Calcitonin Gene-related Peptide Antibodies Research Articles

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.

Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

Anti-CGRP-based Migraine Medications: A Comprehensive Overview

In the early 1990s, the neuropeptide calcitonin gene-related peptide (CGRP) was identified as a key messenger in the pathophysiology of migraine and emerged as a treatment target, fundamentally transforming our approach to migraine therapy. While previous prophylactic drugs were non-specific and often caused intolerable side effects, the discovery of CGRP marked the advent of a new era in migraine treatment. The two main classes of CGRP-specific migraine treatments are monoclonal antibodies that bind to CGRP or the CGRP receptor, and CGRP receptor antagonists, the so-called gepants. Extensive clinical trials have conclusively demonstrated the safety, tolerability, and efficacy of monoclonal CGRP(-receptor) antibodies in the prophylactic treatment of both episodic and chronic migraine. The same positive results apply to the use of various gepants. They have proven to be not only an effective alternative to triptans in acute migraine therapy but also promising options for continuous use as prophylactic treatments. In this review, we aim to present the current state of research on CGRP-specific migraine therapy and insights in real-world data from the first years after their launch in clinical practice.

Efficacy and Safety of Anti-calcitonin Gene-Related Peptide (CGRP) Monoclonal Antibodies in Preventing Migraines: A Systematic Review.

The neuropeptide calcitonin gene-related peptide (CGRP) is an essential pathophysiological treatment for migraines. A unique class of medications called CGRP monoclonal antibodies target CGRP and its receptor and have demonstrated promising benefits in the treatment and prevention of migraines. This study sought to identify and assess the quality of existing systematic reviews about the effectiveness of CGRP antibodies for preventing migraines, as well as systematically review and synthesize the evidence on these topics. This included the four Food and Drug Administration (FDA)-approved medications erenumab, galcanezumab, fremanezumab, and eptinezumab. The effectiveness and safety of these monoclonal antibodies in preventing migraines should also be examined in light of patient characteristics, and any gaps in the body of knowledge should be noted in order to suggest new lines of investigation. Data gathering included a thorough search of internet databases (PubMed, Cochrane Library, Web of Science, and Scopus) for relevant research released between 2018 and 2023. The findings imply that CGRP monoclonal antibodies are efficient and secure for preventing migraines and may be considered a first-line alternative for treating migraines and drug misuse. The results further imply that combination treatment with CGRP antibodies and onabotulinumtoxinA may enhance the prevention of migraine in adults. With suggestions for more studies to find and address these variables, the significance of genetic and epigenetic factors in the progression of pediatric patients' acute postoperative pain to chronic postsurgical pain is underlined. All four anti-CGRP monoclonal antibodies, erenumab, fremanezumab, galcanezumab, and eptinezumab, were shown to be safe and effective for the prevention of migraine when the research additionally looked at their individual effectiveness and safety. Additionally, the study discovered considerable variances in effectiveness amongst various groups. However, further investigation is required to establish the best time and dosage and the effect of patient characteristics on the effectiveness and safety of these medications.

New Daily Persistent Headache (NDPH): Unraveling the Complexities of Diagnosis, Pathophysiology, and Treatment.

The current article aims to provide an overview of new daily persistent headache (NDPH), with a particular emphasis on its pathophysiology, evaluation, and current treatment options. NDPH is an uncommon and heterogeneous condition associated with various comorbidities and is of great significance due to its prolonged duration and high severity. Variable causes and clinical aspects of NDPH may reflect differences in its underlying pathophysiological mechanisms, including genetics, environmental triggers, neuroinflammation, and brain changes. When assessing a patient with NDPH, potential triggers, past medical history, and differential diagnosis should be carefully considered. Non-pharmacological interventions aimed to improve diet, sleep patterns, and reduce consumption of caffeine and alcohol are recommended for all patients. Nerve blockade and nerve stimulation seem to be more efficacious in children than adults. Antiviral medications and neuroinflammation-targeting treatments may be helpful, particularly, when an infectious disease or severe inflammation is suspected. NDPH patients with concurrent affective disorders may benefit from treatment with serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or benzodiazepines. Cerebrospinal-fluid-lowering medications may be useful for headaches started with a thunderclap or a Valsalva maneuver. Possible treatments for refractory NDPH include intravenous ketamine or lidocaine, onabotulinumtoxinA, and calcitonin gene-related peptide antibodies. Considering the variety of NDPH, it is critical to properly screen patients for correct diagnosis. Proper identification of potential mimics may enable precise therapy opportunities, yet there is no gold standard treatment for NDPH. Further well-designed studies are needed to elucidate the underlying mechanisms and develop effective treatment strategies for NDPH.

Is prednisone still a reasonable option in the treatment of withdrawal headache in patients with chronic migraine and medication overuse headache in the age of CGRP antibodies? A narrative review.

Along with the development of novel migraine therapies as the monoclonal antibodies against calcitonin gene-related peptide (CGRP) and its receptor, the question arises if the treatment of chronic migraine (CM) and medication overuse headache (MOH) must be reconsidered. Have previous therapeutic approaches, including glucocorticoids, lost their role in the management of this debilitating disorder? In this narrative review, we present an overview of the available treatment options in CM and MOH in light of CGRP antibodies as well as an evaluation of the role of glucocorticoids in withdrawal therapy. Chronic migraine and medication overuse continues to be a difficult to treat condition. To date, potent treatment options are scarce and algorithms for advising patients with MOH are often still based on expert consensus rather than evidence-based medicine. For years and probably due to lack of effective alternatives, glucocorticoids have been used in MOH, especially to alleviate withdrawal symptoms caused by detoxification. Small case series report positive effects of steroids in this respective patient group; however, randomized controlled trials did not show a consistent benefit, although this may be due to methodological limitations. Because of these discrepancies, their role in MOH has been under debate ever since. We searched the electronic database PubMed for articles up to June 1, 2022 on the use of glucocorticoids in CM and MOH. Despite popular use in clinical practice, there is currently still no scientific evidence for the efficacy of glucocorticoids in patients with CM and MOH. Treatment with monoclonal antibodies achieved high transition rates from medication overuse to non-overuse. However, further research is needed to evaluate the additional benefit of these new agents.

Immunologic aspects of migraine: A review of literature.

Migraine headaches are highly prevalent, affecting 15% of the population. However, despite many studies to determine this disease's mechanism and efficient management, its pathophysiology has not been fully elucidated. There are suggested hypotheses about the possible mediating role of mast cells, immunoglobulin E, histamine, and cytokines in this disease. A higher incidence of this disease in allergic and asthma patients, reported by several studies, indicates the possible role of brain mast cells located around the brain vessels in this disease. The mast cells are more specifically within the dura and can affect the trigeminal nerve and cervical or sphenopalatine ganglion, triggering the secretion of substances that cause migraine. Neuropeptides such as calcitonin gene-related peptide (CGRP), neurokinin-A, neurotensin (NT), pituitary adenylate-cyclase-activating peptide (PACAP), and substance P (SP) trigger mast cells, and in response, they secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) as a selective result of corticotropin-releasing hormone (CRH) secretion. This stress hormone contributes to migraine or intensifies it. Blocking these pathways using immunologic agents such as CGRP antibody, anti-CGRP receptor antibody, and interleukin-1 beta (IL-1β)/interleukin 1 receptor type 1 (IL-1R1) axis-related agents may be promising as potential prophylactic migraine treatments. This review is going to summarize the immunological aspects of migraine.

Characterization of transit rates in the large intestine of mice following treatment with a CGRP antibody, CGRP receptor antibody, and small molecule CGRP receptor antagonists.

ObjectiveTo characterize the effects of blocking calcitonin gene‐related peptide (CGRP) activity in a mouse model of gastrointestinal transport.BackgroundMigraine management using CGRP modulating therapies can cause constipation of varying frequency and severity. This variation might be due to the different mechanisms through which therapies block CGRP activity (e.g., blocking CGRP, or the CGRP receptor) with antibodies or receptor antagonists. The charcoal meal gastrointestinal transit assay was used to characterize constipation produced by these modes of therapy in transgenic mice expressing the human receptor activity–modifying protein 1 (hRAMP1) subunit of the CGRP receptor complex.MethodsMale and female hRAMP1 mice were dosed with compound or vehicle and challenged with a charcoal meal suspension via oral gavage. The mice were then humanely euthanized and the proportion of the length of the large intestine that the charcoal meal had traveled indicated gastrointestinal transit.ResultsAntibody to the CGRP receptor produced % distance traveled (mean ± standard deviation) of 31.8 ± 8.2 (4 mg/kg; p = 0.001) and 33.2 ± 6.0 (30 mg/kg; p < 0.001) compared to 49.7 ± 8.3 (control) in female mice (n = 6–8), and 35.6 ± 13.5 (30 mg/kg, p = 0.019) compared to 50.2 ± 14.0 (control) in male mice (n = 10). Telcagepant (5 mg/kg, n = 8) resulted in % travel of 30.6 ± 14.7 versus 41.2 ± 8.3 (vehicle; p = 0.013) in male mice. Atogepant (3 mg/kg, n = 9) resulted in % travel of 30.6 ± 12.0, versus 41.2 ± 3.7 (control; p = 0.030) in female mice. The CGRP antibody galcanezumab (n = 7–10; p = 0.958 and p = 0.929) did not have a statistically significant effect.ConclusionsThese results are consistent with reported clinical data. Selectively blocking the CGRP receptor may have a greater impact on gastrointestinal transit than attenuating the activity of the ligand CGRP. This differential effect may be related to physiologically opposing mechanisms between the CGRP and AMY1 receptors, as the CGRP ligand antibody could inhibit the effects of CGRP at both the CGRP and AMY1 receptors.

From basic mechanisms to therapeutic perspectives in cluster headache.

The pathophysiological understanding of cluster headache has evolved significantly over the past years. Although it is now well known that the trigeminovascular system, the parasympathetic system and the hypothalamus play important roles in its pathomechanism, we increasingly understand the functional role several neurotransmitters and hormones play in the communication between these structures. This work will give an overview of the current understanding of the role of calcitonin gene-related peptide, vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, melatonin and orexins in cluster headache. On the basis of recent evidence, this study will also review the relevance of the monoclonal calcitonin gene-related peptide antibody galcanezumab as well as the sleep-regulating hormone melatonin in the treatment of cluster headache. Herein, we aim to review the basic mechanisms implicated in the pathophysiology of cluster headache and how the increased mechanistic understanding may lead to the discovery of novel therapeutic targets.

Unable to Work Due to Migraine for Which Tryptan is Taken 14 Times a Month or Less: Medication-Overuse Headache (MOH)

Management of refractory headache, particularly medication-overuse headache (MOH), is often difficult. In the management of MOH, it is important to determine the underlying primary headaches. Therefore, history taking and medical examinations are crucial for the diagnosis of headache type. Patient education and appropriate preventive therapy are beneficial in ameliorating MOH. As migraine is an underlying primary headache, the use of calcitonin gene-related peptide antibodies should be considered.

P 85 Impaired pain processing on a brainstem level in patients with complex regional pain syndrome

Introduction: The complex regional pain syndrome (CRPS) is a chronic pain condition, which can follow limb trauma and is accompanied with sensorimotor dysfunction 1 . Current pathophysiological concepts assume local inflammatory processes that lead to peripheral and central sensitization of the nociceptive system 2 . Secondary maladaptive alterations of cortical sensorimotor excitability and disinhibition are well-established but little is known about the contribution of the brainstem. Preliminary evidence for altered brainstem excitability to trigeminal afferent stimulation was recently provided 3,4 . This study uses a more comprehensive assessment of the nociceptive blink reflex (NBR) to assess the interaction of brainstem excitability and habituation to painful stimuli. Methods : 14 CRPS patients (10 female, 53 ± 17.6 years) and 10 controls (HCs; 9 female, 52±18.3) received assessments of pain and the NBR (R2 component, 2 trials, 10 stimuli/trial, interstimulus interval 3-5s). The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) were measured for the stimulated/non-stimulated side (_s/_ns). Results : Pain levels were 5,0±1,5/10 at rest and 7,2±2,1/10 during movements. ANOVA revealed a significant group effect for patients vs. controls (F=4.0; p=0.015). Post hoc tests were corrected for multiple comparisons and showed exceeding excitability (R2a_s: t=2.42, p=0.048; R2a_ns: t=2.98, p= 0.028) and impaired habituation (R2h_s: t=2.45, p=0.044; R2h_ns t=2.60, p=0.036). No significant associations of both disease duration and pain levels with NBR measurements could be obtained. Discussion : We here provide first evidence of altered NBR excitability and habituation indicating altered pain processing on a brainstem level. These results complement previous findings by demonstrating disinhibition as a source of increased brainstem excitability to painful stimulation remote from the limb directly affected by CRPS 4 . Future investigations are needed for a better understanding of the brainstem and its role in the pathophysiology of CRPS. The potential of the NBR as clinical biomarker, as it has been demonstrated in other pain diseases, should also be clarified in further investigation 5 . Literature: 1 Veldman PH et al. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet 1993. 2 Eldufani J et al. A medical mystery of CRPS. Heliyon. 2020. 3 Thiele A, et al. Treatment with calcitonin gene-related peptide antibodies modifies brainstem excitability and habituation to nociceptive trigeminal stimulation in migraineurs. CEPHALALGIA. 2021. 4 Drummond P et al. The Source of Hemisensory Disturbances in CRPS, The Clinical Journal of Pain: 2021. 5 De Marinis M et al. Decreased habituation of the R2component of the blink reflex in migraine patients. Clinical neurophysiology. 2003.

A Female-Specific Role for Calcitonin Gene-Related Peptide (CGRP) in Rodent Pain Models.

We aimed to investigate a sexually dimorphic role of calcitonin gene-related peptide (CGRP) in rodent models of pain. Based on findings in migraine where CGRP has a preferential pain-promoting effect in female rodents, we hypothesized that CGRP antagonists and antibodies would attenuate pain sensitization more efficaciously in female than male mice and rats. In hyperalgesic priming induced by activation of interleukin 6 signaling, CGRP receptor antagonists olcegepant and CGRP8-37 both given intrathecally, blocked, and reversed hyperalgesic priming only in females. A monoclonal antibody against CGRP, given systemically, blocked priming specifically in female rodents but failed to reverse it. In the spared nerve injury model, there was a transient effect of both CGRP antagonists, given intrathecally, on mechanical hypersensitivity in female mice only. Consistent with these findings, intrathecally applied CGRP caused a long-lasting, dose-dependent mechanical hypersensitivity in female mice but more transient effects in males. This CGRP-induced mechanical hypersensitivity was reversed by olcegepant and the KCC2 enhancer CLP257, suggesting a role for anionic plasticity in the dorsal horn in the pain-promoting effects of CGRP in females. In spinal dorsal horn slices, CGRP shifted GABAA reversal potentials to significantly more positive values, but, again, only in female mice. Therefore, CGRP may regulate KCC2 expression and/or activity downstream of CGRP receptors specifically in females. However, KCC2 hypofunction promotes mechanical pain hypersensitivity in both sexes because CLP257 alleviated hyperalgesic priming in male and female mice. We conclude that CGRP promotes pain plasticity in female rodents but has a limited impact in males.SIGNIFICANCE STATEMENT The majority of patients impacted by chronic pain are women. Mechanistic studies in rodents are creating a clear picture that molecular events promoting chronic pain are different in male and female animals. We sought to build on evidence showing that CGRP is a more potent and efficacious promoter of headache in female than in male rodents. To test this, we used hyperalgesic priming and the spared nerve injury neuropathic pain models in mice. Our findings show a clear sex dimorphism wherein CGRP promotes pain in female but not male mice, likely via a centrally mediated mechanism of action. Our work suggests that CGRP receptor antagonists could be tested for efficacy in women for a broader variety of pain conditions.

Chemical characterization of pineal neurons in perinatal rats

Ample evidence indicates that in several mammalian species the pineal body contains neurons. In adult white albino rats neurons are not present in the pineal body; however, in perinatal rats many neurons were described. It was demonstrated that in adult mammalian species the pineal neurons contained some neuropeptides and neurotransmitters such as leu-enkephalin, met-enkephalin, substance-P, somatostatin and γ-aminobutiric acid. Oxytocin, vasopressin mRNAs and peptides were also demonstrated. No data are available on the chemical nature of the neurons in perinatal rats. In the present experiment we used immunohistochemistry to clarify this issue. After paraformaldehyde fixation frozen sections were prepared and stained for immunoreactivities of several neuropeptides and neurotransmitters. Dopamine β-hydroxylase, neuropeptide-Y, vesicular acetylcholine transporter, vesicular glutamate transporter and calcitonin gene-related peptide antibodies were able to stain fibers. According to previous data these fibers may be sympathetic, parasympathetic or sensory. Vesicular glutamate transporter antibody may stain pinealocytes as well. Some cells were immunoreactive for substance-P, oxytocin, vasopressin, leu-enkefalin and glutamic acid decarboxylase. These immnoreactivities showed colocalization with neuron-specific nuclear protein immunoreactivity indicating that these cells were neurons. Calbindin was observed in oval and elongated cells resembling pinealocytes. Based on the results obtained in adult mammals, the pineal neurons may be analogue to retinal ganglion cells, or they may function as interneurons in the retino-pinealo-retinal neuronal circuit or peptidergic neurons may influence pinealocytes in a paracrine manner.

CGRP antibody rescues tactile sensitization induced by mild traumatic brain injury in mice

Post-traumatic headache (PTH) after mild traumatic brain injury (mTBI) is debilitating and hard to diagnose. Unfortunately, PTH is highly prevalent in active duty personnel, Veterans, as well as sport athletes. The high incidence and chronic nature of PTH underscores the need to study these problems in animal models in order to develop new and effective treatments. Patients suffering from PTH often present the same symptoms as migraine patients, which can be studied in mice. We explored hypersensitivity to a tactile stimulation of the periorbital facial and plantar paw areas in a model of mTBI in mice using von Frey filaments. This mild closed head impact (mCHI) is induced by a weight (30 g) dropped onto the intact skull once a day over 3 consecutive days, after which mice develop a transient cephalic hypersensitivity between day 1 and day 5 after the injury, and then recover to normal thresholds. Additionally, after mice recover from this transient cephalic hypersensitivity, an injection of normally non-noxious triggers such as a low dose of calcitonin gene-related peptide (CGRP) or a low dose of sodium nitroprusside (SNP, a nitric oxide donor) can induce tactile hypersensitivity. This can last for at least 13 weeks after injury. Treatment with a CGRP-blocking monoclonal antibody after injury, but prior to CGRP or SNP administration can alleviate this sensitization. Preliminary data indicate that after injuries, administration of CGRP is also able to induce light aversion at usually non-noxious dim light intensities. In summary, we report that mice are primed by a mild TBI that sensitizes them to subsequent migraine triggers in a CGRP-dependent manner. Dept. Defense W81XWH-16-1-0071, W81XWH-16-1-0211 to AFR; VA-ORD (RRD IHA Research Award and Pilot Grant from Iowa City VA Center for the Prevention and Treatment of Visual Loss to ASW.

Cluster headache pathophysiology - insights from current and emerging treatments.

Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.

Abstract P643: Incidence of Ischemic Stroke Among Migraineurs on Calcitonin Gene-Related Peptide Inhibitors

Introduction: Migraine is common and often disabling. Recent research has focused on a new class of treatments targeting the pain-signaling molecule calcitonin-gene-related peptide (CGRP). CGRP inhibitors are the first preventive therapies designed specifically for migraine. However, CGRP also induces vasodilation, and plays a role in cerebral blood flow autoregulation. The clinical cerebrovascular effects of long-term blockade of CGRP are not yet known. Methods: We analyzed a retrospective cohort of migraine patients from a large administrative dataset in the United States (OPTUM) that covers patients with commercial insurance and Medicare Advantage, during 2018 and 2019, using ICD-10 codes for all types of migraines. Migraine patients were divided into two groups based on their use of CGRP inhibitors (erenumab, fremanezumab, galcanezumab). We determined the incidence of stroke during 2018 and 2019 among both groups. For the group of migraine patients who used CGRP inhibitors, we focused on the incidence of stroke after these medications were initiated. Results: We identified 646,404 migraine patients; 18, 692 (2.9%) of them had used a CGRP inhibitor. Among the users of CGRP inhibitors, 86% were females, and 58% of patients were in the 41 to 65-year-old range. The average time of follow-up was 197 days after initiation of the medication. A total of 1.3 % of patients who used CGRP inhibitors had an ischemic stroke during the follow-up period versus 2.4% of patients who did not use CGRP inhibitors. The lower rate of stroke in the CGRP antibody group was found in both sexes and all age groups. Conclusions: These preliminary results suggest that CGRP inhibitors are not associated with a higher frequency of stroke in the initial months of use. This could be related to the avoidance of these medications in patients with known cardiovascular risk factors. Further analyses will be completed on vascular risk factor incidence in these populations as well as multiple regression. Prospective, long term studies are needed to confirm these results.

Characterization and preclinical evaluation of a protease activated receptor 2 (PAR2) monoclonal antibody as a preventive therapy for migraine.

Migraine pain is thought to result from activation of meningeal nociceptors that might involve dural mast cell degranulation and release of proteases and pronociceptive mediators. Tryptase, the most abundant dural mast cell protease, has been demonstrated to stimulate dural mast cells, as well as trigeminal nociceptors by activating the protease activated receptor 2. Mast cell or neuronal protease activated receptors 2 may therefore represent a novel target for migraine treatment. In this study, we characterized and evaluated a novel protease activated receptor 2 monoclonal antibody as a preventive anti-migraine pain therapy in preclinical models. Flow cytometry, immunocytochemistry, calcium imaging, Homogeneous Time Resolved Technology (HTRF) epitope competition assay and serum pharmacokinetic (PK) assay in rats were performed to confirm the activity, specificity and in vivo stability of PAR650097, a novel anti- protease activated receptor 2 monoclonal antibody. In vivo assessment was performed in female C57BL/6J mice by evaluation of PAR650097 in preventing cutaneous allodynia elicited by (a) supradural injection of the protease activated receptor 2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-amide trifluoroacetate (SLIGRL), or calcitonin gene-related (CGRP) peptide, and (b) induction of latent sensitization by priming with three daily episodes of restraint stress followed by challenge with a subthreshold inhalational exposure to umbellulone (UMB), a transient receptor potential ankyrin 1 (TRPA1) agonist. PAR650097 was administered as a pretreatment prior to the first restraint stress, umbellulone exposure, SLIGRL or calcitonin gene-related peptide injection. Additionally, fremanezumab, a calcitonin gene-related peptide antibody was administered as pre-treatment prior to supradural administration of calcitonin gene-related peptide or SLIGRL. In vitro, PAR650097 demonstrated rapid interaction with protease activated receptor 2, enabling it to fully inhibit protease-induced protease activated receptor 2 activation, in human and mouse cells, with high potency. Furthermore, PAR650097 was highly selective for protease activated receptor 2, demonstrating no affinity for protease activated receptor 1 protein and no functional effect on the activation of cellular protease activated receptor 1 with thrombin. In addition, PAR650097 had an acceptable PK profile, compatible with testing the effects of selective protease activated receptor 2 inhibition in vivo. In vivo, PAR650097 blocked cutaneous allodynia induced by either supradural SLIGRL or calcitonin gene-related peptide. Fremanezumab abolished cutaneous allodynia induced by supradural CGRP, and partially attenuated cutaneous allodynia induced by SLIGRL. Administration of PAR650097, before the first restraint stress episode, did not prevent the acute stress-induced cutaneous allodynia or restraint stress priming revealed by cutaneous allodynia induced by inhalational umbellulone. In contrast, PAR650097 prevented expression of cutaneous allodynia when given before the umbellulone challenge in restraint stress-primed animals. PAR650097 specifically inhibits endogenously expressed protease activated receptor 2 in human and mouse cells with high potency. This antibody has an acceptable PK profile in rodents and effectively blocked SLIGR-induced cutaneous allodynia. PAR650097 additionally prevented cutaneous allodynia induced by supradural calcitonin gene-related peptide, indicating that the protease activated receptor 2 receptor is a downstream consequence of calcitonin gene-related peptide actions. Fremanezumab effectively blocked calcitonin gene-related peptide-induced cutaneous allodynia and only partially reduced cutaneous allodynia induced by a protease activated receptor 2 activator, suggesting both calcitonin gene-related peptide-dependent and -independent mechanisms in promoting migraine pain. While PAR650097 did not prevent stress-induced cutaneous allodynia or priming, it effectively prevented cutaneous allodynia induced by a TRPA1 agonist in animals with latent sensitization. Activation of protease activated receptor 2, therefore, contributes to both calcitonin gene-related peptide-dependent and -independent mechanisms in promoting migraine-like pain. Therapeutic targeting of protease activated receptor 2 receptors may represent an anti-migraine pain strategy with a potentially broad efficacy profile.

Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts.

ObjectiveTo assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions.BackgroundCalcitonin gene-related peptide has an important pathophysiological role in cluster headache. Although the randomised controlled trial with the calcitonin gene-related peptide antibody galcanezumab was negative, chronic cluster headache patients with insufficient response to other preventive treatments have been receiving individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies.MethodsData from 22 chronic cluster headache patients who received at least one dose of a calcitonin gene-related peptide(-receptor) antibody and recorded attack frequency in a headache diary were retrospectively collected at eight headache centres.ResultsThe number of previous preventive therapies was 6.5 ± 2.4 (mean ± standard deviation, range: 2–11). The average number of attacks per week was 23.3 ± 16.4 at baseline and significantly decreased by −9.2 ± 9.7 in the first month of treatment with a calcitonin gene-related peptide(-receptor) antibody (p < 0.001). Fifty-five percent of the patients were 50% responders and 36% were 75% responders with respect to attack frequency. Significant reduction of attack frequency started at week 1 (−6.8 ± 2.8 attacks, p < 0.01). Results were corroborated by significant decreases in weekly uses of acute headache medication (−9.8 ± 7.6, p < 0.001) and pain intensity during attacks (−1.2 ± 2.0, numerical rating scale (NRS) [0–10], p < 0.01) in the first month. In months 2 (n = 14) and 3 (n = 10), reduction of attack frequency from baseline was −8.0 ± 8.4 (p = 0.004) and −9.1 ± 10.0 (p = 0.024), respectively.ConclusionUnder real-world conditions, individual treatment with calcitonin gene-related peptide(-receptor) antibodies was effective in 55% of our chronic cluster headache patients. This finding supports individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies in chronic cluster headache patients insufficiently responding to other therapies.

Two-Hour CGRP Infusion Causes Gastrointestinal Hyperactivity: Possible Relevance for CGRP Antibody Treatment.

The monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double-blind cross-over study of CGRP infusion for 2hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies. Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP 1.5µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2×50mg) 1day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12-hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018. On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment. We conclude that a 2-hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists.

Cervicogenic Headache Responsive To Galcanezumab In Patients With Comorbid Migraine: A Case Series. Running Head: CH And Migraine Responsive To CGRP Abs

Introduction Cervicogenic headache (CH) is a chronic headache that is referred to the head from the cervical spine that typically starts or worsens with neck movement. The pain typically presents posteriorly with anterior radiation. Nociceptive input from structures innervated by the upper three cervical spinal nerves can theoretically exacerbate primary headache disorders like migraine. We present three cases of CH related to C1-C2 joint arthropathy that significantly improved after treatment with calcitonin gene-related peptide (CGRP) antibodies initiated for chronic comorbid migraine. Case Descriptions We describe a case series of 3 patients with co-morbid CH and migraine that were treated with CGRP antibodies. All three patients had significant improvement in their migraines with C1-C2 joint injections and subsequently CGRP antibodies provided a greater than 50% benefit in each patient preventing the need for repeat injections. Conclusions The diagnosis of CH in patients is confirmed when treatment of the cervical spine lesion alleviates pain significantly. While CH itself has not been shown to be associated with elevated serum CGRP as has been demonstrated in migraine, animal models of osteoarthritis have shown reduction of hyperalgesia with galcanezumab. An upregulation in CGRP related to nociceptive input from degenerative changes in the cervical spine could lead to potentiation and sensitization which could potentially respond to systemic administration of CGRP antibodies. As a result, the presence of features suggestive of CH in patients with migraine may be a predictor of a positive response to CGRP antibodies. For patients with comorbid migraine and CH, CGRP antibodies could prevent the need for invasive injection treatments.

Calcitonin Gene-Related Peptide (CGRP) and Cluster Headache.

Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.