Search

Background: Medication overuse headache (MOH) is the most common secondary headache disorder, resulting from chronic and excessive use of medication to treat headaches, for example, sumatriptan. In a recent study, we have shown that the peripheral C-C motif ligand 2 (CCL2), C-C motif chemokine receptor 2 (CCR2) and calcitonin-gene-related peptide (CGRP) signaling pathways interact with each other and play critical roles in the development of chronic migraine-related behavioral and cellular sensitization. In the present study, we investigated whether CCL2-CCR2 and CGRP signaling pathways play a role in the development of sumatriptan overuse-induced sensitization, and whether they are involved in its resolution by the low-dose interleukin-2 (LD-IL-2) treatment. Methods: Mice received daily sumatriptan administration for 12 days. MOH-related behavioral sensitization was assessed by measuring changes of periorbital mechanical thresholds for 3 weeks. CCL2-CCR2 and CGRP signaling pathways were inhibited by targeted gene deletion or with an anti-CCL2 antibody. Ca2+-imaging was used to examine whether repetitive sumatriptan treatment enhances CGRP and pituitary adenylate cyclase–activating polypeptide (PACAP) signaling in trigeminal ganglion (TG) neurons. LD-IL-2 treatment was initiated after the establishment of sumatriptan-induced sensitization. Immunohistochemistry and flow cytometry analyses were used to examine whether CCL2-CCR2 signaling controls regulatory T (Treg) cell proliferation and/or trafficking. Results: CCL2, CCR2 and CGRPα global KO mice exhibited robust sumatriptan-induced behavioral sensitization comparable to wild-type controls. Antibody neutralization of peripheral CCL2 did not affect sumatriptan-induced behaviors either. Repeated sumatriptan administration did not enhance the strength of CGRP or PACAP signaling in TG neurons. Nevertheless, LD-IL-2 treatment, which facilitated the resolution of sumatriptan-induced sensitization in wild-type and CGRPα KO mice, was completely ineffective in mice with compromised CCL2-CCR2 signaling. In CCL2 KO mice, we observed normal LD-IL-2-induced Treg expansion in peripheral blood, but the increase of Treg cells in dura and TG tissues was significantly reduced in LD-IL-2-treated CCL2 KO mice relative to wild-type controls. Conclusions: These results indicate that the endogenous CCL2-CCR2 and CGRP signaling pathways are not involved in sumatriptan-induced behavioral sensitization, suggesting that distinct molecular mechanisms underlie chronic migraine and MOH. On the other hand, peripheral CCL2-CCR2 signaling is required for LD-IL-2 to reverse chronic headache-related sensitization. [ABSTRACT FROM AUTHOR]

Aims: In this study, we aimed to evaluate the relationship between the dietary inflammatory index (DII) and mental health outcomes among patients with migraine headaches. Methods: In this cross-sectional study, 262 subjects were included. The dietary intakes were collected using a validated 168-item semi-quantitative food frequency questionnaire. Items were scored according to their inflammatory potential, so a higher DII indicated a more pro-inflammatory diet. The association between DII and the mental health of participants was investigated using multinomial logistic regression and odds ratio (OR) with a corresponding 95% confidence interval (CI) was reported. Results: Overall, 224 women and 38 men, with a mean (standard error) DII of −2.96 (0.06), age of 36.1 (0.53) years, and BMI of 25.55 (0.21) kg/m2, comprised our study population. DII was positively associated with a higher risk of depression in patients with the highest adherence to a pro-inflammatory diet compared to those with the lowest adherence (OR = 1.76; 95%CI: 1.04, 3.00; Ptrend = 0.035). Adjustments for age, sex, marital status, smoking status, migraine headache index score, number of family members, mean arterial pressure, medication, physical activity, and BMI intensified the association in a way that the risk of depression was 2.03 times higher in patients with the highest adherence to a pro-inflammatory diet compared to those with the lowest adherence to a pro-inflammatory diet (OR = 2.03; 95%CI: 1.18, 3.49; Ptrend = 0.011). Conclusion: Our findings suggest that depression was positively associated with adherence to a pro-inflammatory diet. However, no significant association was observed between anxiety and stress with DII. [ABSTRACT FROM AUTHOR]

Background: In addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors. Methods: In a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague–Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration. Results: Both doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP. Conclusions: The findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine. [ABSTRACT FROM AUTHOR]

Aim: Successful acute migraine treatment potentially prevents emergency room (ER) consultations but requires that the diagnosis of migraine was given earlier. The aim of this study is to quantify the problem of missed migraine diagnosis prior to ER visits. Methods: Inclusion criterion for this single-center prospective study was the presentation at the ER for acute headache. Patients with acute migraine attacks were assessed for previous migraine attacks, and whether they were given a diagnosis of migraine in the past. Results: Of 137 patients with migraine diagnosis at discharge, 108 (79%) had previous headache attacks fulfilling the criteria for migraine according to The International Classification of Headache Disorders 3rd edition (ICHD-3). Of those, 54 (50%) received the diagnosis for the first time. Conclusion: Half of the migraine patients (50%) presenting in the ER for headache could have been diagnosed earlier. This highlights the need for better detection and treatment of migraine by pre-hospital healthcare providers, as earlier diagnosis and specific acute treatment could have prevented the ER visit. [ABSTRACT FROM AUTHOR]

Migraine is a prevalent neurological disorder, particularly among individuals aged 20–50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Migraine is a severe neurological disorder that is recognized as one of the most common debilitating diseases worldwide. Although the exact cause of migraine is not known, research suggests that inflammation, oxidative stress, mitochondrial dysfunction, and insufficient nutrients may contribute to its development. Studies indicate that nutrition-based approaches are safer and more cost-effective strategies for managing migraine symptoms compared to medication. In this regard, the impact of nutrition, as a complementary medicine, is largely attributed to that of certain nutrients on inflammation and mitochondrial function. It is hypothesized that alpha-linolenic acid and L-carnitine, which possess anti-inflammatory and antioxidant properties, may be synergically beneficial for migraine patients. Therefore, this study will be conducted to assess the efficacy of alpha-linolenic acid and L-carnitine co-supplementation in patients with migraine. Methods: This is a parallel, randomized, triple-blind, placebo-controlled clinical trial, in which 80 women aged 20 to 50 years with migraine will be assigned to receive either intervention group (n = 40) receiving both 1000 mg/day flaxseed oil and 500 mg/day L-carnitine simultaneously for 12 weeks, or control group (n = 40) receiving both 1000 mg/day paraffin oil and 500 mg/day maltodextrin as the placebos for the same duration. The primary outcomes include changes in clinical symptoms of migraine, including frequency, severity, and duration of attacks, serum levels of C–reactive protein (CRP), total antioxidant capacity (TAC), nitric oxide (NO), malondialdehyde (MDA), and superoxide dismutase (SOD). Secondary outcomes include mental health, sleep quality, and quality of life (QOL). Discussion: In this study, we aim to investigate the potential benefits of combining alpha-linolenic acid and L-carnitine as a treatment option for migraine sufferers. Migraine, characterized by recurrent severe headaches, affects a significant portion of the population and can significantly impact an individual's quality of life. By studying alternative therapies such as alpha-linolenic acid and L-carnitine, researchers hope to expand the range of treatment options available and potentially provide relief to migraine sufferers. Trial registration: Iranian Registry of Clinical Trials (www.irct.ir) (ID: IRCT20121216011763N57). Registration date: 29 March 2023. Trial status: The protocol is version 1.0 dated December 30, 2023. Recruitment began on July 10, 2023, and is expected to be completed by January 22, 2024. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusion To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults.Zavegepant is a high‐affinity, selective, small‐molecule calcitonin gene–related peptide receptor antagonist administered as a nasal spray approved in the United States for the acute treatment of migraine. Triptans, including sumatriptan, are a different class of drugs for acute migraine treatment and are associated with a risk of increased blood pressure (BP). Hence, it is important to study the drug–drug interactions between zavegepant and sumatriptan due to potential coadministration in clinical settings.This was a Phase 1, single‐center, partially blind, randomized, placebo‐controlled, single‐arm study. Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years. On Day 1, participants received sumatriptan 2 × 6 mg subcutaneous injections (1 h apart) and were then randomized (6:1 ratio) to receive zavegepant 2 × 10 mg nasal spray (1 in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. BP, PK, and safety were evaluated at pre‐specified time points.Forty‐two participants enrolled in the study received at least one dose of any treatment and were included in the safety analyses. Forty‐one participants who completed the study were included in the BP and PK analyses. The mean (standard deviation) time‐weighted average (TWA) of mean arterial pressure (MAP [sumatriptan + zavegepant 87.2 (6.8) vs. sumatriptan 86.9 (6.0)]), diastolic BP (DBP [sumatriptan + zavegepant 72.3 (6.8) vs. sumatriptan 72.1 (6.2)]), and systolic BP (SBP [sumatriptan + zavegepant 116.8 (10.2) vs. sumatriptan 116.2 (8.6)]) did not change following zavegepant and sumatriptan coadministration on Day 4 compared to sumatriptan alone on Day 1. Statistical comparisons of the TWA of MAP, DBP, and SBP between sumatriptan and zavegepant coadministration and sumatriptan alone were similar; the differences observed were 0.04 mmHg for MAP (90% confidence interval [CI]: −0.69, 0.77 mmHg), 0.00 mmHg for DBP (90% CI: −0.76, 0.76 mmHg), and 0.33 mmHg for SBP (90% CI: −0.97, 1.63 mmHg). Sumatriptan PK after sumatriptan and zavegepant coadministration versus sumatriptan alone was similar; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC0‐inf and 104.1% (90% CI: 98.0%, 110.6%) for Cmax. A small difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone was not considered clinically relevant: the comparison ratios were 112.4% (90% CI: 103.4%, 122.3%) for AUC0–24 and 96.7% (90% CI: 88.9%, 105.2%) for Cmax. Overall, 90% (38/42) of participants experienced ≥ 1 treatment‐emergent adverse event that was mild or moderate in severity. All treatments were generally safe and well tolerated.Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults. [ABSTRACT FROM AUTHOR]

Objective: Small molecule calcitonin gene-related peptide (CGRP) antagonists such as rimegepant, ubrogepant, and atogepant have been approved for migraine treatment and/or prevention. These molecules are metabolized by cytochrome P-450 3A4 (CYP3A4) enzymes in vivo, hence they are contraindicated or recommended to be avoided in combination with strong/moderate CYP3A4 inhibitors, namely posaconazole (strong) and isavuconazonium (moderate). However, no literature has been published on the impact this interaction has on patient safety and tolerability. In this case series, we report five cases in which CGRP antagonists and azole antifungal therapy were given concurrently, to provide real-world outcomes of this interaction. Data sources: Electronic medical records at our hospital system were reviewed between January 2021 and December 2023 to find patients who met the criteria of hematological malignancy, taking CGRP-antagonist and azole antifungal therapy. Records were then further investigated to find cases where CGRP antagonists and azole antifungals were used concomitantly. Data summary: Concurrent use of CGRP antagonists and azole antifungal therapy was feasible for patients with migraines and hematological malignancies. None of the patients experienced any grade 3 or higher non-hematological toxicity from the proposed over-exposure to CGRP antagonist. The combination was well tolerated without any need for therapy discontinuation or dose modifications. Conclusions: It is recommended to follow the manufacturers' guidance on drug interactions, however, in the setting where there are no other options, concomitant use of CGRP antagonists with azole antifungals is possible with monitoring and observation for adverse effects. [ABSTRACT FROM AUTHOR]

Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the use of onabotulinumtoxin A (ONA) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the treatment of PTH. A comprehensive literature search was conducted on PubMed, including studies published up to September 2024, focusing on the efficacy, safety, and mechanisms of onabotulinumtoxin A and anti-CGRP mAbs in PTH. Both clinical trials and observational studies were reviewed. ONA, widely recognized for its efficacy in chronic migraine, has shown limited benefits in PTH with only one trial involving abobotulinumtoxin A in a cohort of 40 subjects. A phase 2 trial with fremanezumab, an anti-CGRP monoclonal antibody, failed to demonstrate significant efficacy in PTH, raising questions about the utility of targeting CGRP in this condition. ONA may offer advantages over anti-CGRP mAbs, not only in terms of its broader mechanism of action but also in cost-effectiveness and higher patient adherence. Both ONA and anti-CGRP mAbs are potential options for the management of PTH, but the current evidence is insufficient to establish clear guidelines. The negative results from the fremanezumab trial suggest that CGRP inhibition may not be sufficient for treating PTH, whereas onabotulinumtoxin A's ability to target multiple pain pathways may make it a more promising candidate. [ABSTRACT FROM AUTHOR]

Migraine has a high prevalence worldwide and is one of the main disabling neurological diseases in individuals under the age of 50. In general, treatment includes the use of oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for mild attacks, and, for moderate or severe attacks, triptans or 5-HT1B/1D receptor agonists. However, the administration of antimigraine drugs in conventional oral pharmaceutical dosage forms is a challenge, since many molecules have difficulty crossing the blood-brain barrier (BBB) to reach the brain, which leads to bioavailability problems. Efforts have been made to find alternative delivery systems and/or routes for antimigraine drugs. In vivo studies have shown that it is possible to administer drugs directly into the brain via the intranasal (IN) or the nose-to-brain route, thus avoiding the need for the molecules to cross the BBB. In this field, the use of lipid nanoparticles, in particular solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has shown promising results, since they have several advantages for drugs administered via the IN route, including increased absorption and reduced enzymatic degradation, improving bioavailability. Furthermore, SLN and NLC are capable of co-encapsulating drugs, promoting their simultaneous delivery to the site of therapeutic action, which can be a promising approach for the acute migraine treatment. This review highlights the potential of using SLN and NLC to improve the treatment of acute migraine via the nose-to-brain route. First sections describe the pathophysiology and the currently available pharmacological treatment for acute migraine, followed by an outline of the mechanisms underlying the nose-to-brain route. Afterwards, the main features of SLN and NLC and the most recent in vivo studies investigating the use of these nanoparticles for the treatment of acute migraine are presented. [ABSTRACT FROM AUTHOR]

This document contains summaries of various research studies conducted in Spain. The studies cover a range of topics, including antibiotic effectiveness in treating urinary tract infections, adverse events associated with immune checkpoint inhibitors, non-commercial clinical trials, compliance with safety reporting regulations, clinical trial safety activities and workload, the efficacy of montelukast in long COVID patients, prospective genotyping for statin therapy, sex-based differences in adverse events, anti-cytomegalovirus T lymphocyte therapy, nabiximols for cannabis detoxification, gender differences in alcohol effects, and the safety and efficacy of platelet-rich plasma for erectile dysfunction. These studies provide valuable insights into different medical conditions and treatments, highlighting the need for further research and personalized care. [Extracted from the article]

This document provides summaries of several articles related to pharmacology and toxicology. The first article focuses on late adverse events in patients with aggressive B-cell non-Hodgkin lymphoma treated with CAR T-cell therapy, finding that infections and cytopenias were the most common late adverse events. The second article discusses the implementation of automated systems for detecting adverse drug reactions in hospitalized patients, which improved patient safety. The third article examines the profile of patients admitted to a hospital for acute drug poisoning, with benzodiazepines, 4-aminophenol derivatives, and antipsychotics being the most common substances involved. The fourth article characterizes a patient cohort with multiple adverse drug reactions, finding that comorbidities, age, and sex played a role in adverse drug reaction generation. The final article emphasizes the importance of data quality in multi-database pharmacoepidemiologic studies for generating reliable real-world evidence. Additionally, there are summaries of studies on the effectiveness and cost of monoclonal antibodies for migraine treatment, non-response to antiplatelet therapy in high-risk patients, the scientific production generated by a database of real-world data, therapeutic recommendations for ADHD patients, and the chemopreventive effect of antiplatelet drugs on digestive cancers. [Extracted from the article]

Objective: Our primary outcome was to determine the feasibility of patients with post‐traumatic headache (PTH) keeping a daily headache diary and using sumatriptan as directed. Secondary outcomes include determining if sumatriptan is effective in aborting PTH and whether headache resolution is dependent on PTH phenotype. Background: PTH is prevalent and persistent after traumatic brain injury, yet there have been few studies evaluating the effects of pharmacological treatments in individuals with PTH. Methods: This is a single‐arm, prospective, non‐randomized phase 2 clinical trial registered at Clinicaltrials.gov (NCT01854385) and conducted from 2013 to 2017. Data analysis was completed in 2022. Of the 299 participants screened, 40 were enrolled in the study. Participants kept a headache diary documenting headache characteristics and severity. Headache characteristics were used to determine PTH phenotypes of migraine‐like, probable migraine‐like, or non‐migraine‐like. Participants reported whether sumatriptan was used for their headache, their response to the medication, if a second dose was taken, and their response to the second dose. Results: A total of 15 participants out of the 40 enrolled (mean [SD] age, 41.9 [14.2] years, and 53% [21/40] male), met the criteria for the use of sumatriptan, and completed all assessments. Average headache diary compliance rate for the final month of the study was 80% (372/465). While sumatriptan was used for only 19% (122/654) of all reported headaches, 72% (88/122) of those headaches resolved within 2 h of taking the medication. Resolution of headaches with sumatriptan was not significantly different among headache phenotypes (migraine‐like: 22/38 [58%], probable migraine‐like: 24/29 [83%], non‐migraine‐like: 6/15 [40%]; p = 0.154). Conclusions: A daily headache diary is feasible for tracking headache symptoms. Preliminary results also suggest that sumatriptan, a migraine‐specific medication, may be beneficial for the treatment of PTH of different clinical phenotypes. Future studies, such as a phase 3 clinical trial with a larger sample size, are needed to better understand the efficacy of sumatriptan in the treatment of PTH. Plain Language Summary: Headache is the most common persistent symptom after traumatic brain injury, yet there are no evidence‐based treatments for post‐traumatic headache (PTH). In this study, we evaluated the ability of individuals with PTH to complete a daily headache diary and their response to treatment with sumatriptan. About 80% of participants completed the daily headache diary, and 72% of headaches resolved within 2 h of taking sumatriptan, so we concluded that a daily headache diary is useful in documenting headache symptoms and sumatriptan may be an effective treatment for PTH. [ABSTRACT FROM AUTHOR]

Background: Calcitonin gene-related peptide (CGRP), implicated in migraine pain, also possesses bone anabolic properties, which leads to the possibility that monoclonal antibodies targeting CGRP (anti-CGRPs) might increase the risk of bone density abnormalities. Objective: The objective of this study was to explore bone mineral density abnormalities in a cohort of migraine patients treated with anti-CGRPs. Methods: This was a single-center, cross-sectional, cohort study including migraine patients who underwent a densitometry assessment during anti-CGRP treatment. We assessed the frequency of osteopenia or osteoporosis (OSTEO+ status), defined as a bone mineral density T-score of −1 to −2.5, and <−2.5 standard deviations from the young female adult mean, respectively. Additionally, the association of OSTEO+ status with anti-CGRP treatment duration and primary osteoporosis' risk factors was investigated using logistic regression models. Results: Data from 51 patients (43 female, mean age 46 ± 13.9 years) were evaluated. The mean duration of anti-CGRP treatment was 15.7 (±11.8) months. Twenty-seven patients (53%) were OSTEO+ (n = 22 osteopenia; n = 5 osteoporosis). In the final model, menopause [odds ratio 11.641 (95% confidence interval 1.486–91.197), p = 0.019] and anti-seizure drug use [odds ratio 12.825 (95% confidence interval 1.162–141.569), p = 0.037] were associated with OSTEO+ status. Conclusions: In our cohort of migraine patients, no evidence of an association between anti-CGRP treatment duration and an increasing risk of bone mineral density abnormalities was found. However, these findings are preliminary and necessitate further longitudinal research with larger cohorts and extended follow-up to be validated. [ABSTRACT FROM AUTHOR]

Background: About 9% of the overall population suffers from migraine headaches, with a female majority. For the prevention of migraines, the two most often prescribed drugs are topiramate (TPM) and flunarizine. Regarding TPM and flunarizine's long-term efficacy, safety, and adverse effects on migraine prevention, little is known. To evaluate the effectiveness of flunarizine against TPM in migraine prophylaxis and its impact on psychomotor ability, the current study was designed. Aims and Objectives: The aim of the study was to compare the efficacy of flunarizine and TPM in the prophylaxis of migraine and to assess change in the psychomotor ability of the brain using different psychomotor analysis scoring systems. Materials and Methods: A comparative, open-label, and prospective study was carried out on patients with chronic migraine from the outpatient department of the neurology department at Uttar Pradesh University of Medical Sciences, Saifai, Uttar Pradesh, with flunarizine and TPM treatment (n = 20/group) for 2 months. Data regarding patient's scores of headache severity on the Visual Analogue Scale (VAS), digit later substitution test, 6 letter cancellation test, digit span test, mathematical ability test, and flicker fusion apparatus test were recorded and analyzed. Results: When compared to the baseline, the mean±standard deviation pain severity score on the VAS was 2.9 ± 0.8 in the flunarizine group and 3.7 ± 1.4 in the TPM group, with a P < 0.001. Furthermore, the flunarizine group showed less decline in performances in the scores of each psychomotor test as compared with the scores of the TPM treatment group when baseline values were compared at 1 and 2 months. Conclusion: Flunarizine is well tolerated, has a better safety profile, and has less cognitive decline as compared to TPM. [ABSTRACT FROM AUTHOR]

Background: Existing literature on the impact of lipid accumulation product (LAP) and visceral adiposity index (VAI) on severe headache or migraine is limited. This study aims to elucidate the association between LAP and VAI and the prevalence of migraine. Methods: Data for this study were sourced from the 1999–2004 National Health and Nutrition Examination Survey (NHANES). A database-self-administered questionnaire was used to assess severe headache or migraine. A weighted logistic regression model was employed to assess the relationship between LAP and VAI with migraine prevalence. Complementary analytical approaches included subgroup analysis, restricted cubic spline (RCS), and threshold effect analysis to validate the findings. Results: In the end, 4572 people were recruited for the research, including 880 with migraine and 3692 without migraine. Following adjustment for the relevant covariables, weighted logistic regression analysis (OR = 1.409, 95% CI: 1.054, 1.883, P = 0.022; OR = 1.288, 95% CI: 1.010, 1.642, P = 0.042) revealed significantly elevated odds of migraine prevalence in participants within the highest tertile (T3) of LAP and VAI than those in the lowest tertile (T1). The nonlinear association between migraine prevalence and both VAI and LAP was further elucidated through a restricted cubic spline. The threshold analysis pinpointed 2.142 (log-likelihood ratio = 0.016) as the critical inflection point for VAI. Subgroup analysis and interaction testing revealed the significant association was independent in different subgroup factors. Conclusions: The data indicate a robust association between higher levels of LAP and VAI and an increased prevalence of migraine. [ABSTRACT FROM AUTHOR]

Chronic orofacial pain disorders are common debilitating conditions, affecting the trigeminal system. Its underlying pathophysiological mechanisms are still unclear and the therapy is often unsatisfactory, therefore, preclinical models are crucial to identify the key mediators and novel treatment options. Complete Freund's adjuvant (CFA)-induced orofacial inflammatory allodynia/hyperalgesia is commonly used in rodents, but it has not been validated with currently used drugs. Here we tested the effects of the adjuvant analgesic/antiepileptic voltagegated Na+ channel blocker complex mechanism of action topiramate in comparison with the gold standard antimigraine serotonin 5-HT1B/D receptor agonist sumatriptan in this model. CFA was injected subcutaneously into the right whisker pad of male Sprague-Dawley rats (250-300 g), then mechanonociceptive threshold values were investigated with von Frey filaments (3, 5, and 7 days after CFA injection). Effects of topiramate (30 mg/kg per os) and sumatriptan (1 mg/kg subcutaneous) on the adjuvantinduced chronic inflammatory orofacial allodynia were investigated 60, 120, and 180 min after the treatments each day. To determine the optimal concentration for drug effect analysis, we tested the effects of two different CFA-concentrations (1 and 0.5 mg/mL) on mechanonociceptive thresholds. Both concentrations of CFA induced a chronic orofacial allodynia in 60% of all rats. Although, higher CFA concentration induced greater allodynia, much more stable threshold reduction was observed with the lower CFA concentration: on day 3 the thresholds decreased from 18.30 g to approximately 11 g (low) and 5 g (high), respectively, however a slight increase was observed in the case of higher CFA concentration (on days 5, 7, and 11). In all investigation days, topiramate showed significant anti-allodynic effect comparing the pre and post drug dose and comparing the vehicle treated to the drug treated groups. Sumatriptan also caused a significant threshold increase compared to pre dose thresholds (day 3) and also showed a slight anti-allodynic effect compared to the vehicle-treated group (day 3 and 5). In the present study CFA-induced chronic orofacial allodynia was reversed by topiramate in rats validating the model with the adjuvant analgesic. Other than establishing a validated orofacial pain-related syndrome model in rats, new ways are opened for the repurposing of topiramate. [ABSTRACT FROM AUTHOR]

Introduction: Migraine, a debilitating neurological disorder characterized by recurrent headaches, affects over 1.1 billion individuals globally. Diabetes mellitus (DM), a chronic metabolic condition marked by high blood sugar levels, affects 463 million individuals according to the International Diabetes Federation. Our study aimed to evaluate the association between migraine and DM and to identify several demographic, socioeconomic, and lifestyle factors, as well as medical and psychiatric comorbidities, associated with migraine among individuals with DM. Methods: This cross-sectional study is based on data from the European Health Interview Surveys conducted in 2009, 2014, and 2019 in Hungary. Pearson's chisquared tests and multiple logistic regression models were used to assess associations. Statistical significance was set at p<0.05. Results: In multiple regression analyses, we found no significant association between DM and migraine after adjusting for socioeconomic status, various health conditions, and lifestyle factors (OR=0.84, 95% CI: 0.66-1.06). However, adults with DM who had comorbid conditions including stroke (OR=2.08, 95% CI: 1.06-4.08), low back pain (OR=3.52, 95% CI: 2.13-5.84), and depression (OR=4.91, 95% CI: 2.84-8.47) were significantly more likely to suffer from migraine. Discussion: Our study found no significant difference in the prevalence of migraine among adults with and without diabetes mellitus. However, several comorbidities were found to be significantly associated with migraine occurrence in those with DM. Thus, the study's results highlight the need for proper management of diabetes, especially in terms of comorbidities, to mitigate migraine risk factors and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Varied responses to acute migraine medications have been observed, with over one‐third (34.5%) of patients reporting insufficient headache relief. Sumatriptan‐naproxen sodium, a single, fixed‐dose combination tablet comprising sumatriptan 85 mg and naproxen sodium 500 mg, was developed with the rationale of targeting multiple putative mechanisms involved in the pathogenesis of migraine to optimise acute migraine care. Methods: A narrative review of clinical trials investigating sumatriptan‐naproxen sodium for both adults and adolescents was performed in March 2024. Results: Across a total of 14 clinical trials in nine publications, sumatriptan‐naproxen sodium offered greater efficacy for 2‐h pain freedom (14/14) and sustained pain‐free response up to 24 h (13/14) compared with monotherapy and/or placebo for both adult and adolescent study participants with an acceptable and well‐tolerated adverse effect profile. Clinical trial data also demonstrates the effectiveness of sumatriptan‐naproxen sodium in participants with allodynia, probable migraine, menstrual‐related migraine and those with poor responses to acute, non‐specific, migraine medication. Conclusions: Multi‐mechanistic therapeutic agents offer an opportunity to optimise acute medications by targeting multiple mediators involved in the pathogenesis of migraine. Sumatriptan‐naproxen sodium resulted in greater initial and sustained pain freedom, compared with either sumatriptan, naproxen‐sodium and/or placebo, for the treatment of single or multiple attacks of migraine across both adult and adolescent study populations. [ABSTRACT FROM AUTHOR]

A single-blind, randomized controlled trial comparing oxycodone and fentanyl for patient-controlled intravenous analgesia (PCIA) after laparoscopic hysteromyomectomy found comparable pain relief between the two groups. The study included 60 participants, with NRS scores for pain at rest and when moving showing no significant differences between oxycodone and fentanyl groups at various time points postoperatively. Self-rating depression scale scores were also similar between the groups at 48 h. However, patients' satisfaction with PCIA was higher in the oxycodone group, with 73.3% reporting being very satisfied compared to 36.7% in the fentanyl group. Additionally, the oxycodone group had fewer incidences of headaches within 48 h postoperatively compared to the fentanyl group. These findings suggest that oxycodone may offer comparable pain relief, higher patient satisfaction, and fewer headaches for patients undergoing laparoscopic hysteromyomectomy compared to fentanyl, making it a suitable option for postoperative pain management in this population. Clinical trial registration number The study was registered with CHICTR.org, ChiCTR2100051924. [ABSTRACT FROM AUTHOR]

Transient Receptor Potential Vanilloid 1 (TRPV1) is a protein that functions as a non-selective channel receptor that is widely expressed in skin tissue, including keratinocytes, peripheral sensory nerve fibers, and immune cells. Several structural features of TRPV1 are involved in heat-induced activation, where stimulation of TRPV1 elicits a burning sensation, reflecting the receptor's important role in pain. A TRPV1-mediated signalling pathway that functions as an endogenous pain resolution mechanism by inducing nuclear translocation of β-arrestin2 to minimize desensitization of μ-opioid receptors (MOR). TRPV1 agonists can reduce pain primarily by interfering with pain nerve conduction. Several TRPV1 antagonist drug candidates have failed in clinical trials because by interfering with the detection of the above-mentioned stimuli, they triggered serious side effects such as hyperthermia and painful impaired heat detection. In the case of agonists, systemic administration causes more severe side effects such as respiratory damage. Therefore, only topical preparations with limited effectiveness have been developed. The TRPV1 agonist capsaicin is currently the only one approved for the treatment of muscle, bone, neuropathic pain and migraine, and is only available as a low-concentration cream or as a transdermal patch. [ABSTRACT FROM AUTHOR]

The study investigated associations between chronotypes (Morning [M], Neither [N], Evening [E]), sociodemographic characteristics, body mass index (BMI), smoking habits, years with migraines, sleep quality (PSQI), anxiety (HADS-A), depression (HADS-D), migraine disability (MIDAS), headache frequency, and pain intensity (VAS) in 80 individuals with migraine. Significant age differences emerged (p < 0.001), with M-types being the oldest. BMI also varied, with M-types presenting the highest median BMI (p = 0.005). While migraine duration and headache frequency showed no significant variance, sleep quality did, with E-types reporting the poorest sleep (p = 0.030). Anxiety and depression were significantly worse in E-types (HADS-A: p = 0.002; HADS-D: p = 0.010). Differences in MIDAS levels were notable (p = 0.038); however, differences in MIDAS scores were not significant (p = 0.115). Pain intensity varied, with E-types experiencing the most severe pain (p = 0.009). Post-hoc analysis showed higher MIDAS scores in E-types compared to N-types (χ2 = 6.56, p = 0.038, ε2 = 0.0831). The findings highlight the need for thorough patient evaluations and tailored care, considering the complex interplay of factors affecting migraine severity, particularly among different chronotypes. [ABSTRACT FROM AUTHOR]

Long-term frequent use of acute pain medication for the treatment of headaches has paradoxically been shown to increase the frequency of headaches. So-called medication-overuse headache (MOH) is particularly problematic in patients with migraine who overuse triptans and opioids. Prevention through education remains the most important management strategy. Once established, MOH can be difficult to treat. Although complete or near-complete withdrawal of acute pain medication for 8–12 weeks has been shown to benefit most patients, this can be hard to achieve. The use of OnabotulinumtoxinA and drugs that target the calcitonin gene-related peptide system for the prevention of migraines have been shown to benefit patients with MOH. Furthermore, the use of novel acute pain medication for migraines, including Gepants and Ditans, which do not cause MOH, are likely to improve patient outcomes. In this review article we examine the following: the burden of MOH; who develops MOH; the pathophysiological mechanisms; and the treatment strategies. [ABSTRACT FROM AUTHOR]

Background Chemometrics is a discipline that allows the spectral resolution of drugs in a pharmaceutical formulation along with degradation product and it is an alternative to chromatographic methods. Objective Sumatriptan (SUM) is co-formulated with naproxen (NAP) and used in acute migraine attacks. SUM, which has physiological importance, has not been subjected to any stability-indicating chemometric approaches yet, so there is a need for an accurate and safe method for the assay of the cited drug in its preparations. The greenness and blueness assessment was applied using different ecological metrics, including the Green Analytical Procedure Index (GAPI), Analytical Greenness Metric (AGREE), Analytical Eco-Scale (AES) and new "blueness" evaluation using the Blue Applicability Grade Index (BAGI) tool. Methods SUM was determined in pharmaceutical formulation along with NAP and in presence of alkali-induced degradation product with simple and cost-effective multivariate approaches using spectrophotometric data. Three chemometric approaches were applied for the stability-indicating determination of SUM in the presence of NAP. Classical least-squares (CLS), partial least-squares regression (PLS), and principal components regression (PCR)—three multivariate calibration numerical models that were applied to the UV spectra of the mixtures—were used to achieve the best resolution. Results Sumatriptan was analyzed with mean accuracies for PLS (100.29% ± 1.318) and for PCR (100.60% ± 1.564). The presented methods were compared and validated for their quantitative analyses. Moreover, statistical comparison between the results obtained by the proposed models and the official methods showed no significant differences. Conclusion The proposed multivariate calibrations were accurate and specific for quantitative analysis of the studied component. PLS is the best method that has the capacity for qualitative analysis of SUM and it is suitable for routine analysis and stability studies of SUM in QC laboratories. Various ecological assessment metrics confirmed the long-standing eco-friendliness of the suggested models. Highlights Severally overlapped mixtures of SUM along with co-formulated drug NAP and an alkali-induced degradation product were analyzed by three chemometric approaches. The analytical performance of PLS and PCR was compared and validated in terms of root-mean-square error of calibration (RMSEC), SE of prediction, and recoveries. PLS gave the highest predicted concentrations with the lowest RMSEC and root-mean-square error of prediction. The standard addition was applied for accuracy assessment and the results were compared to those of official methods. Proposed models determined SUM in synthetic mixtures and pharmaceutical formulation in QC laboratories and stability studies. Ecological evaluation tools for measuring the environmental friendliness of chemicals were utilized for the first time in the analysis of SUM. [ABSTRACT FROM AUTHOR]

Introduction: Glucagon-like peptide-1 receptor agonist use has increased over the last decade for glycemic control in type 2 diabetes mellitus, cardiovascular risk reduction, and weight loss. Clinical trials indicate that gastrointestinal adverse effects are commonly experienced and severe hypoglycemia is rare; however, there is little data regarding glucagon-like peptide-1 receptor agonist in overdose. Methods: We performed a retrospective chart review evaluating and characterizing glucagon-like peptide-1 receptor agonist exposures reported to a single poison center between 2006 and 2023. Patient demographics, circumstances of exposure, clinical effects, and outcomes were abstracted from charts. Descriptive statistics were utilized to summarize demographic information and clinical factor data. Results: A total of 152 charts met inclusion criteria. Therapeutic errors accounted for 91% of exposures. Most patients (67%) reported no symptoms, although not all patients were followed to a definitive outcome. Nausea, vomiting, generalized weakness, and abdominal pain were the predominant symptoms reported. Most patients (62%) were monitored and closely followed in the home setting. Hypoglycemia was rare but occurred in the setting of a single agent glucagon-like peptide-1 receptor agonist exposure in two patients. Two additional patients who developed hypoglycemia involved co-administration of insulin. 21% of the exposures were related to errors on initial use of the pen. Conclusion: Exposures to glucagon-like peptide-1 receptor agonist have increased substantially over the years. Effects from an exposure tended to be mild and primarily involve gastrointestinal symptoms. Hypoglycemia was rare. Therapeutic and administration errors were common. Education on pen administration may help to reduce errors. [ABSTRACT FROM AUTHOR]

In the diagnosis of migraine, which is a neurovascular disease, gadolinium-based contrast agents (GBCAs) are used to rule out more serious conditions. On the other hand, it remains unclear as a scientific gap whether GBCAs may trigger migraine-related pain. The aim of this study was to investigate the effect of GBCAs on mechanical and thermal pain behaviour in a nitroglycerin (NTG)-induced migraine model in mice. NTG (10 mg/kg) was administered intraperitoneally to adult (6–8 weeks old) BALB/c mice 2 h before behavioral tests 5 times every other day on days 1st, 3rd, 5th and 9th to induce migraine model (N = 50). As GBCAs, gadobenate dimeglumine (linear-ionic), Gadodiamide (linear-nonionic), and gadobutrol (macrocyclic-nonionic) were delivered intravenously through the tail vein of mice for 5 days on test days. Mechanical pain threshold (plantar and facial withdrawal threshold) was evaluated by plantar von Frey and periorbital von Frey tests on days 1st, 5th, and 9th, and thermal pain threshold (latency) was evaluated by hot plate and cold plate tests on days 3rd and 7th. There was a statistically significant increase in mechanical and thermal hyperalgesia in NTG administered groups compared to the control group. Gadodiamide, gadobutrol and gadobenate dimeglumine administration significantly decreased latency, paw and facial withdrawal threshold (0.18 ± 0.05, 0.17 ± 0.07, 0.16 ± 0.09; 9th day values respectively) compared to NTG group (0.27 ± 0.05). The results of this in vivo study show that GBCAs produce effects that may trigger migraine attacks in migraine. It is recommended that these effects be further investigated and supported by further clinical studies. [ABSTRACT FROM AUTHOR]

Abstract Background Triptans are potent 5-HT1B/1D/1F receptor agonists used in migraine therapy, thought to act through peripheral mechanisms. It remains unclear whether triptans cross the blood-brain barrier (BBB) sufficiently to stimulate central 5-HT1B/1D/1F receptors. This study investigates the disposition of eletriptan and sumatriptan in central nervous system (CNS) and peripheral nervous system (PNS) regions and predicts regional 5-HT1B/1D/1F receptor occupancies at clinically relevant concentrations. Methods Using the Combinatory Mapping Approach (CMA) for regions of interest (ROI), we assessed the unbound tissue-to-plasma concentration ratio (Kp, uu, ROI) in rats at steady state across CNS (hypothalamus, brain stem, cerebellum, frontal cortex, parietal cortex, striatum, hippocampus, whole brain, and spinal cord) and PNS (trigeminal ganglion and sciatic nerve) regions. We used Kp, uu, ROI values to estimate unbound target-site concentrations and 5-HT1B/1D/1F receptor occupancies in humans. Results We observed heterogenous triptan transport across CNS and PNS regions with the highest extent of unbound drug transport across the blood-nerve barrier in the trigeminal ganglion (Kp, uu, TG: eletriptan: 0.519, and sumatriptan: 0.923). Both drugs displayed restricted entry across the BBB (Kp, uu, whole brain: eletriptan: 0.058, and sumatriptan: 0.045) combined with high inter-regional variability. We estimated near-complete receptor occupancy in the trigeminal ganglion, while lower occupancies were observed in the whole brain, irrespective of the drug or receptor subtype. For instance, eletriptan was predicted to achieve 84% 5-HT1B receptor occupancy in the trigeminal ganglion and 37% in the whole brain at clinically relevant concentrations. Conclusions This study suggests that despite low BBB transport, both eletriptan and sumatriptan achieve unbound concentrations sufficient to stimulate 5-HT1B, 5-HT1D, and 5-HT1F receptors not only in the trigeminal ganglion, but also in the CNS. Further research is needed to determine whether central mechanisms contribute to triptan’s antimigraine effect and/or side effects. Graphical Abstract

Background and Objective: STS101 is an investigational drug–device combination comprising 5.2 mg dihydroergotamine (DHE) powder (6.0 mg DHE mesylate) in a single-use nasal delivery device for the acute treatment of migraine. The primary objective of the ASCEND trial was to assess long-term safety and tolerability of STS101 in the acute treatment of migraine attacks across 12–18 months, with secondary objectives describing efficacy. Methods: ASCEND was an open-label study of STS101 in adults aged 18–65 years with a ≥ 1 year history of migraine with or without aura, with onset before the age of 50 years and 4–12 migraine attacks/month and < 15 headache days/month in each of the 3 months prior to screening. Exclusion criteria included diagnosis of non-migraine headache, history of cerebrovascular disease, and ≥ 2 cardiovascular risk factors. After establishing eligibility, participants could self-administer STS101 5.2 mg as needed for up to 2 doses within 24 h to treat a single migraine attack and up to 12 doses/month. Safety and tolerability evaluations included physical and nasal examinations, vital signs, laboratory tests, and treatment-emergent adverse event (TEAE) assessments. Participants used an electronic diary to record exploratory efficacy parameters, including intensity of headache pain and associated migraine symptoms (photophobia, phonophobia, and nausea). Participant impression questions were asked at months 3, 6, and 12. Results: Of the 6610 migraine attacks treated with a total of 8234 STS101 doses in 344 participants, 945/6610 (14.3%) were associated with a TEAE. Events were predominantly mild or moderate in nature and rarely led to premature study discontinuation (15/344 [4.4%] participants). Treatment was associated with rapid onset of freedom from pain (36.6%, 67.1%, and 85.5% of treated attacks 2, 4, and 24 h post-dose, respectively), freedom from most bothersome symptoms (54.3%, 79.6%, and 91.3%), and headache relief (66.5%, 89.1%, and 94.3%). Most participants rated treatment results as good or very good and ease of use as easy or very easy at all time points (months 3, 6, and 12) and indicated they were likely or very likely to use STS101 again. Conclusions: The repeated long-term, as-needed use of STS101 was well tolerated, demonstrating a favorable safety profile in the acute treatment of migraine attacks in appropriately indicated adults. Exploratory efficacy evaluations indicated beneficial effects, which warrant further evaluation. Trial Registration: ClinicalTrials.gov identification NCT04406649. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (Covid-19) is a pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In Covid-19, there is uncontrolled activation of immune cells with a massive release of pro-inflammatory cytokines and the development of cytokine storm. These inflammatory changes induce impairment of different organ functions, including the central nervous system (CNS), leading to acute brain injury and substantial changes in the neurotransmitters, including serotonin (5-HT) and calcitonin gene-related peptide (CGRP), which have immunomodulatory properties through modulation of central and peripheral immune responses. In Covid-19, 5-HT neurotransmitters and CGRP could contribute to abnormal and atypical vascular reactivity. Sumatriptan is a pre-synaptic 5-HT (5-HT1D and 5-HT1B) agonist and inhibits the release of CGRP. Both 5-HT and CGRP seem to be augmented in Covid-19 due to underlying activation of inflammatory signaling pathways and hyperinflammation. In virtue of its anti-inflammatory and antioxidant properties with inhibition release of 5-HT and CGRP, Sumatriptan may reduce Covid-19 hyperinflammation. Therefore, Sumatriptan might be a novel potential therapeutic strategy in managing Covid-19. In conclusion, Sumatriptan could be an effective therapeutic strategy in managing Covid-19 through modulation of 5-HT neurotransmitters and inhibiting CGRP. [ABSTRACT FROM AUTHOR]

Background: Diverse studies have revealed discrepant evidence concerning the causal association between Corona Virus Disease 2019 (COVID-19) and COVID-19 vaccination in relation to migraines. Investigating the correlation between the former two factors and migraines can facilitate policymakers in the precise formulation of comprehensive post-pandemic interventions while urging the populace to adopt a judicious perspective on COVID-19 vaccination. Methods: We undertook a Mendelian randomization (MR) study. The primary assessment of the causal relationship between the three different COVID-19 exposures and migraine was conducted using the standard inverse variance weighted (IVW) approach. In the supplementary analysis, we also employed two methodologies: the weighted median estimator (WME) and the MR-Egger regression. Ultimately, the reliability and stability of the outcomes were assessed via Cochran's Q test, the leave-one-out method, the MR-Egger intercept test, and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Results: The results indicate an absence of correlation between genetically predicted COVID-19 (①Very severe respiratory confirmed COVID-19: odds ratio [OR], 1.0000881; 95%CI, 0.999748–1.000428; p = 0.6118; ②Hospitalized COVID-19: OR, 1.000024; 95%CI, 0.9994893–1.000559; p = 0.931;③SARS-CoV-2 infection: OR, 1.000358; 95%CI, 0.999023–1.001695; p = 0.5993) and the risk of migraine. Furthermore, the MR-Egger regression and WME also yielded no evidence of COVID-19 elevating the risk of migraine occurrence. Sensitivity analysis affirmed the robustness and consistency of all outcomes. Conclusions: The results of this study do not offer genetic evidence to substantiate a causal relationship between COVID-19 and migraines. Thus, the deduction drawn from COVID-19 genetic data is that COVID-19 vaccination is unlikely to exert an impact on the occurrence of migraines, though this conclusion warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the real-world profile of adverse events (AEs) associated with gepant medications in the clinical treatment of migraines by analyzing data collected from the VigiAccess database and the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. As novel migraine therapies, gepants act by targeting the calcitonin gene-related peptide (CGRP) pathway, demonstrating effective control of migraine attacks and good tolerability. Nonetheless, comprehensive realworld studies on the safety of gepants are still lacking, particularly regarding their safety in large populations, long-term use, and potential adverse reactions in specific groups, which necessitates further empirical research. Leveraging these two international adverse event reporting system databases, we systematically gathered and analyzed reports of AEs related to gepant medications, such as rimegepant. Our focus encompasses but is not limited to severe, new, and rare adverse reactions induced by the drugs, as well as safety issues pertaining to the gastrointestinal, cardiovascular, hepatic, and renal systems. Through descriptive statistical analyses, we assessed the incidence and characteristics of AEs, compared AEs among gepants, and uncovered previously unknown AE information, all with the goal of providing a reference for the selection of clinical treatment regimens and AE monitoring. Methods: By extracting all AE reports concerning "rimegepant", "atogepant", and "ubrogepant" from the VigiAccess and FAERS database since its establishment up to 31 March 2024, a retrospective quantitative analysis was conducted. The reporting odds ratio (ROR) method were used to compare AEs among the three gepants. Results: In the VigiAccess and FAERS databases, 23542 AE reports in total, respectively, were identified as being related to gepant medications. Among gastrointestinal system AEs, rimegepant had the greatest proportion and greatest signal strength; nausea was most severe and had the strongest signal in rimegepant AEs, whereas constipation was most prominent and had the strongest signal in atogepant AEs. In skin and subcutaneous tissue disorders, rash and pruritus were more frequently observed with rimegepant, followed by ubrogepant. Alopecia emerged as a novel AE, being more severe in rimegepant and secondarily in atogepant. Regarding cardiac disorders, the three gepants showed comparable rates of cardiac AEs, yet rimegepant exhibited the strongest AE signal. In musculoskeletal and connective tissue AEs, ubrogepant presented the most positive signals for skeletal muscle AEs. Furthermore, among the rare blood and lymphatic system disorder AEs, rimegepant had the highest number of reports of Raynaud's phenomenon and the strongest signal. The study also revealed that while reports of AEs involving liver diseases were scarce across the three gepants, severe AEs were detected in clinical trials, highlighting the need for continued, enhanced monitoring of liver system AEs through large-scale datasets. Conclusion: Gepant medications exhibit similarities and differences in their safety profiles. Analysis of the two databases indicated the presence of AEs across various systems, including gastrointestinal disorders, skin and subcutaneous tissue diseases, musculoskeletal and connective tissue disorders, organ-specific effects, and liver diseases. However, each drug displays distinct incidences and signal intensities for these AEs. Additionally, the study revealed a rare AE in the form of Raynaud's phenomenon. These findings suggest that during clinical use, individualized medication selection and AE monitoring should be based on the patient's physiological condition and specific characteristics. [ABSTRACT FROM AUTHOR]

Background: Migraine and dizziness often coexist, with vestibular migraine (VM) presenting with vestibular symptoms and headaches. Calcitonin gene-related peptide (CGRP) may be involved in motion-induced symptoms; however, studies on the use of anti-CGRP monoclonal antibodies (mAbs) for the treatment of VM have yielded conflicting results. This study aimed to clarify the effectiveness of anti-CGRP mAbs in VM treatment. Methods: This retrospective observational cohort study, conducted between 1 January 2021 and 31 March 2023, assessed 12 Japanese patients with VM who were treated with anti-CGRP mAbs (CGRP group) for 6 months and 11 Japanese patients who received standard of care for VM and served as controls. Clinical questionnaires and equilibrium tests were administered, with primary outcomes including changes in Dizziness Handicap Inventory (DHI) scores compared with baseline values. Objective variables included the DHI score and explanatory variables included demographic data, balance test results, head-up tilt (HUT) test results, vestibular test results and questionnaire survey results. Analysis of variance was used to assess the treatment effects of anti-CGRP mAbs, and multivariate regression analysis was performed to identify mAb responders. Results: After 6 months, the CGRP group showed significant improvements in DHI scores [0 versus 6 months, odds ratio (95% confidence interval): 22.01 (0.13–43.88)] and number of vertigo/dizziness attacks per month [0 versus 6 months: 10.28 (2.80–17.76)]. No significant difference was observed in the control group [DHI scores, 0 versus 6 months: 0.65 (−26.84 to 28.14); number of vertigo/dizziness attacks per month, 0 versus 6 months: − 8.07 (− 23.77 to 7.62)]. Multivariate regression analysis showed that autonomic function at baseline was associated with mAb response in patients [β estimates (95% confidence interval): 3.63 (0.21–7.06)]. Conclusions: Treatment with anti-CGRP mAbs was more effective than conventional treatment in preventing migraine in patients with VM. While the identified factors associated with treatment responsiveness offer valuable insights into personalised treatment approaches, further prospective studies are warranted to validate the findings due to our study's retrospective design and limited sample size. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are novel high-cost treatments for the prevention of migraine. This study presents data on utilization, expenditure, and treatment patterns with CGRP mAbs available under a managed access protocol in Ireland, to a cohort of treatment refractory patients (failed 3 or more previous treatments) with chronic migraine. Data were extracted from the Primary Care Reimbursement Service High Tech claims database and special drug request online system and analyzed using Microsoft Excel and SAS. Treatment persistence was evaluated by refill patterns, and adherence was evaluated using the proportion of days covered method. Expenditure data were extracted directly from the database. Between September 1, 2021 and April 30, 2023, 1517 applications for reimbursement approval for a CGRP mAb were received; 1458 (96.1%) were approved for reimbursement. Total expenditure on CGRP mAbs in year 1 (September 1, 2021 to August 31, 2022) was €3.2 million. The majority of patients initiated treatment with fremanezumab (60.8%) or erenumab (37.1%). Almost 90% of patients were considered adherent, and treatment persistence was high, with more than 75% of patients receiving more than 12 months of treatment in our 18-month study time frame. This study demonstrates the importance of active health technology management, after reimbursement, in enabling cost-effective use of high-cost treatments while providing budget certainty for the healthcare payer. High levels of adherence and persistence suggest that treatment is successfully targeted in situations which unmet clinical need is greatest. • Calcitonin gene-related peptide monoclonal antibodies are novel, high-cost treatments for the prevention of migraine. • In 1 year of reimbursement in Ireland, the total expenditure on calcitonin gene-related peptide was €3.2 million, with the majority of approved patients being highly treatment adherent. • Health technology management can ensure cost containment while maintaining access to treatment in situations which unmet clinical need is greatest. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding the best antibiotic regimen and the route of administration to treat acute focal bacterial nephritis (AFBN) is scarce. The aim of the present study was to compare the effectiveness of intravenous (IV) β-lactam antibiotics versus oral quinolones. Methods: This is a retrospective single centre study of patients diagnosed with AFBN between January 2017 and December 2018 in Hospital Universitari Vall d'Hebron, Barcelona (Spain). Patients were identified from the diagnostic codifications database. Patients treated with oral quinolones were compared with those treated with IV β-lactam antibiotics. Therapeutic failure was defined as death, relapse, or evolution to abscess within the first 30 days. Results: A total of 264 patients fulfilled the inclusion criteria. Of those, 103 patients (39%) received oral ciprofloxacin, and 70 (26.5%) IV β-lactam. The most common isolated microorganism was Escherichia coli (149, 73.8%) followed by Klebsiella pneumoniae (26, 12.9%). Mean duration of treatment was 21.3 days (SD 7.9). There were no statistical differences regarding therapeutic failure between oral quinolones and IV β-lactam treatment (6.6% vs. 8.7%, p = 0.6). Out of the 66 patients treated with intravenous antibiotics, 4 (6.1%) experienced an episode of phlebitis and 1 patient (1.5%) an episode of catheter-related bacteraemia. Conclusions: When susceptible, treatment of AFBN with oral quinolones is as effective as IV β-lactam treatment with fewer adverse events. [ABSTRACT FROM AUTHOR]

The use of haloperidol in pain management has been a topic of interest for several decades. Haloperidol is a widely used antipsychotic medication with unique pharmacologic properties that make it a potential candidate for pain management. However, the efficacy and safety of haloperidol for pain management remain controversial. This narrative review provides a summary of the current literature on the use of haloperidol for pain management, including its pharmacology, clinical effectiveness, adverse effects, and dosing regimens. We performed a comprehensive search of the literature for this review. The most robust clinical data from the past decade suggest that haloperidol has good efficacy in the treatment of pain related to gastroparesis and migraines and has shown promise for opioid use reduction in patients with chronic pain or receiving palliative care. The overall side effect profile is excellent, with zero reported events of QT-related cardiac arrest and minimal reports of sedation and transient extrapyramidal effects such as akathisia. Dosing regimens used were heterogeneous, with most ranging from 1 to 5 mg per dose via intravenous, intramuscular, or oral route. Studies with designs that isolated the effects of haloperidol from combinations of other drugs were extremely limited. Further high-quality prospective studies are needed to determine the ideal role of haloperidol in the routine clinical management of painful conditions. [ABSTRACT FROM AUTHOR]

Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development. [ABSTRACT FROM AUTHOR]

Around 91% of migraine patients use over-the-counter medicines to treat attacks, often without further treatment or medical consultation. This therapeutic principle is established in most countries, regardless of how the healthcare system is otherwise structured or financed. Using Germany as an example, the basis for an expansion of attack therapy with rizatriptan as an over-the-counter triptan is described. To achieve the best possible tolerability and safety in the context of self-medication, the lowest possible dose should be selected to provide the most favourable tolerability and safety profile in the context of self-medication through low dosages. The lowest approved dose of rizatriptan is 5 mg. This was investigated in three randomized controlled trials with 752 patients. The results show that rizatriptan at a dose of 5 mg is more effective than the triptans naratriptan 2.5 mg, almotriptan 12.5 mg and sumatriptan 50 mg, which were previously available for self-medication in Germany. There was no significant difference in the frequency of adverse events with rizatriptan 5 mg compared to placebo. Rizatriptan 5 mg does not have a higher side effect potential than sumatriptan 50 mg, which is already exempt from the prescription requirement. The reasons given show that rizatriptan in a dose of 5 mg for the treatment of acute migraine attacks fulfils the requirements for a transfer from prescription to pharmacy-only status at least as well as sumatriptan 50 mg, naratriptan 2.5 mg and almotriptan 12.5 mg. From a clinical care perspective, it is desirable for affected patients to have other options available for self-medication. Non-responders to other substances also have a further treatment option with rizatriptan 5 mg, with the same or even better risk–benefit profile, to treat migraine attacks safely, effectively and in a tolerable manner as part of self-medication. [ABSTRACT FROM AUTHOR]

Objective: Closure surgery of patent foramen ovale (PFO) has been found to effectively control cryptogenic stroke and migraine, but it is uncertain whether PFO closure could also alleviate epileptic seizures. This study aims to observe the therapeutic effect of PFO closure on epileptic seizures. Methods: Since July 11th, 2017, in the neurology department of West China Hospital, Sichuan University, Chengdu, we have been regularly monitoring patients with epilepsy who have undergone PFO closure. The patient's clinical information, such as frequency, duration, and severity of seizures, before and after surgery was recorded in detail as well as postoperative safety events. Results: Of the 31 epilepsy patients who confirmed PFO observed (27 cases were drug‐resistant epilepsy, 87.10%), average age of surgery was 23.74 years, and 12 cases were female (38.71%). After one‐year follow‐up, 26 patients (83.87%) achieved remission of seizure frequency, and 22 of whom (70.97%) experienced a remission of more than 50%. Additionally, compared to before surgery, 22 cases (70.97%) reported a decrease in the average seizure duration, and 20 cases (64.52%) reported a reduction in seizure severity. In the seizure indicators of frequency, average duration and severity, significant differences were identified between preoperative and postoperative comparisons with all test p values were <0.05. Furthermore, no serious safety events were reported except for one patient who briefly reported chest pain, and all patients expressed effective PFO closure. Significance: The PFO closure has been shown for the first time to result in a significant reduction in the frequency, duration, and severity of seizures. Patients with drug‐resistant epilepsy and PFO with a large shunt are ideal candidates for undergoing PFO closure. Plain Language Summary: Since PFO closure was found to have a good therapeutic effect on cryptogenic stroke and migraine, it has become a credible complementary therapy for the treatment of neurological diseases, and drug‐resistant epilepsy with PFO is expected to become the next target disease that PFO closure could significantly improve. [ABSTRACT FROM AUTHOR]

Rationale: Reducing the risk of exacerbation is a fundamental goal in managing stable chronic obstructive pulmonary disease (COPD). Guidelines recommend triple therapy (inhaled corticosteroids, long-acting muscarinic antagonists, and long-acting β-agonists) only as a stepup from dual therapy (long-acting muscarinic antagonists and long-acting β-agonists) for patients at continued high risk of exacerbation, because of the trade-off of an increased risk of pneumonia associated with inhaled corticosteroid–containing therapies. However, there is little evidence on the optimum timing of initiating triple therapy. Objectives: To perform a benefit–harm analysis to evaluate the net benefit of earlier initiation of triple therapy for the prevention of acute exacerbations in patients with COPD compared with standard timing recommended in current guidelines. Methods: We used a validated whole-disease microsimulation model of COPD in the Canadian general population aged ⩾40 years to determine the benefit versus harm of earlier initiation of triple therapy over a 20-year time horizon compared with standard care. We assessed net change in quality-adjusted life-years (QALYs) from the reduction in risk of acute exacerbations and the increased risk of treatment-related pneumonia in subgroups of patients with COPD defined by exacerbation history, symptoms, and disease severity. Model parameters were determined from clinical trials and other published literature. Key parameters were varied in one-way sensitivity analysis. Results: In patients at high risk of acute exacerbation (54.7% female; mean age, 74.0 yr; 68% Global Initiative for Chronic Obstructive Lung Disease grades I and II), earlier initiation of triple therapy was associated with a net QALY gain of 4.8 per 100 patients with COPD over 20 years compared with standard care. The net QALY gain increased to 5.9 per 100 patients in the subgroup of patients with a high symptom burden (modified Medical Research Council dyspnea scale score, >1). Earlier initiation remained net beneficial in all subgroup and sensitivity analysis scenarios. Conclusions: Modeling suggests that earlier initiation of triple therapy is likely to be net beneficial for patients at high risk of acute exacerbation, with an even greater benefit to patients with a high symptom burden. Further clinical research is needed to verify these findings in empirical studies. [ABSTRACT FROM AUTHOR]

Purpose: The prevalence of migraine headache is higher in women. Low barometric pressure is a factor in headache triggering, but sex-related differences have not been identified. The purpose of this study was to examine sex-related differences in headache triggered by low barometric pressure. Methods: Study subjects aged 20–49 years were randomly selected from a research company's (Macromill, Inc.) web panel. Those with chronic migraine or tension-type headache invited to complete a web-based self-administered questionnaire. Logistic regression analysis was performed with the objective variable as the Headache Impact Test-6 (HIT-6) high scores (56 or more) or headache triggered by low barometric pressure. Results: Participants were 332 women and 337 men in the headache population. HIT-6 high scores were associated with age at headache occurrence 20 years or younger (OR: odds ratio 1.85, 95% CI: confidence interval 1.15–2.99, p = 0.012) and headache triggered by low barometric pressure (OR 2.11, 95%CI 1.51–2.94, p < 0.001). Headache triggered by low barometric pressure was significantly associated with women (OR 2.92, 95%CI 2.12–4.02, p < 0.001). Conclusions: Headache triggered by low barometric pressure were related to sex-related differences. It was suggested that a sex-specific treatment approach for headache triggering is needed. [ABSTRACT FROM AUTHOR]

Nandina domestica: Thunb. is a traditional Chinese herbal drug that has long been used in China and Japan for the treatment of colds, fevers, asthma, chronic bronchitis, conjunctivitis, whooping cough, pharyngeal tumors, etc. Published data have reported at least 366 constituents from N. domestica, including alkaloids, flavonoids, lignans, terpenoids, phenolic acids and their derivatives, fatty acids, and others. Of these, the isoquinoline alkaloids are considered characteristic markers for N. domestica. These alkaloids also showed the most promising bioactivities. The crude extracts or semi-purified constituents of N. domestica exhibit a variety of activities, including antitumor, dermatological, antiinflammatory, antioxidant, antimicrobial, and detoxification activities, as well as effects on respiratory system, etc. The fruit is considered poisonous when eaten raw, with nausea, vomiting, diarrhea, and abdominal pain as side effects after ingestion. Most traditional uses are supported by biological activities demonstrated in modern experimental studies, suggesting a potential medicinal value of N. domestica. However, more information is needed on its mechanisms of activity, pharmacokinetic profile of the constituents, and its safety and efficacy profile in humans. [ABSTRACT FROM AUTHOR]

Due to more frequent and intense attacks, chronic migraine (CM) sufferers usually report more disability compared to patients with episodic migraine (EM). There is increasing evidence that points to inflammatory diet and lifestyle as a probable underlying cause of migraine. The present study investigated the association of dietary and lifestyle inflammation scores (DLIS) with the odds of CM in Iranian women. In the current study, 285 women with migraine enrolled. Migraine was diagnosed by a single neurologist based on the third edition of the International Classification of Headache Disorders (ICHD-III). The women were categorized into CM and EM groups based on their attack frequency per month. Adherence to the dietary inflammation score (DIS), Lifestyle Inflammatory Score (LIS), and DLIS (DIS + LIS) was assessed based on last year's dietary intakes collected using a semi-quantitative food frequency questionnaire (FFQ). The Odds Ratio (OR) for CM across the DIS, LIS, and DLIS tertiles were assessed through logistic regression. Most of the participants were overweight or obese (74.4%). The percentage of women with CM was 40.7%. Women with CM had significantly higher DIS (P = 0.002) and DLIS (P = 0.04) than women with EM. There was a significant positive association between CM and DIS. Those in the third tertile of the DIS had almost two times higher chance of experiencing chronic migraine compared with those in the first tertile [OR = 2.02; 95% CI 1.06–3.82; P = 0.03]. the P-value for the trend also was significant (0.03). In terms of LIS and DLIS tertiles, no significant association was observed. Adherence to the more inflammatory diets was associated with higher chances of experiencing CM in women. [ABSTRACT FROM AUTHOR]

Migraine is a complex disorder characterized by episodes of moderate-to-severe, often unilateral headaches and generally accompanied by nausea, vomiting, and increased sensitivity to light (photophobia), sound (phonophobia), and smell (hyperosmia). Photophobia is considered the most bothersome symptom of migraine attacks. Although the underlying mechanism remains unclear, the intrinsically photosensitive retinal ganglion cells (ipRGCs) are considered to be involved in photophobia associated with migraine. In this study, we investigated the association between the sensitivity of ipRGCs and migraines and cortical spreading depression (CSD), which may trigger migraine attacks. The pupillary responses closely associated with the function of ipRGCs in patients with migraine who were irradiated with lights were evaluated. Blue (486 nm) light irradiation elicited a response from ipRGCs; however, red light (560 nm) had no such effect. Melanopsin, a photosensitive protein, phototransduces in ipRGCs following blue light stimulation. Hypersensitivity of ipRGCs was observed in patients with migraine. CSD was more easily induced with blue light than with incandescent light using a mouse CSD model. Moreover, CSD was suppressed, even in the presence of blue light, after injecting opsinamide, a melanopsin inhibitor. The hypersensitivity of ipRGCs in patients with migraine may induce CSD, resulting in migraine attacks. [ABSTRACT FROM AUTHOR]