To analyze the specificity of calcitonin gene-related peptide (CGRP) levels, we measured alpha-CGRP circulating levels in a large series of patients with a recent diagnosis of inflammatory bowel disease (IBD) who were interviewed regarding comorbid headache.
Several studies have found an association between migraine and IBD.
In this cross-sectional study performed in an IBD clinic, morning serum alpha-CGRP levels were measured by enzyme-linked immunosorbent assay in 96 patients who were recently diagnosed with IBD and compared to those from 50 similar patients with chronic migraine (CM) and 50 healthy controls (HC).
Alpha-CGRP levels were higher in patients with IBD (median [interquartile range] 56.9 [35.6-73.9] pg/mL) and patients with CM (53.0 [36.7-73.9] pg/mL) compared to HC (37.2 [30.0-51.8] pg/mL; p = 0.003; p = 0.019, respectively). Regarding IBD diagnostic subtypes, alpha-CGRP levels for ulcerative colitis (67.2 ± 49.3 pg/mL; 57.0 [35.6-73.4] pg/mL) and Crohn\'s disease (54.9 ± 27.5 pg/mL; 57.7 [29.1-76.1] pg/mL) were significantly higher than those of HC (p = 0.013, p = 0.040, respectively). Alpha-CGRP levels were further different in patients with IBD with migraine (70.9 [51.8-88.7] pg/mL) compared to HC (p < 0.001), patients with IBD without headache (57.5 [33.3-73.8] pg/mL; p = 0.049), and patients with IBD with tension-type headache but without migraine (41.7 [28.5-66.9] pg/mL; p = 0.004), though alpha-CGRP levels in patients with IBD without migraine (53.7 [32.9-73.5] pg/mL) remained different over HC (p = 0.028).
Together with CM, circulating alpha-CGRP levels are different in patients with IBD, perhaps reflecting a chronic inflammatory state. IBD is an example of how alpha-CGRP levels are not a totally specific migraine biomarker. However, alpha-CGRP levels were further increased in patients with IBD who have a history of migraine, which reinforces its role as a biomarker in migraine patients, always bearing in mind their comorbidities.

BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene-related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date.
OBJECTIVE: Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration).
METHODS: Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double-blind treatment period. In addition, migraine-related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non-reverters using the Headache Impact Test-6 (HIT-6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS).
RESULTS: Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1-2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT-6 total score for reverters versus non-reverters compared to placebo (erenumab: -9.5 [0.6] vs. -5.1 [0.5]; placebo: -8.9 [0.7] vs. -4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: -22.1 [1.2] vs. -6.3 [1.8]; placebo: -19.9 [1.3] vs. -7.9 [1.6]). Substantial improvements were reported in MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non-reverters in erenumab treatment groups (MPFID-PI: -5.9 [0.3] vs. -1.9 [0.6]; MPFID-EA: -7.9 [0.4] vs. -3.4 [0.6]) and in placebo (MPFID-PI: -5.4 [0.4] vs. -1.0 [0.5]; MPFID-EA: -7.1 [0.5] vs. -3.2 [0.5]).
CONCLUSIONS: This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient-reported outcomes in the erenumab group.

Migraine, a prevalent and debilitating disease, involves complex pathophysiology possibly including inflammation and heightened pain sensitivity. The current study utilized the complete Freund\'s adjuvant (CFA) model of inflammation, with onabotulinumtoxinA (BoNT/A) as a treatment of interest due to its use in clinical migraine management. Using an animal model, the study sought to investigate the role of BoNT/A in modulating CFA-induced inflammation, alterations in pain sensitivity, and the regulation of calcitonin gene-related peptide (CGRP) release. Further, we aimed to assess the changes in SNAP-25 through western blot analysis to gain insights into the mechanistic action of BoNT/A.
BoNT/A or control was administered subcutaneously at the periorbital region of rats 3 days before the induction of inflammation using CFA. Periorbital mechanical sensitivity was assessed post-inflammation, and alterations in CGRP release were evaluated. Changes in SNAP-25 levels were determined using western blot analysis.
Upon CFA-induced inflammation, there was a marked increase in periorbital mechanical sensitivity, with the inflammation side showing increased sensitivity compared to other periorbital areas. BoNT/A did decrease the withdrawal thresholds in the electronic von Frey test. Despite not being able to observe differences in pain thresholds or CGRP release, BoNT/A reduced baseline release under CFA inflamed conditions. Analysis of SNAP-25 levels in the trigeminal ganglion revealed both intact and cleaved forms that were notably elevated in BoNT/A-treated animals. These findings, derived from western blot analysis, suggest an effect on neurotransmitter release.
Our investigation highlights the role of BoNT/A in reducing baseline CGRP in the context of inflammation and its involvement in SNAP-25 cleavage. In contrast, BoNT/A did not appear to alter facial pain sensitivity induced by inflammation, suggesting that mechanisms other than baseline CGRP could be implicated in the elevated thresholds in the CFA model.

BACKGROUND: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene-related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders.
METHODS: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM).
RESULTS: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation.
CONCLUSIONS: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults.
BACKGROUND: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309).

The objectives are to know the opinion of neurologists and hospital pharmacists on those aspects still under debate regarding the role of anti-CGRP monoclonal antibodies in the preventive treatment of migraine. To identify those controversies that still exist. To propose agreed recommendations for improvement of care. And to promote access of clinicians and patients to these new treatments in the prevention of migraine with biological drugs, in order to improve patient care and follow-up.
Recommendations for the use of biological drugs in the prevention of migraine were identified and evaluated through the Delphi consensus methodology, proposing 88 statements grouped into three themes: a clinical module that deals with the management of biological treatments in migraine; a patient module that discusses patient education and adherence improvement strategies; and a coordination module that includes statements related to strategies to improve joint work between the two groups. The 9-point Likert ordinal scale was used to score these recommendations and, subsequently, the data was statistically analyzed through different metrics.
After both rounds of voting, consensus was reached in agreement on 71 of the 88 statements (80.7%), leaving one statement (1.1%) with consensus in disagreement and 16 remaining as indeterminate (18.2%).
The high degree of consensus indicates that the opinion of neurologists and hospital pharmacists on the role of anti-CGRP monoclonal antibodies in the treatment of migraine is very similar and allows identifying those controversies that still exist, to improve the care and follow-up of patients with migraine.

Migraine is a common neurologic disorder with clinical phenotypes encompassing a variety of symptoms which all contribute to the burden felt by patients. In addition to negative impacts on a patient\'s quality of life, migraine has both direct medical costs and indirect costs related to missed work and decreased productivity that affect individuals as well as society at large. Unfortunately, migraine diagnoses are often missed, and many patients do not receive appropriate treatment. Primary care providers are in a key position to provide timely diagnosis and effectively manage migraine for many patients. This review aims to be a guide for improving migraine management in the primary care setting by providing strategies to overcome common challenges in migraine diagnosis; summarizing current knowledge on the mechanism of action, efficacy, and safety of calcitonin gene-related peptide (CGRP) pathway-targeting therapies; and reviewing approaches to incorporate traditional and emerging treatment options into a patient-centric migraine management strategy.

OBJECTIVE: Chronic cluster headache (CH) substantially affects patients\' quality of life, and treatment remains challenging. The current article reviewed controlled studies for new treatment options targeting calcitonin gene-related peptide (CGRP) or its receptors in CH and discussed the current gaps and future directions for the treatment of chronic CH.
RESULTS: Two anti-CGRP monoclonal antibodies (i.e., galcanezumab and fremanezumab) completed randomized-control trials for efficacy for the preventive treatment of episodic and chronic CH. Galcanezumab was effective for preventing episodic CH but not chronic CH. Fremanezumab was ineffective in preventing episodic and chronic CH. Studies for other anti-CGRP monoclonal antibodies and CGRP antagonists are still pending for results. There are no randomized controlled trials for CGRP-targeted therapies that showed efficacy for chronic CH prevention. The different responses to galcanezumab between episodic and chronic CH may be due to the study design, i.e., the allowance of concomitant preventive therapies in the chronic CH study but not in the episodic CH study. Another reason for the discrepancies is the different roles and sensitivity of CGRP in chronic CH.

OBJECTIVE: The prevalence and characteristics of COVID-19-related headaches are not known in Indian patients. We aim to determine the prevalence and characteristics of headache in COVID-19-infected individuals and make a comparison with those without headaches.
METHODS: This prospective cross-sectional observational study was conducted from 1 October to 31 October 2020. Data were collected using a detailed questionnaire. We compared the data of those with and without headaches to identify the differences between the groups.
RESULTS: During the study period of 1 month, among 225 COVID-19-infected patients, 33.8% patients had headaches. The mean age of patients with headache was 48.89 ± 15.19 years. In all, 53.9% were females. In 65.8%, headache occurred at the onset of viral illness; 44.7% described the headache as dull aching; 39.5% had bifrontal headache; and 32.9% had holocranial headache. In total, 78.9% had complete resolution of headache within 5 days. A comparison between those with and without headaches showed that those with headaches were more younger (48.89 ± 15.19 vs 54.61 ± 14.57 years, p = 0.007) and of female gender (41/76(53.9%) vs 41/149 (27.5%), p = 0.001). Primary headache disorders were more common in the headache group. Levels of inflammatory markers such as leukocyte count (7234.17 ± 3054.96 vs 8773.35 ± 5103.65, p = 0.017), erythrocyte sedimentation rate (39.28 ± 23.29 vs 50.41 ± 27.61, p = 0.02) and ferritin (381.06 ± 485.2 vs 657.10 ± 863.80, p = 0.014) were lower in those with headaches.
CONCLUSIONS: Headaches are a common and early symptom of acute SARS-CoV-2 infection more frequently seen in young females and in those with a history of primary headache disorders. The lower level of inflammatory markers in those with headaches suggests that these headaches are probably due to the local spread of virus through the trigeminal nerve endings, resulting in activation of the trigeminovascular system.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of migraine.
METHODS: In the double-blind, phase 3 ADVANCE trial, participants with 4-14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time course of efficacy of atogepant for the preventive treatment of migraine. Analyses included change from baseline in mean monthly migraine days during each of the three 4-week treatment periods, change in weekly migraine days during weeks 1-4, and proportion of participants with a migraine on each day during the first week.
RESULTS: We analyzed 873 participants (n = 214 atogepant 10 mg, n = 223 atogepant 30 mg, n = 222 atogepant 60 mg, n = 214 placebo). For weeks 1-4, mean change from baseline in mean monthly migraine days ranged from -3.1 to -3.9 across atogepant doses vs -1.6 for placebo (p < 0.0001). For weeks 5-8 and 9-12, reductions in mean monthly migraine days ranged from -3.7 to -4.2 for atogepant vs -2.9 for placebo (p ≤ 0.012) and -4.2 to -4.4 for atogepant vs -3.0 for placebo (p < 0.0002), respectively. Mean change from baseline in weekly migraine days in week 1 ranged from -0.77 to -1.03 for atogepant vs -0.29 with placebo (p < 0.0001). Percentages of participants reporting a migraine on post-dose day 1 ranged from 10.8% to 14.1% for atogepant vs 25.2% with placebo (p ≤ 0.0071).
CONCLUSIONS: Atogepant demonstrated treatment benefits as early as the first full day after treatment initiation, and sustained efficacy across each 4-week interval during the 12-week treatment period.Clinical trial registration: ClinicalTrials.gov identifier: NCT03777059.

We examined the efficacy and tolerability of calcitonin gene-related peptide-targeted monoclonal antibodies (CGRP-targeted mAbs) as add-on therapy for patients with chronic migraine (CM) undergoing treatment with onabotulinumtoxinA (onabot) who require additional preventive therapy.
We reviewed medical records of patients with CM receiving treatment with onabot who were subsequently prescribed a CGRP-targeted mAb medication. The primary outcome was the change in number of monthly headache days (MHDs) reported. Secondary outcomes were change in headache pain severity, discontinuation due to lack of tolerability, and severe adverse events.
Of 153 patients, 111 (72.5%) reported a decrease in either MHDs or headache pain severity, with documentation of MHDs in 66 patients. Among these 66 patients, the average number of MHDs before initiation of onabot treatment was 25.7. After onabot treatment, an average decrease of 10.9 MHDs was reported (P < 0.001). After the addition of a CGRP-targeted mAb medication, patients experienced a further decrease of 5.7 MHDs (P < 0.001). With combined therapy, patients reported a total decrease of 16.6 MHDs (P < 0.001). Adverse effects occurred in 13 patients (8.5%) after addition of the CGRP-targeted mAb and included constipation, injection site reaction, and fatigue. No serious adverse events were reported.
Adding a CGRP-targeted mAb to onabot in patients with CM was associated with further reductions in MHDs without major tolerability issues across a range of mAbs. This retrospective review supports the conduct of a well-designed double-blind study adding a CGRP-targeted mAb or placebo to onabot.