Reporting Quality and Risk of Bias Analysis of Published RCTs Assessing Anti-CGRP Monoclonal Antibodies in Migraine Prophylaxis: A Systematic Review.

Objective: Phase II/III randomized clinical trials (RCTs) are vulnerable to many types of bias beyond randomization. Insights into the reporting quality of RCTs involving migraine patients treated with monoclonal antibodies targeting the calcitonin gene-related peptide system (anti-CGRP MAbs) are currently lacking. Our aim was to analyze the reporting quality of phase II/III RCTs involving migraine patients treated with anti-CGRP MAbs. Methods: A systematic search was performed on the PubMed and EMBASE databases, according to PRISMA guidelines, for relevant RCTs in either episodic or chronic migraine prevention. Additionally, an adapted version of the 2010 CONSORT statement checklist was utilized. The ROBvis online tool was used to document the risk of bias. Results: From the initially identified 179 articles, we finally found 31 RCTs that were eligible for evaluation. The average CONSORT compliance was 88.7% (69.7-100%), while 93.5% (N = 29) of the articles had a compliance greater than 75%. Twenty-eight CONSORT items were reported in more than 75% of the articles. The average compliance of the analyzed RCTs was 93.9% for Galcanezumab, 91.3% for Fremanezumab, followed by 85.4% for Erenumab and Eptinezumab studies. Implementation of the ROB2 tool showed some concerning "missing information" arising from the inadequate reporting. Specifically, 50% of the studies (N = 16) were categorized as having inadequate information regarding the randomization process. Conclusions: Adequate reporting quality was disclosed in the evaluated RCTs with anti-CGRP MAbs in migraine prevention. However, some methodological issues need to be highlighted to be addressed in future studies assessing the efficacy of new molecules targeting CGRP or other candidate pathways implicated in migraine pathophysiology.

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

BACKGROUND: We primarily aimed to ascertain whether treatment with OnabotulinumtoxinA (BoNTA) might influence the extent of the interictal burden and cutaneous allodynia in patients with chronic migraine (CM). METHODS: Seventy CM patients, who received three consecutive cycles of BoNTA, were studied. The interictal burden was assessed with the Migraine Interictal Burden Scale (MIBS-4), while cutaneous allodynia was examined with the Allodynia Symptom Checklist (ASC-12) together with PI-NRS VAS to obtain hair brushing scores, and then these were compared from baseline (T0) to the last efficacy evaluation follow-up (T1). Efficacy outcomes, mostly mean headache days (MHD) and "Headache Impact Test" scores, were also assessed between T0 and T1. RESULTS: BONTA improved the interictal burden, with a decrease in MIBS-4 scoring by an average of -7 at T1, compared to baseline (p < 0.001). The percentage of patients with a moderate/severe interictal burden was substantially decreased. Likewise, BoNTA reduced the extent of cutaneous allodynia, with a significant reduction in both the ASC-12 (1 vs. 6; p < 0.001) and PI-NRS VAS (1 vs. 5; p < 0.001) to hair brushing median scores at T1, compared to baseline. Reduced MHD rates were significantly associated with a smaller interictal burden at T1. The efficacy of BoNTA, with a significant reduction in MHD and HIT-6 scores at T1 compared to T0, was re-confirmed. CONCLUSIONS: BoNTA resulted in a statistically significant reduction in the interictal burden and also improved cutaneous allodynia. The reduction in ictal burden was associated with the down-scaling of the interictal burden. Hence, BoNTA improved the full spectrum of migraine impairment by diminishing the clinical expression of central sensitization.

Incidence and risk factors for developing chemotherapy-induced neuropathic pain in 500 cancer patients: A file-based observational study.

OBJECTIVE: To define the incidence and risk factors for developing chemotherapy-induced neuropathic pain (CINP). METHODS: Retrospective, file-based analysis on cancer patients who received any type of conventional chemotherapy and for whom neurological evaluation was asked to reveal the extent of chemotherapy-induced peripheral neurotoxicity (CIPN) with or without CINP. CINP was assessed by means of the PI-NRS and Douleur Neuropathique-4 questionnaire. The total neuropathy score-clinical version graded the severity of CIPN. RESULTS: The medical files of 500 chemotherapy-treated cancer patients were reviewed. Any grade chronic CIPN was disclosed in 343 (68.6%) patients and CINP in 127 (37%) of them, corresponding to an overall percentage of 25.4% among all 500 included patients. The logistic regression analysis identified as independent predictors for CINP development the presence of uncomplicated diabetes (OR: 2.17; p = .039) and grade 2-3 chronic CIPN (OR: 1.61; p < .001) as also the administration of combined paclitaxel plus cisplatin (reference variable), compared to oxaliplatin (OR: 0.18; p = .001) and taxanes (OR: 0.16; p < .001). The increased severity of acute OXAIPN was associated with CINP (OR: 4.51; p < .001). OXA-treated patients with persistent CINP presented a worst likelihood to improve after chemotherapy discontinuation, than patients receiving combined paclitaxel plus cisplatin (OR: 50; p < .001). CONCLUSION: The incidence of CINP in our cohort was comparable to previous reports, with severities fluctuating upwards during chemotherapy and declined post-chemotherapy. Uncomplicated diabetes, the combined paclitaxel plus cisplatin treatment and the increased severity of acute oxaliplatin neurotoxicity mostly increase the risk for developing CINP. OXA-treated patients present less possibilities to recover from CINP after chemotherapy discontinuation, than other chemotherapies.

Nine-Month Continuous Fremanezumab Prophylaxis on the Response to Triptans and Also on the Incidence of Triggers, Hypersensitivity and Prodromal Symptoms of Patients with High-Frequency Episodic Migraine.

Objective: To investigate whether the incidence of triggers, prodromal symptoms, hypersensitivity symptoms accompanying headache and responses to triptans were modified during a continuous 9-month fremanezumab therapy for migraine prophylaxis. Patients and methods: We studied 63 patients with high-frequency episodic migraine (HFEM). Enrolled patients received fremanezumab for nine consecutive months before defining the response rates and being stratified into treatment responders (≥50-74% reduction in monthly headache days (MHDs)), super responders (≥75%), partial non-responders (<50%) and super non-responders (<30%). Through headache diaries, patients provided data in order to document the impact of fremanezumab on the incidence of triggers, associated symptoms followed by headache and response to triptans (the use of the migraine treatment optimization questionnaire-4 (mTOQ-4)) during the 9-month treatment period. Results: Fremanezumab had early (after 3 monthly cycles) beneficial effects on the response to triptans in the majority of responders with relevant increases in mTOQ-4 scoring, but also in half of partial non-responders. A significant reduction in median days with migraine-associated symptoms was seen in responders after 6 months of therapy with fremanezumab, mostly for osmophobia, photophobia, phonophobia and nausea/vomiting, but partial non-responders also benefited. Likewise, the incidence of self-reported prodromal symptoms was significantly reduced in responders and was modestly diminished in partial non-responders. Triggers remained unaffected in both responders and non-responders. Conclusions: Fremanezumab given for at least 6-9 months may exert neuromodulatory effects in the migraine brain. These effects could result both in the inhibition of migraine chronification, but also in the diminishing of the magnitude of migraine-associated symptoms, mostly in responders and in partial non-responders.

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)-a white paper.

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.

Single OnabotulinumtoxinA Session Add-On to Carbamazepine or Oxcarbazepine in Treatment-Refractory Trigeminal Neuralgia: A Case Series with 24-Week Follow Up.

We sought to assess the efficacy of combining onabotulinumtoxinA (BoNTA) as add-on therapy to carbamazepine or oxcarbazepine in treatment-refractory patients with trigeminal neuralgia (TGN) who failed to respond (less than 30% response rate) to adequate monotherapy. We conducted a retrospective study on 15 patients with a definite diagnosis of TGN, according to the established criteria, and underwent BoNTA as part of their treatment plan. A single BoNTA session was administered subcutaneously, according to patients' perceived zone of pain, at different dosages ranging from 30 to 200 units (mean ± standard deviation: 87.3 ± 39.2). All patients (15/15; 100%) reported large reductions in the severity of their TGN-related neuropathic pain. The mean pain score on the VAS scale significantly decreased from 9.3 ± 1.1 to 3.7 ± 1.2 at 2 weeks after injecting BoNTA (p < 0.001) and remained stable at 4 and 24 weeks post-injection. Regarding the impact of BoNTA on patients' health-related quality of life, there were significant improvements in both the physical and mental health domains (p < 0.05) of SF-36 tool. BoNTA may be a safe and effective treatment option for patients with refractory TGN when added on to carbamazepine or oxcarbazepine. The use of a single BoNTA session for TGN treatment may be an alternative to surgical interventions and as add-on treatment to oral medications, providing patients with a minimally invasive, effective, safe and well-tolerated option.

Effects of Fremanezumab on Psychiatric Comorbidities in Difficult-to-Treat Patients with Chronic Migraine: Post Hoc Analysis of a Prospective, Multicenter, Real-World Greek Registry.

OBJECTIVE: this post hoc analysis aimed to evaluate the efficacy of fremanezumab in difficult-to-treat chronic migraine (CM) patients with and without psychiatric comorbidities (PCs), mainly anxiety and/or depression. METHODS: We assessed data from CM patients with and without PCs who failed at least 3 preventives and eventually received at least 3 consecutive monthly doses of fremanezumab 225 mg. Outcomes included the crude response (≥50% reduction in monthly headache days (MHDs)) rates to fremanezumab from the baseline to the last clinical follow-up. The changes in MHDs; MHDs of moderate/greater severity; monthly days with intake of abortive medication; and the proportion of patients' changing status from with PCs to decreased/without PCs were also compared. Disability and quality of life (QOL) outcomes were also assessed. RESULTS: Of 107 patients enrolled, 65 (60.7%) had baseline PCs. The percentage of patients with (n = 38/65; 58.5%) and without (n = 28/42; 66.6%) PCs that achieved a ≥50% reduction in MHDs with fremanezumab was comparable (p = 0.41), whereas MHDs were significantly reduced (difference vs. baseline) in both patients with PCs (mean -8.9 (standard error: 6.8); p < 0.001) and without PCs (-9.8 (7.5); p < 0.001). Both groups experienced significant improvements in all other efficacy, disability, and QOL outcomes at comparable rates, including in MHD reduction. A significant proportion of fremanezumab-treated patients with baseline PCs de-escalated in corresponding severities or even reverted to no PCs (28/65; 43.1%) post-fremanezumab. CONCLUSIONS: fremanezumab appears to be effective as a preventive treatment in difficult-to-treat CM patients with and without PCs while also being beneficial in reducing the severity of comorbid anxiety and/or depression.

Predictors of Response to Fremanezumab in Migraine Patients with at Least Three Previous Preventive Failures: Post Hoc Analysis of a Prospective, Multicenter, Real-World Greek Registry.

OBJECTIVE: To define, in a real-world population of patients with high-frequency episodic (HFEM) or chronic migraine (CM), the predictive role of socio-demographic or phenotypic profiling of responders to fremanezumab. PATIENTS AND METHODS: Two-hundred and four adult fremanezumab-treated patients with either HFEM or CM, who failed to at least three preventive treatments, provided data at baseline on several individual socio-demographic and phenotypic variables. These variables were analyzed for their ability to independently predict the response (50-74% response rates) or super-response (≥ 75% response rates) to fremanezumab. Patients were followed from 3-18 months of fremanezumab exposure. RESULTS: The main finding to emerge from univariate analyses was that three baseline socio-demographic/clinical variables, i.e., age group 41-70 years (p = 0.02); female gender (p = 0.03); patients with HFEM (p = 0.001), and three clinical phenotypic variables, i.e., strict unilateral pain (p = 0.05); pain in the ophthalmic trigeminal branch (p = 0.04); and the "imploding" quality of pain (p = 0.05), were significantly related to fremanezumab response. However, in multivariate analysis, only HFEM (p = 0.02), the presence of strict unilateral (p = 0.03), and pain location in the ophthalmic trigeminal branch (p = 0.036) were independently associated with good fremanezumab response. Allodynia (p = 0.04) was the only clinical predictive variable of super-responsiveness to fremanezumab. CONCLUSIONS: A precise phenotypic profiling with identification of pain characteristics consistent with peripheral and/or central sensitization might reliably predict the responsiveness to fremanezumab in migraine prophylaxis.

A Survey of Greek Primary Care Physicians on Their Likeability in Treating Migraines and Other Common Diseases.

Background and objectives: Migraine is considered the most clinically important primary headache due to its high prevalence and significant burden. Although globally categorized as one of the leading causes of disability, it is still largely underdiagnosed and undertreated. Worldwide, migraine care is in most cases provided by primary care physicians. The aim of our study was to assess the attitudes of Greek primary care physicians toward treating migraine compared to other common neurological and general medical disorders. Methods: We surveyed 182 primary care physicians with the use of a 5-point questionnaire regarding their preference in treating ten common medical conditions, including migraine, hypertension, hyperlipidemia, upper respiratory tract infections, diabetes mellitus, lower back pain, dizziness, transient ischemic attack, diabetic peripheral neuropathy, and fibromyalgia. Results: Overall, with regards to preference to treat, migraine scored very low (3.6 ± 1.0), next to diabetic peripheral neuropathy (3.6 ± 1.0), and third from the bottom to fibromyalgia (3.25 ± 1.06). In contrast, physicians reported a much higher preference to treat hypertension (4.66 ± 0.60) and hyperlipidemia (4.6 ± 1.0). Conclusions: Our results indicate that Greek primary care physicians dislike treating migraines but also other neurological diseases. Topics for further investigation include the reasons for this dislike, any associations with poor patient satisfaction, treatment results, or both.

Axonal degeneration in chemotherapy-induced peripheral neurotoxicity: clinical and experimental evidence.

Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.

Efficacy and safety of fremanezumab for migraine prophylaxis in patients with at least three previous preventive failures: Prospective, multicenter, real-world data from a Greek registry.

OBJECTIVE: To prospectively assess the efficacy and safety of fremanezumab for migraine prophylaxis in patients with failure of at least three previous preventive treatments. Changes in disability as quality-of-life outcomes after fremanezumab treatment were also examined. METHODS: Two hundred and four patients with either high-frequency EM (HFEM) or chronic migraine (CM), who attained at least three consecutive monthly sessions with fremanezumab 225 mg and otherwise met the inclusion criteria, were included in the study. The crude response (at least 50% reduction in monthly headache days [MHD]) rates to fremanezumab were assessed. Scores in the following efficacy outcomes were then compared from baseline to the last efficacy evaluation follow-up: (i) MHD, (ii) monthly days with moderate/severe peak headache intensity, and (iii) monthly days with intake of abortive medication. The disability was evaluated with the Migraine Disability Assessment; the quality of life (QOL) status was assessed with the Headache Impact-6 Test, and the EQ-5D questionnaire. RESULTS: In the majority of HFEM cases (n = 81/97; 83.5%) and CM patients (n = 67/107; 62.6%), fremanezumab proved effective in reducing the MHDs by at least 50% and was associated with clinically meaningful improvement in all other efficacy variables. The migraine-related disability experienced by our patients decreased and their QOL increased. We recorded just 36 cases reporting mild adverse events, including pain, rash or pruritus (n = 26), flu-like symptoms (n = 8), and hair loss (n = 2). CONCLUSION: With our prospective results, we provide further real-world data to support the favorable benefit/risk profile of fremanezumab in the prophylaxis of both HFEM and CM.

Treatment for cognitive and neuropsychiatric non-motor symptoms in Parkinson's disease: current evidence and future perspectives.

INTRODUCTION: Non-motor symptoms (NMS) affect patients with Parkinson's disease (PD) from the prodromal to the advanced stages. NMS phenotypes greatly vary and have a huge impact on patients' and caregivers' quality of life (QoL). The management of cognitive and neuropsychiatric NMS remains an unmet need. AREAS COVERED: The authors, herein, review the dopaminergic and non-dopaminergic pathogenesis, clinical features, assessment, and pharmacological and non-pharmacological treatments of cognitive and neuropsychiatric NMS in PD. They discuss the current evidence and report the findings of an overview of ongoing trials on pharmacological and selected non-pharmacological strategies. EXPERT OPINION: The treatment of cognitive and neuropsychiatric NMS in PD is poorly explored, and therapeutic options are unsatisfactory. Pharmacological treatment of cognitive NMS is based on symptomatic active principles used in Alzheimer's disease. Dopamine agonists, selective serotonin, and serotonin-norepinephrine reuptake inhibitors have some evidence on PD-related depression. Clozapine, quetiapine, and pimavanserin may be considered for psychosis in PD. Evidence on the treatment of other neuropsychiatric NMS is limited or lacking. Addressing pathophysiological and clinical issues, which hamper solid evidence on the treatment of cognitive and neuropsychiatric NMS, may reduce the impact on QoL for PD patients and their caregivers.

Neurological Complications of Conventional and Novel Anticancer Treatments.

Various neurological complications, affecting both the central and peripheral nervous system, can frequently be experienced by cancer survivors after exposure to conventional chemotherapy, but also to modern immunotherapy. In this review, we provide an overview of the most well-known adverse events related to chemotherapy, with a focus on chemotherapy induced peripheral neurotoxicity, but we also address some emerging novel clinical entities related to cancer treatment, including chemotherapy-related cognitive impairment and immune-mediated adverse events. Unfortunately, efficacious curative or preventive treatment for all these neurological complications is still lacking. We provide a description of the possible mechanisms involved to drive future drug discovery in this field, both for symptomatic treatment and neuroprotection.

OnabotulinumtoxinA Add-On to Monoclonal Anti-CGRP Antibodies in Treatment-Refractory Chronic Migraine.

We sought to assess the effectiveness of combining dual therapy with onabotulinumtoxinA (BTX) add-on to anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (anti-CGRP MAbs) in treatment-refractory patients with chronic migraine (CM). We retrospectively reviewed the medical files of 19 treatment-refractory patients with CM who had failed to two oral migraine preventatives, at least three consecutive BTX cycles (less than 30% response rate), at least three consecutive sessions with either fremanezumab or erenumab (less than 30% response rate), and were eventually switched to dual therapy with BTX add-on to any of the already-given anti-CGRP MAbs. We then assessed from baseline to each monotherapy or dual intervention predefined efficacy follow-up the changes in the following efficacy outcomes: (i) monthly headache days (MHD), (ii) monthly days with moderate/severe peak headache intensity, and (iii) monthly days with intake of any acute headache medication. Response (50% reduction in MHD) rates, safety, and tolerability were also determined. In the majority of cases (n = 14), dual targeting proved effective and was associated with clinically meaningful improvement in all efficacy variables; 50% response rates (also disability and QOL outcomes) coupled with favorable safety/tolerability. Our results advocate in favor of the view that dual therapy is effective and should be considered in difficult-to-treat CM patients who have failed all available monotherapies.

Results of a Web-based survey of 2105 Greek migraine patients in 2020: demographics, clinical characteristics, burden and the effects of the COVID-19 pandemic on the course of migraine.

The Greek Society of Migraine and Headache Patients (GSMHP), maintaining a strong commitment to research and information, conducted its second web-based online survey named "Migraine in Greece-2020", following its first one conducted in 2018. The 2020 study included 2,105 migraine patients who were called to answer 151 questions. The purposes of the current research were to record the demographic and clinical characteristics of migraine patients in Greece, including the severity and effects of migraine on respondents' quality of life, as well as to survey the effects of the coronavirus pandemic on the course of migraine. Our population, internet-based study provides data that will hopefully contribute to better comprehend the clinical phenotype and course of migraine during the COVID-19 pandemic.

Wearables, sensors, and smart devices for the detection and monitoring of chemotherapy-induced peripheral neurotoxicity: Systematic review and directions for future research.

Chemotherapy-induced peripheral neurotoxicity (CIPN) diagnosis is largely based on patient reported outcomes. Wearables, sensors, and smart devices may potentially provide early detection and monitoring of CIPN. We systematically reviewed data on wearables, sensors, and smart devices to detect and/or monitor signs and symptoms of CIPN. Moreover, we provide directions and recommendations for future studies. A literature search using PubMed/MEDLINE, Web of Science, IEEE Xplore, and CINHAL databases was conducted from database inception until March 2021. The search was further updated in July 2022 to ensure currency of results. A total of 1885 records were title-abstract screened, 33 full texts were assessed, and 16 were included. The retrieved papers were heterogeneous in terms of study design, sample size, CIPN severity, chemotherapy agents, type of wearable/sensor/device applied, parameters of interest, and purpose. Data are promising and provide preliminary evidence on wearables, sensors, and smart devices for CIPN detection and monitoring. There are several issues and knowledge gaps that should be addressed. We propose a framework for future studies.

Prospective Comparison of Longer Needle Lengths to Assess the Risk of OnabotulinumtoxinA-Associated Neck Pain in Patients with Chronic Migraine.

BACKGROUND: We aimed to prospectively assess the role of needle length in improving the tolerability/safety profile of OnabotulinumtoxinA (BoNTA) for chronic migraine (CM) prophylaxis, with a specific focus on neck pain, based on patients' body habitus and other variables. METHODS: BoNTA was administered quarterly for two consecutive cycles, using the standard 0.5-inch 27 G needle at all pre-defined PREEMPT injection sites, except the left-hand side trapezius and paraspinal muscles, which were injected using longer needles of 1-inch 23 G at first and 1-inch 27 G at second infusion. Participants were interviewed at day 14 following each session for evidence of neck pain. The predictive significance of Body Mass Index (BMI) and other variables with neck pain was also examined. RESULTS: A total of 100 consecutive CM patients were evaluated, and each patient served as her/his self-control. The incidence, duration and intensity of neck pain did not significantly differ using either 1-inch needle compared with standard 0.5-inch 27 G needle, although the incidence and characteristics of neck pain with the use of longer needles appeared slightly higher and more intense. The BMI index and other tested variables remained unrelated to neck pain. CONCLUSIONS: We were not able to identify significant differences or correlations in the incidence, characteristics and location of neck pain with the use of different needle length to inject BoNTA, although the use of the longer 1-inch needles likely increased the risk of this adverse event.

A systematic review with expert opinion on the role of gepants for the preventive and abortive treatment of migraine.

INTRODUCTION: Gepants are small molecules targeting the calcitonin gene-related peptide (CGRP) that have been recently introduced and are under additional clinical development as preventive and abortive treatment options for migraine. AREAS COVERED: After providing a narrative overview of current preventive and acute treatment options for migraine and summarizing the pathophysiology of migraine attack and the role of CGRP, we performed a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on trials on gepants in preventive and acute treatment of migraine. Studies and results were reviewed and discussed, and expert opinion was presented. We also collected data on relevant ongoing trials. EXPERT OPINION: Whether direct targeting CGRP pathways within the central nervous system or indirectly modulating them from the peripheral nervous system is more effective and safer in migraine remains still unclear. The available data on the efficacy and safety of gepants suggest they may represent an abortive, and to some extent, preventive treatment option for migraine, in patients who do not respond or have adverse effects to first/second line treatments or at high risk for medication overuse headache; thus opening new therapeutic horizons.

Assessing the Significance of the Circadian Time of Administration on the Effectiveness and Tolerability of OnabotulinumtoxinA for Chronic Migraine Prophylaxis.

We aimed to provide insights on the role of the circadian time of administration in influencing the efficacy and tolerability/safety profile of OnabotulinumtoxinA (BoNTA) for chronic migraine (CM) prophylaxis. Methods: We retrospectively reviewed the medical files of BoNTA-naïve patients with CM who completed three consecutive cycles of treatment, according to the standard PREEMPT paradigm. Participants were classified to those scheduled to be treated in the morning hours from 8:00 to 12:00 (AM) or afternoon hours from 13:00 to 18:00 (PM). We then assessed and compared between groups the changes from baseline (T0­trimester before BoNTA's first administration) to the period after its third administration (T3) in the following efficacy outcomes: (i) mean number of headache days/month, (ii) mean number of days/month with peak headache intensity of >4/10, (iii) mean number of days/month with consumption of any abortive treatment. Safety−tolerability was also compared between groups. Results: A total of 50 AM and 50 PM-treated patients were evaluated. The within-group analysis in both groups showed a significant decrease in all efficacy variables between T0 and T3. However, the between-group comparisons of all BoNTA-related efficacy outcomes at T3 vs. T0 documented comparable improvements between AM vs. PM-treated patients. Safety/tolerability was also similar between groups. Conclusions: We were not able to identify significant differences between patients treated in the AM vs. PM, so as to demonstrate that the circadian time of administration should be considered before initiating BoNTA in CM patients.