 109) (P = .015). AEs were reported by 48% (105/220) of onabotulinumtoxinA and 79% (112/142) of topiramate patients. Results were similar in those who crossed over to onabotulinumtoxinA. CONCLUSIONS: While using imputation methods of accounting for differences in discontinuation rates, we found onabotulinumtoxinA to have greater clinical utility than topiramate, largely because of tolerability issues associated with the latter and a relatively higher number of onabotulinumtoxinA patients remaining on treatment.

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.

A Randomized Trial of a Long-Acting Depot Corticosteroid Versus Dexamethasone to Prevent Headache Recurrence Among Patients With Acute Migraine Who Are Discharged From an Emergency Department.

STUDY OBJECTIVE: Migraine patients continue to report headache during the days and weeks after emergency department (ED) discharge. Dexamethasone is an evidence-based treatment of acute migraine that decreases the frequency of moderate or severe headache within 72 hours of ED discharge. We hypothesize that intramuscular methylprednisolone acetate, a long-acting steroid that remains biologically active for 14 days, will decrease the number of days with headache during the week after ED discharge by at least 1 day compared with intramuscular dexamethasone. METHODS: We conducted a randomized, blinded clinical trial comparing intravenous metoclopramide at 10 mg+intramuscular dexamethasone at 10 mg with intravenous metoclopramide at 10 mg+intramuscular methylprednisolone acetate at a dose of 160 mg for patients presenting to 2 different EDs with moderate or severe migraine. Outcomes were assessed by telephone with a standardized instrument. The primary outcome was number of days with headache during the week after ED discharge. Secondary outcomes were complete freedom from headache, without the necessity of additional headache medication for the entire week after ED discharge, and medication preference, as determined by asking the patient whether he or she would want to receive the same medication again. RESULTS: One hundred nine patients received dexamethasone and 111 received methylprednisolone acetate. We obtained primary outcome data from 101 dexamethasone patients and 106 methylprednisolone acetate patients. Dexamethasone patients reported 3.0 headache days and methylprednisolone acetate 3.3 headache days (95% confidence interval for rounded mean difference of 0.4 days: -0.4 to 1.1). Of 107 dexamethasone patients with analyzable data, 10 (9%) reported complete freedom from headache at 1 week versus 6 of 110 (5%) methylprednisolone acetate patients (95% confidence interval for difference of 4%: -3% to 11%). In the dexamethasone group, 76 of 101 (75%) patients would want the same medication again versus 75 of 106 (71%) of methylprednisolone acetate patients (95% confidence interval for difference of 4%: -8% to 17%). Other than injection site reactions, which were more common in the methylprednisolone acetate group, there were no substantial differences in frequency of adverse events. CONCLUSION: Methylprednisolone acetate does not decrease the frequency of post-ED discharge headache days compared with dexamethasone. Most migraine patients are likely to continue to experience headache during the week after ED discharge.

The crossover design for migraine preventives: an analyses of four randomized placebo-controlled trials.

AIMS: To evaluate the crossover design in migraine preventive treatment trials by assessing dropout rate, and potential period and carryover effect in four placebo-controlled randomized controlled trials (RCTs). METHODS: In order to increase statistical power, the study combined data from four different RCTs performed from 1998 to 2015 at St. Olavs Hospital, Norway. Among 264 randomized patients, 120 received placebo treatment before and 144 after active treatment. RESULTS: Only 26 (10%) dropped out during the follow-up period of 30-48 weeks, the majority (n = 19) in the first 12 weeks. No period effect was found, since the treatment sequence did not influence the responder rate after placebo treatment, being respectively for migraine 30.5% vs. 27.4% (p = 0.59) and for headache 25.0% vs. 24.8% (p = 0.97, Chi-square test) when placebo occurred early or late. Furthermore, no carryover effect was identified, since the treatment sequence did not influence the treatment effect (difference between placebo and active treatment). There was no significant difference between those who received active treatment first and those who received placebo first with respect to change in number of days per 4 week of headache (- 0.9 vs. -1.3, p = 0.46) and migraine (- 1.2 vs. -0.9, p = 0.35, Student's t-test). CONCLUSIONS: Summary data from four crossover trials evaluating preventive treatment in adult migraine showed that few dropped out after the first period. No period or carryover effect was found. RCT studies with crossover design can be recommended as an efficient and cost-saving way to evaluate potential new preventive medicines for migraine in adults.

Real-world effectiveness of onabotulinumtoxinA treatment for the prevention of headaches in adults with chronic migraine in Australia: a retrospective study.

BACKGROUND: OnabotulinumtoxinA (BOTOX®, Allergan plc, Dublin, Ireland) is approved for the preventive treatment of headaches in adult patients with chronic migraine (CM) in Australia by the country's reimbursement mechanism for medicines, the Pharmaceutical Benefits Scheme (PBS). To our knowledge, this study represents the first focused report evaluating real-world evidence of onabotulinumtoxinA treatment via the PBS in Australian clinics. METHODS: This study reviewed the medical records of adults with inadequately controlled CM from 7 private neurology practices in Australia who, beginning in March 2014, received PBS-subsidized onabotulinumtoxinA per product labelling for the first time. The primary effectiveness measure was the percentage of patients achieving a response defined by 50% or greater reduction in headache days from baseline after 2 treatment cycles. Additional data were recorded in the case report form when available and included demographics, clinical characteristics, headache severity and frequency, Headache Impact Test (HIT-6) score, medication use, and days missed of work or study at baseline, after 2 treatment cycles, and at last follow-up. Differences in mean changes from baseline were evaluated with a 1-tailed t-test or Pearson's chi-squared test (p < 0.05). RESULTS: The study population included 211 patients with a mean (SD) of 25.2 (5.3) monthly headache days at baseline. In the primary outcome analysis, 74% of patients achieved a response, with a mean (SD) of 10.6 (7.9) headache days after 2 treatment cycles (p < 0.001). Secondary effectiveness outcomes included mean (SD) reductions in HIT-6 score of - 11.7 (9.8) and - 11.8 (12.2) after 2 treatment cycles (p < 0.001) and final follow-up (p < 0.001), respectively, and mean (SD) decreases in days per month of acute pain medication use of - 11.5 (7.6) after 2 treatment cycles (p < 0.001) and - 12.7 (8.1) at final follow-up (p < 0.001). CONCLUSION: This study provides additional clinical evidence for the consistent effectiveness of onabotulinumtoxinA for the treatment of CM in Australia. This effectiveness was made evident by reductions in migraine days, severe headache days, and HIT-6 scores from baseline.

Medication-overuse headache.

Medication-overuse headache is defined as headache occurring on more than 15days in a month in people with pre-existing primary headache, and developing as a consequence of regular overuse of acute headache treatments. Medication-overuse headache is common in general neurology clinics and can be difficult to manage. Most patients have a background of migraine, which has slowly transformed over months and years from the episodic to chronic form; with this comes an increased use of acute migraine treatment. This paper identifies who is at risk of developing medication-overuse headache, and reviews preventive measures and current treatment strategies.