Calcitonin Gene-related Peptide Receptor Antagonist Research Articles

Effect of chronic intermittent hypoxia on ocular and intraoral mechanical allodynia mediated via the calcitonin gene-related peptide in a rat.

Obstructive sleep apnea, a significant hypoxic condition, may exacerbate several orofacial pain conditions. The study aims to define the involvement of calcitonin gene-related peptide (CGRP) in peripheral and central sensitization and in evoking orofacial mechanical allodynia under chronic intermittent hypoxia (CIH). Male rats were exposed to CIH. Orofacial mechanical allodynia was assessed using the eyeblink test and the two-bottle preference drinking test. The CGRP-immunoreactive neurons in the trigeminal ganglion (TG), CGRP-positive primary afferents projecting to laminae I-II of the trigeminal spinal subnucleus caudalis (Vc), and neural responses in the second-order neurons of the Vc were determined by immunohistochemistry. CGRP receptor antagonist was administrated in the TG. CIH-induced ocular and intraoral mechanical allodynia. CGRP-immunoreactive neurons and activated satellite glial cells (SGCs) were significantly increased in the TG and the number of cFos-immunoreactive cells in laminae I-II of the Vc were significantly higher in CIH rats compared to normoxic rats. Local administration of the CGRP receptor antagonist in the TG of CIH rats attenuated orofacial mechanical allodynia; the number of CGRP-immunoreactive neurons and activated SGCs in the TG, and the density of CGRP-positive primary afferent terminals and the number of cFos-immunoreactive cells in laminae I-II of the Vc were significantly lower compared to vehicle-administrated CIH rats. An increase in CGRP in the TG induced by CIH, as well as orofacial mechanical allodynia and central sensitization of second-order neurons in the Vc, supported the notion that CGRP plays a critical role in CIH-induced orofacial mechanical allodynia.

Characteristics associated with response to subcutaneously administered anti-CGRP monoclonal antibody medications in areal-world community cohort of persons living with migraine: Aretrospective clinical and genetic study.

To evaluate response to anti-calcitonin gene-related peptide (CGRP) migraine preventives in a real-world community cohort of persons living with migraine and to identify clinical and genetic characteristics associated with efficacious response. Erenumab-aooeb, fremanezumab-vrfm, and galcanezumab-gnlm target CGRP or its receptor; however, many patients are non-responsive. In this retrospective clinical and genetic study, we identified 1077 adult patients who satisfied the International Classification of Headache Disorders, 3rd edition, criteria for migraine without aura, migraine with aura, or chronic migraine and who were prescribed an anti-CGRP migraine preventive between May 2018 and May 2021. Screening of 558 patients identified 289 with data at baseline and first follow-up visits; data were available for 161 patients at a second follow-up visit. The primary outcome was migraine days per month (MDM). In 198 genotyped patients, we evaluated associations between responders (i.e., patients with ≥50% reduction in MDM at follow-up) and genes involved in CGRP signaling or pharmacological response, and genetic and polygenic risk scores. The median time to first follow-up was 4.4 (0.9-22) months after preventive start. At the second follow-up, 5.7 (0.9-13) months later, 145 patients had continued on the same preventive. Preventives had strong, persistent effects in reducing MDM in responders (follow-up 1: η2 = 0.26, follow-up 2: η2 = 0.22). At the first but not second follow-up: galcanezumab had a larger effect than erenumab, while no difference was seen at either follow-up between galcanezumab and fremanezumab or fremanezumab and erenumab. The decrease in MDM at follow-up was generally proportional to baseline MDM, larger in females, and increased with months on medication. At the first follow-up only, patients with prior hospitalization for migraine or who had not responded to more preventive regimens had a smaller decrease in MDM. Reasons for stopping or switching a preventive varied between medications and were often related to cost and insurance coverage. At both follow-ups, patient tolerance (1: 92.2% [262/284]; 2: 95.2% [141/145]) and continued use (1: 77.5% [224/289]; 2: 80.6% [116/145]) were high and similar across preventives. Response consistency (always non-responders: 31.7% [46/145]; always responders: 56.5% [82/145], and one-time only responders: 11.7% [17/145]) was also similar across preventives. Non-responder status had nominally significant associations with rs12615320-G in RAMP1 (odds ratio [95% confidence interval]: 4.7 [1.5, 14.7]), and rs4680-A in COMT (0.6[0.4, 0.9]). Non-responders had a lower mean genetic risk score than responders (1.0 vs. 1.1; t(df) = -1.75(174.84), p = 0.041), and the fraction of responders increased with genetic and polygenic risk score percentile. In this real-world setting, anti-CGRP preventives reduced MDM persistently and had similar and large effect sizes on MDM reduction; however, clinical and genetic factors influenced response.

Inhibition of Neurogenic Inflammatory Pathways Associated with the Reduction in Discogenic Back Pain.

Retrospective cohort study. This study aimed to determine whether the initiation of anti-calcitonin gene-related peptide (CGRP inhibitor) medication therapy for migraines was also associated with improvements in back/neck pain, mobility, and function in a patient population with comorbid degenerative spinal disease and migraine. CGRP upregulates pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, brain-derived neurotrophic factor, and nerve growth factor in spinal spondylotic disease, which results in disc degeneration and sensitization of nociceptive neurons. Although CGRP inhibitors can quell neurogenic inflammation in migraines, their off-site efficacy as a therapeutic target for discogenic back/neck pain conditions remains unknown. All adult patients diagnosed with spinal spondylosis and migraine treated with CGRP inhibitors at a single academic institution between 2017 and 2020 were retrospectively identified. Patient demographic and medical data, follow-up duration, migraine severity and frequency, spinal pain, functional status, and mobility before and after the administration of CGRP inhibitors were collected. Paired univariate analysis was conducted to determine significant changes in spinal pain, headache severity, and headache frequency before and after the administration of CGRP inhibitors. The correlation between changes in the spinal pain score and functional or mobility improvement was assessed with Spearman's rho. In total, 56 patients were included. The mean follow-up time after the administration of CGRP inhibitors was 123 days for spinal pain visits and 129 days for migraine visits. Back/neck pain decreased significantly (p <0.001) from 6.30 to 4.36 after starting CGRP inhibitor therapy for migraine control. As recorded in the spine follow-up notes, 25% of patients experienced a functional improvement in the activities of daily living, and 17.5% experienced mobility improvement while taking CGRP inhibitors. Change in back/ neck pain moderately correlated (ρ=-0.430) with functional improvement but was not correlated with mobility improvement (ρ=-0.052). Patients taking CGRP inhibitors for chronic migraines with comorbid degenerative spinal conditions experienced significant off-target reduction of back/neck pain.

Lessons learned in translating pain knowledge into practice.

During the past 2 decades, basic research deciphering the underlying mechanisms of nociception and chronic pain was thought to finally step beyond opioids and nonsteroidals and provide patients with new analgesics. But apart from calcitonin gene-related peptide antagonists, nothing arrived in hands of clinicians. To present existing evidence of 3 representative target molecules in the development of novel pain treatment that, so far, did not result in approved drugs. This Clinical Update aligns with the 2022 IASP Global Year Translating Pain Knowledge into Practice and selectively reviews best available evidence and practice. We highlight 3 targets: a ion channel, a neuronal growth factor, and a neuropeptide to explore why these drug targets have been dropped in clinical phase II-III trials. Antibodies to nerve growth factor had very good effects in musculoskeletal pain but resulted into more patients requiring joint replacements. Blockers of NaV1.7 were often not effective enough-at least if patients were not stratified. Blockers of neurokinin receptor were similarly not successful enough. In general, failure was most often to the result of a lack of effect and to a lesser extend because of unexpected severe side effects. However, all studies and trials lead to an enormous move in the scientific community to better preclinical models and testing as well as revised methods to molecularly phenotype and stratify patients. All stakeholders in the process can help in the future: better preclinical studies, phenotyping and stratifying patients, and participation in clinical trials to move the discovery of analgesics forward.

Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA

Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist that is approved for acute treatment of migraine. The prodrome is the earliest phase of a migraine attack and is characterised by non-aura symptoms that precede headache onset. The aim of this trial was to evaluate the efficacy, safety, and tolerability of ubrogepant 100 mg compared with placebo for the acute treatment of migraine when administered during the prodrome. This PRODROME trial was a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial of ubrogepant 100 mg conducted at 75 research centres and headache clinics in the USA. Eligible participants were adults aged 18-75 years who had at least a 1-year history of migraine with or without aura and a history of two to eight migraine attacks per month with moderate to severe headache in each of the 3 months before screening. Eligible participants were randomly assigned (1:1) to either receive placebo to treat the first qualifying prodrome event and ubrogepant 100 mg to treat the second qualifying prodrome event or to receive ubrogepant 100 mg to treat the first qualifying prodrome event and placebo to treat the second qualifying prodrome event. An automated interactive web-response system used permuted blocks of four to manage randomisation. All people giving interventions and assessing outcomes were masked to group assignment during the study. People doing data analysis, which occurred after study completion, were not masked to group assignment. During the double-blind treatment period, each participant was instructed to orally take two tablets of the study drug at the onset of each qualifying prodrome event. The primary endpoint was absence of moderate or severe intensity headache within 24 h after study-drug dose; efficacy analyses were conducted with the modified intention-to-treat (mITT) population, defined as all randomly assigned participants with at least one headache assessment within 24 h after taking the study drug during the treatment period. The safety population included all treated participants who took at least one administration of study drug. The trial is registered with ClinicalTrials.gov (NCT04492020). Between Aug 21, 2020, and April 19, 2022, 518 participants were randomly assigned to double-blind crossover treatment. The safety population included 480 participants and the mITT population included 477 participants; 421 (88%) of 480 participants were female and 59 (12%) were male. Absence of moderate or severe headache within 24 h after a dose occurred after 190 (46%) of 418 qualifying prodrome events that had been treated with ubrogepant and after 121 (29%) of 423 qualifying prodrome events that had been treated with placebo (odds ratio 2·09, 95% CI 1·63-2·69; p<0·0001). Adverse events that occurred within 48 h after study-drug administration were reported after 77 (17%) of 456 qualifying prodrome events that had been treated with ubrogepant and after 55 (12%) of 462 events that had been treated with placebo. Ubrogepant was effective and well tolerated for the treatment of migraine attacks when taken during the prodrome. AbbVie.

Treatment patterns for patients initiating novel acute migraine specific medications (nAMSMs) in the context of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway

BackgroundNew acute and preventive migraine medications are available, but data on current treatment patterns are limited. This study describes migraine treatment patterns among patients initiating novel acute migraine specific medications (nAMSMs), overall and by prior use of anti-calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies (mAbs).MethodsIn this retrospective cohort study using IQVIA open-source pharmacy and medical claims data, we identified patients with ≥ 1 claim for a nAMSM (ubrogepant, rimegepant, lasmiditan) between 01/01/2020 and 09/30/2020 (index period). Patients were indexed on their first nAMSM claim and stratified into 2 cohorts: patients with prior mAb use (≥ 1 claim for erenumab, fremanezumab, galcanezumab in the 6-month pre-index period) or patients without prior mAb use. Treatment patterns were assessed during the 6-month post-index period.ResultsOverall, 78,574 patients were identified (63% indexed on ubrogepant, 34% on rimegepant, and 3% on lasmiditan) with 26,656 patients (34%) having had prior mAb use. In the pre-index period, 79% of patients used non-mAb preventive medications and 75% of patients used acute medications. Following the index nAMSM claim, 65% of patients had ≥ 1 refill and 21% had ≥ 4 refills of their index nAMSM; 10% of patients switched to another nAMSM. Post-index mAb use was observed in 82% of patients with a prior mAb and 15% of patients without. Among patients with pre- and post-index use of acute medications, 38% discontinued ≥ 1 acute medication class in the post-index period. Among patients with concomitant use of traditional preventive medications at index, 30% discontinued ≥ 1 concomitant preventive anti-migraine medication in the post-index period.ConclusionsMost patients initiating nAMSMs had prior treatment with acute and preventive medications. Approximately one-third of patients had prior treatment with anti-CGRP pathway mAbs. After starting nAMSMs, more than one-third of patients discontinued at least one traditional acute medication and one-third of patients discontinued at least one traditional preventive medication.Despite nAMSM initiation, most patients with prior anti-CGRP pathway mAb use continued mAb use. Around 15% of patients without a prior mAb newly started a mAb. These results provide insight into how nAMSMs and mAbs have been integrated into clinical management of migraine in the real-world.

A Comprehensive Review of the Mechanism, Efficacy, Safety, and Tolerability of Ubrogepant in the Treatment of Migraine.

Ubrogepant is an innovative medication designed for the acute treatment of migraine, a debilitating neurological condition that profoundly impairs quality of life, productivity, and social interactions. This comprehensive review assesses the efficacy, safety, tolerability, and mechanism of action of ubrogepant through a rigorous methodology, including an in-depth literature review from reputable databases like PubMed, Web of Science, Embase, Scopus, and Cochrane. Classified as a calcitonin gene-related peptide (CGRP) receptor antagonist, ubrogepant has emerged as a potential revolutionary medication for migraine treatment. CGRP is a peptide integral to migraine pathophysiology, and its blockade has demonstrated great therapeutic potential. Unlike triptans, known for their cardiovascular risks, ubrogepant lacks vasoconstrictive properties, making it a safer alternative for a broader patient population. Ubrogepant offers significant potential for pain relief, symptom reduction, and restoration of normal function during a migraine attack, and it outperforms placebo in terms of efficacy. It also presents favorable safety, with generally mild adverse drug events (ADEs), such as nausea, dizziness, and somnolence, similar to placebo effects. Consistent results from clinical trials confirm its tolerability, with minor ADEs and no safety alerts for the tested doses, indicating that ubrogepant is a safe and well-tolerated option for migraine treatment. As an effective oral medication, ubrogepant could be an alternative to traditional acute migraine treatments. Its benefits include a unique mechanism of action, rapid onset, and favorable safety profile. However, specific contraindications, such as hypersensitivity, severe hepatic impairment, concurrent use of CYP3A4 inhibitors, pregnancy or breastfeeding, and uncontrolled hypertension, require caution or avoidance of ubrogepant. Despite these limitations, ubrogepant signals a promising new direction in migraine therapeutics.

Real-World Use of Ubrogepant as Acute Treatment for Migraine with an Anti-Calcitonin Gene-Related Peptide Monoclonal Antibody: Results from COURAGE.

Although acute and preventive treatments for migraine are commonly given in combination, data on the real-world effectiveness of ubrogepant as an acute treatment when used with an anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (with or without onabotulinumtoxinA) are limited. This analysis sought to evaluate the real-world effectiveness, treatment satisfaction, and optimization of ubrogepant for the acute treatment of migraine when used in combination with an anti-CGRP monoclonal antibody, with or without concomitant onabotulinumtoxinA. This prospective, multiple-attack, open-label, observational study (COURAGE) assessed meaningful pain relief (MPR), return to normal function (RNF), treatment satisfaction, and acute treatment optimization of ubrogepant (50 or 100mg) when combined with an anti-CGRP monoclonal antibody, onabotulinumtoxinA, or both in adult users of Migraine Buddy, a migraine tracking application. In the ubrogepant and anti-CGRP monoclonal antibody arm (n = 245), following the first ubrogepant-treated attack, 61.6% (151/245) and 80.4% (197/245) of ubrogepant-treated participants achieved MPR at 2 and 4h post-dose, respectively, and 34.7% (85/245) and 55.5% (136/245) achieved RNF at 2 and 4h post-dose, respectively. Across up to 10 ubrogepant-treated attacks (N = 1153), MPR was achieved in 51.3% (592/1153) and 73.5% (847/1153) at 2 and 4h post-dose, respectively. RNF was achieved by 32.2% (371/1153) and 53.2% (613/1153) at 2 and 4h post-dose. After 30days, 72.7% (168/231) of participants reported satisfaction (using a 7-point scale) with ubrogepant when used in combination with an anti-CGRP monoclonal antibody, and 79.7% (184/231) of participants achieved acute treatment optimization (defined as moderate-maximum treatment efficacy using the Migraine Treatment Optimization Questionnaire-4). Real-world ubrogepant use with an anti-CGRP monoclonal antibody was associated with MPR, RNF, satisfaction, and acute treatment optimization.

Sensory nerves, but not sympathetic nerves, promote reparative dentine formation after dentine injury via CGRP-mediated angiogenesis: An in vivo study.

Dental pulp is richly innervated by nerve fibres, which are mainly involved in the sensation of pain. Aside from pain sensation, little is known regarding the role of dental innervation in reparative dentine formation. We herein generated a mouse model of experimental dentine injury to examine nerve sprouting within the odontoblast and subodontoblastic layers and investigated the potential effects of this innervation in reparative dentinogenesis. Mouse tooth cavity model (bur preparation + etching) was established, and then nerve sprouting, angiogenesis and reparative dentinogenesis were determined by histological and immunofluorescent staining at 1, 3, 7, 14 and 28 days postoperatively. We also established the mouse-denervated molar models to determine the role of sensory and sympathetic nerves in reparative dentinogenesis, respectively. Finally, we applied calcitonin gene-related peptide (CGRP) receptor antagonist to analyse the changes in angiogenesis and reparative dentinogenesis. Sequential histological results from dentine-exposed teeth revealed a significant increase in innervation directly beneath the injured area on the first day after dentine exposure, followed by vascularisation and reparative dentine production at 3 and 7 days, respectively. Intriguingly, abundant type H vessels (CD31+ Endomucin+ ) were present in the innervated area, and their formation precedes the onset of reparative dentine formation. Additionally, we found that sensory denervation led to blunted angiogenesis and impaired dentinogenesis, while sympathetic denervation did not affect dentinogenesis. Moreover, a marked increase in the density of CGRP+ nerve fibres was seen on day 3, which was reduced but remained elevated over the baseline level on day 14, whereas the density of substance P-positive nerve fibres did not change significantly. CGRP receptor antagonist-treated mice showed similar results as those with sensory denervation, including impairments in type H angiogenesis, which confirms the importance of CGRP in the formation of type H vessels. Dental pulp sensory nerves act as an essential upstream mediator to promote angiogenesis, including the formation of type H vessels, and reparative dentinogenesis. CGRP signalling governs the nerve-vessel-reparative dentine network, which is mostly produced by newly dense sensory nerve fibres within the dental pulp.

Potential Predictors of Response to CGRP Monoclonal Antibodies in Chronic Migraine: Real-World Data.

Real-world data (RWD) has identified potential predictors of response to anti-CGRP therapies in patients with chronic migraine (CM). This review aims to synthesize the most remarkable findings published to date regarding this topic. Migraine features such as unilateral pain and positive triptan response and chronic features such as daily headache or medication overuse (MO) emerge as predictors of positive outcomes, potentially linked to elevated baseline serum anti-calcitonin gene-related peptide (anti-CGRP) levels. Demographic and baseline characteristics, encompassing obesity, psychiatric comorbidities, and prior refractoriness to prophylactic treatments, are associated with poor responses in both treatment-naïve patients and after-switch scenarios. Nevertheless, the consistency of these predictors across diverse populations requires further investigation. Recent RWD literature highlights emerging predictors of response of different sources among patients with CM receiving anti-CGRP therapies. Comprehending these predictors and identifying novel biomarkers of response hold the potential to refine treatment strategies for CM patients, enhancing their management and therapeutic outcomes.

Depression and treatment with anti-calcitonin gene related peptide (CGRP) (ligand or receptor) antibodies for migraine.

The aim was to evaluate the effect of anti-calcitonin gene related peptide (CGRP) (ligand or receptor) antibodies on depressive symptoms in subjects with migraine and to determine whether depressive symptoms predict treatment response. Patients with migraine treated with erenumab and fremanezumab at the Leiden Headache Centre completed daily E-headache diaries. A control group was included. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Center for Epidemiological Studies Depression Scale (CES-D) questionnaires at baseline (T0) and after 3 months (T1). First, the effect of treatment on the reduction in HADS-D and CES-D scores was assessed, with reduction in depression scores as the dependent variable and reduction in monthly migraine days (MMD) and treatment with anti-CGRP medication as independent variables. Second, depression as a predictor of treatment response was investigated, using the absolute reduction in MMD as a dependent variable and age, gender, MMD, active depression, impact, stress and locus of control scores as independent variables. In total, n = 108 patients were treated with erenumab, n = 90 with fremanezumab and n = 68 were without active treatment. Treatment with anti-CGRP medication was positively associated with a reduction in the HADS-D (β = 1.65, p = 0.01) compared to control, independent of MMD reduction. However, the same effect was not found for the CES-D (β = 2.15, p = 0.21). Active depression predicted poorer response to erenumab (p = 0.02) but not to fremanezumab (p = 0.09). Anti-CGRP (ligand or receptor) monoclonals lead to improvement of depressive symptoms in individuals with migraine, independent of migraine reduction. Depression may predict treatment response to erenumab but not to fremanezumab.

Patterns of anti-CGRP mAbs use and variation of triptan consumption following treatment initiation: A descriptive drug utilization study in the Tuscany region, Italy.

To describe the pattern of anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) utilization in the Tuscany region, Italy, and the variation of triptan consumption after treatment initiation. Given the recent commercialization of anti-CGRP mAbs as migraine preventive medications, real-world evidence on their patterns of utilization and their impact on migraine abortive medication use is still limited. A retrospective, descriptive, cohort study on the real-world utilization of anti-CGRP mAbs was performed using the population-based regional administrative database of Tuscany. Patients with ≥1 anti-CGRP mAb dispensing (namely erenumab, galcanezumab, fremanezumab) between April 1, 2019, and September 30, 2021, were identified. The first dispensing was the cohort entry (CE). New users (NUs) were patients with no anti-CGRP mAb dispensing before CE. Kaplan-Meier (KM) curves were plotted to describe the cumulative probability of remaining with the initial anti-CGRP mAb during a 15-month follow-up period as a measure of treatment persistence. Among NUs with ≥2 triptan dispensings during the 6 months before CE (i.e., baseline), the mean monthly number of triptan dosage units dispensed was measured in five consecutive follow-up time windows (months 1-3, 4-6, 7-9, 10-12, 13-15) and the difference from the baseline was calculated. A total of 624 NUs (erenumab = 295, galcanezumab = 223, fremanezumab = 106) were identified, of whom 188 (78%) were women. Mean age was 49.2 years (standard deviation [SD] = 12.6). The survival to discontinuation at 6, 12, and 15 months was about 69%, 48%, and 6%, respectively. The survival to switch was about 6% at 15 months. The observed variation of triptan consumption at 3/6/9/12/15 months and the corresponding SD was -4.4 [8.2]/-5.2 [9.0]/-5.5 [9.2]/-5.4 [9.2]/-4.5 [10.0], respectively. Patient demographics reflect the place of these medications in therapy. Overall, findings seem to indicate a favorable tolerability and effectiveness profile. Further studies are warranted to better establish the long-term comparative effectiveness, safety, and cost effectiveness of anti-CGRP mAbs compared to other preventive medications.

Antinociceptive effect of the calcitonin gene-related peptide receptor antagonist BIBN4096BS in mice with bacterial cystitis.

Patients with urinary tract infections (UTIs) suffer from urinary frequency, urgency, dysuria, and suprapubic pain, but the mechanisms by which bladder afferents sense the presence of uropathogens and encode this information is not well understood. Calcitonin gene-related peptide (CGRP) is a 37-mer neuropeptide found in a subset of bladder afferents that terminate primarily in the lamina propria. Here, we report that the CGRP receptor antagonist BIBN4096BS lessens lower urinary tract symptoms and prevents the development of pelvic allodynia in mice inoculated with uropathogenic Escherichia coli (UPEC) without altering urine bacterial loads or the host immune response to the infection. These findings indicate that CGRP facilitates the processing of noxious/inflammatory stimuli during UPEC infection. Using fluorescent in situ hybridization, we identified a population of suburothelial fibroblasts in the lamina propria, a region where afferent fibers containing CGRP terminate, that expresses the canonical CGRP receptor components Calcrl and Ramp1. We propose that these fibroblasts, in conjunction with CGRP+ afferents, form a circuit that senses substances released during the infection and transmit this noxious information to the central nervous system.NEW & NOTEWORTHY Afferent C fibers release neuropeptides including calcitonin gene-related peptide (CGRP). Here, we show that the specific CGRP receptor antagonist, BIBN409BS, ameliorates lower urinary tract symptoms and pelvic allodynia in mice inoculated with uropathogenic E. coli. Using fluorescent in situ hybridization, we identified a population of suburothelial fibroblasts in the lamina propria that expresses the canonical CGRP receptor. Our findings indicate that CGRP contributes to the transmission of nociceptive information arising from the bladder.

Long-Term Management of Migraine With OnabotulinumtoxinA (Botox) vs Calcitonin Gene-Related Peptide Antibodies (Anti-CGRP).

In this literature review, we will evaluate the effectiveness of OnabotulinumtoxinA (Botox) and anti-calcitonin gene-related peptide (anti-CGRP) in the treatment of migraine headaches. Both therapies are frequently prescribed for managing and preventing migraines and have received Food and Drug Administration (FDA) approval. The mechanism of action, side effects, compliance, cost-effectiveness, and migraine treatment provided by these two medicines were compared in the analysis of several studies. Many studies found that as Botox was administered by a doctor every three months and had fewer side effects than anti-CGRP, which is self-administered every month, it was more compliant than anti-CGRP. After examining the data, Botox is believed to be the most effective therapy. Although both therapies are efficient, this article compares them to determine which is the best management strategy.

A retrospective analysis of migraine prophylaxis with anti-CGRP monoclonal antibodies at the hospital of Lithuanian University of Health Sciences Kaunas Clinics

Background. Migraine is a primary headache disorder described by episodic attacks that can progress to chronic migraine. Preventive treatment of anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) is currently being widely investigated worldwide.Materials and methods. A total of 85 patients with migraine were enrolled in a retrospective study conducted in 2019-2021. Demographic and clinical data were collected and analyzed. Subjects were divided into groups by migraine course: chronic migraine (CM) and episodic migraine (EM), and according to the medicine used (erenumab, fremanezumab). Treatment efficacy was assessed at 3 and 6 months after the start of treatment. A reduction of &gt;50% in monthly headache days (MHDs) was considered a good response. Statistical analysis was performed using IBM SPSS statistics 27.0, the χ² test of homogeneity, Fisher’s exact, Student’s t, and Mann-Whitney tests.Results. Of the 85 migraine patients, 75 (88.2%) were women. EM was diagnosed in 33 (38.8%) and CM in 52 (61.2%) patients. After treatment, the number of MHDs was significantly reduced in both anti-CGRP mAbs therapy groups (p&lt;0.001). The response to anti-CGRP mAbs was similar between the EM and CM groups. A slightly better response was achieved with fremanezumab than erenumab (83.3% vs. 73.1% at 3 months; 83.3% vs. 65.7% at 6 months), but the difference was not significant (p=0.541; p=0.149). In 24 (58.5%) patients initially given 70 mg erenumab, after a median follow-up of 3 months (interquartile range: 2-6) it was decided to increase the dose of erenumab to 140 mg due to insufficient effect. The initial dose was increased more often in patients with chronic migraine (p=0.027).Conclusions. Erenumab and fremanezumab are equally effective and equivalent for both migraine types. It was observed that more than half of the patients required a dose increase when treated with erenumab 70 mg, especially in CM group.

Comparative Efficacy and Safety of Five Anti-Calcitonin Gene-Related Peptide Agents for Migraine Prevention: A Network Meta-Analysis.

Anti-Calcitonin gene-related peptide (CGRP) agents are some of the newest preventive medications for migraine. There is limited literature comparing the efficacy of the most recent CGRP antagonist, atogepant, to CGRP monoclonal antibodies (mAbs) for migraine prevention. In this network meta-analysis (NMA), the efficacy and safety of migraine treatments including different doses of atogepant and CGRP mAbs were evaluated to provide a reference for future clinical trials. A search using PubMed, Embase and Cochrane Library identified all randomized controlled trials (RCTs) published through May 2022 and including patients diagnosed with episodic or chronic migraine and treated with erenumab, fremanezumab, eptinezumab, galcanezumab, atogepant, or placebo. The primary outcomes were the reduction of monthly migraine days, 50% response rate, and the number of adverse events (AEs). The Cochrane Collaboration tool was used to assess the risk of bias. In this study, 24 articles were considered for analysis. Regarding effectiveness, all interventions were superior to placebo with a statistically significant difference. The most effective intervention was monthly fremanezumab 225mg in change from baseline of migraine days (SMD=-0.49,95%CI[-0.62, -0.37]) and 50% response rate (RR=2.98,95%CI[2.16,4.10]), while the optimal choice for reducing acute medication days was monthly erenumab 140mg(SMD=-0.68,95%CI[-0.79, -0.58]). In terms of AEs, all therapies and placebo did not achieve statistical significance except for monthly galcanezumab 240mg and quarterly fremanezumab 675mg. There was no significant difference in discontinuation due to AEs between interventions and placebo. All anti-CGRP agents were more effective than placebo in migraine prevention. Overall, monthly fremanezumab 225mg, monthly erenumab 140mg, and daily atogepant 60mg were effective interventions with fewer side effects.

S2543 Pan-Colitis Secondary to Calcitonin Gene-Related Peptide (CGRP) Antagonist for Migraines

S2543 Pan-Colitis Secondary to Calcitonin Gene-Related Peptide (CGRP) Antagonist for Migraines

Preventive and abortive treatment of migraine with traditional drugs. The state of the art

IntroductionMigraine is a chronic neurological disease, with a prevalence of 15.2% in Brazil. It is 2.2 times more prevalent in women, predominantly in the 18-50 age group. Its pathophysiological mechanism is still not completely understood. Possibly headache attacks and symptoms are associated with cortical spreading depression, the trigeminovascular system, neurogenic inflammation, vasodilation and genetic vulnerability.ObjectiveThis is a narrative review of preventive and abortive treatment of migraine.CommentMigraine treatment is based on three pillars: patient education, treatment of the disease itself or prevention of attacks, and acute treatment of headache attacks. The therapeutic classes of traditional drugs used in migraine prevention are beta-blockers, tricyclic antidepressants, calcium channel antagonists or blockers, and anticonvulsant neuromodulators. Specific drugs used in the treatment of headache attacks are triptans or serotonergic 5-HT1B/1D receptor agonists, ditans or 5-HT1F receptor agonists, and gepants or CGRP receptor antagonists.ConclusionTraditional drugs used in the preventive or abortive treatment of migraine are considered to be effective. Through modulation of the disease mechanisms, there is a reduction in the frequency, intensity and duration of headache attacks, and also in the disability caused by the headache. All this to improve the quality of life of patients. The therapeutic classes of traditional drugs used in migraine prevention are beta-blockers, tricyclic antidepressants, antagonists or blockers of calcium channels and anticonvulsant neuromodulators. Specific drugs used in the treatment of headache attacks are triptans or serotonergic 5-HT1B/1D receptor agonists,ditans or 5-HT1F receptor agonists, and gepants or CGRP receptor antagonists.

Novel peptide calcitonin gene-related peptide antagonists for migraine therapy.

It has previously been shown that the peptide (34Pro,35Phe)CGRP27-37 is a potent calcitonin gene-related peptide, CGRP receptor antagonist, and in this project we aimed to improve the antagonist potency through the structural modification of truncated C-terminal CGRP peptides. Six peptide analogues were synthesized and the anti-CGRP activity confirmed using both in vitro and in vivo studies. A 10 amino acid-containing peptide VPTDVGPFAF-NH2 (P006) was identified as a key candidate to take forward for in vivo evaluation, where it was shown to be an effective antagonist after intraperitoneal injection into mice. P006 was formulated as a preparation suitable for nasal administration by spray drying with chitosan to form mucoadhesive microcarriers (9.55 ± 0.91 mm diameter) and a loading of 0.2 mg peptide per 20 mg dose. The project has demonstrated the potential of these novel small peptide CGRP antagonists, to undergo future preclinical evaluation as anti-migraine therapeutics.

Conventional and unconventional treatments for migraine

Migraine is one of the leading causes of disability in humans. It causes significant deterioration in patients' lives and prevents daily functioning. Its main symptoms include photophobia, an enormous stabbing headache, nausea and vomiting. In addition, it can be accompanied by tinnitus, visual disturbances or dizziness. Before diagnosing migraine, serious intracranial pathology or other neurological conditions should be ruled out. Treatment of acute migraine is difficult due to significant rates of nonresponse to medications and the difficulty in predicting individual response to a particular agent or dose. A new class of drugs, calcitonin gene-related peptide (CGRP) antagonists, has been approved for the prevention of migraine in adults. In contrast, effective first-line therapies for mild to moderate migraine are over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) and combination analgesics containing paracetamol, aspirin and caffeine.