Switching anti-CGRP(R) monoclonal antibodies in multi-assessed non-responder patients and implications for ineffectiveness criteria: A retrospective cohort study.

BACKGROUND: A pharmacological class effect was initially proposed for monoclonal antibodies against the calcitonin gene related peptide pathway. However, preliminary evidence shows that switching patients who were non-responding to one monoclonal antibody to another could provide some benefit. Herein, we assess treatment response to an anti-calcitonin gene related peptide/receptor monoclonal antibody in patients who have failed to respond to anti-calcitonin gene related peptide/ligand monoclonal antibodies calcitonin gene related peptide/ligand monoclonal antibodies and vice versa. In addition, we select non-responders to the first anti- monoclonal antibody by three or five more stringent variables. METHODS: Retrospective cohort study including outpatients treated consecutively with two anti-calcitonin gene related peptide monoclonal antibodies. Ineffectiveness to the first monoclonal antibody was assessed using three (MIDAS score, monthly headache days, and analgesic monthly days) variables or five (monthly headache days, MIDAS score, analgesic monthly days, analgesic monthly number and HIT-6 score) variables in the same cohort of patients. The primary endpoints were the absolute change from baseline in monthly headache days, response rate, and persistence in medication overuse at three months of treatment with the second anti-CGRP mAb. RESULTS: In patients selected by three variables, a sustained reduction in monthly headache days, analgesic monthly days, MIDAS and HIT-6 scores was observed at month-3 of treatment with the second monoclonal antibody. Ten (45.4%) patients achieved at least a ≥30% response rate. No difference was reported switching anti-CGRP mAb against ligand or receptor. In the patient subgroup selected by five variables, only HIT-6 was reduced from baseline at month-3. However, a trend toward a reduction in monthly headache days, analgesic monthly days, and MIDAS score was observed at month-3. CONCLUSIONS: Switching anti-calcitonin gene related peptide monoclonal antibodies in selected patients might be an option to achieve or improve clinical benefit. More studies are required to establish the effectiveness of switching these treatments.

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

OBJECTIVE: 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. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Utilization patterns, cardiovascular risk, and concomitant serotoninergic medications among triptan users between 2008 and 2018: A gender analysis in one Italian region, Tuscany.

OBJECTIVE: To describe the pattern of triptan use by gender in Tuscany, Italy, focusing on special user populations in which evidence on triptan safety is still not conclusive. BACKGROUND: Growing evidence supports the role of gender differences in migraine pathophysiology and treatment. However, gender impact on triptan real-word utilization has been poorly investigated. METHODS: A retrospective, descriptive, cohort study was performed using the population-based Administrative Healthcare Database of Tuscany region (Italy). Subjects registered in the database on the January 1 of each year between 2008 and 2018 were identified. New users (NU) of triptans (ATC:N02CC*) were patients with one or more triptan dispensation during the year of interest and none in the past. Age, cardiovascular comorbidities representing an absolute or a possible contraindication to triptan utilization, concomitant serotonergic medications, and pattern of triptan use during 1-year follow-up were described by gender. RESULTS: A total of 86,109 patients who received one or more triptan dispensing were identified. Of 64,672 NU (men = 17,039; women = 47,633), 10.2% (6823/64,672) were aged >65 years, who were mostly women (n = 4613). Among NU, men and women with absolute cardiovascular contraindications were 4.3% (740/17,039) and 2.1% (1022/47,633), respectively, while those concomitantly taking serotonergic medications were 17.2% (267/1549) and 21.9% (949/4330), respectively (949/4330). Regular users (two or more dispensing with ≥3 months between first and last observed dispensing) accounted for 26.4% of women (12,597/47,633) and 19.11% of men (3250/17,039); frequent users (≥15 dosage units/month during ≥3 consecutive months) were overall 0.1% (94/64,672) and 62.0% (58/94) of them concomitantly received serotonergic medications. CONCLUSION: Considering gender differences in triptan use highlighted here, large scale observational studies are warranted to better define what populations are safe to use triptans and whether it is appropriate to tighten or relax certain recommendations on triptan use. In the meantime, any suspected adverse drug reaction observed in the special user populations highlighted in this study should be promptly reported.

Validation of the Italian version of the Cluster Headache Impact Questionnaire (CHIQ).

BACKGROUND: The Cluster Headache Impact Questionnaire (CHIQ) is a specific and easy-to-use questionnaire to assess the current impact of cluster headache (CH). The aim of this study was to validate the Italian version of the CHIQ. METHODS: We included patients diagnosed with episodic CH (eCH) or chronic CH (cCH) according to the ICHD-3 criteria and included in the "Italian Headache Registry" (RICe). The questionnaire was administered to patients through an electronic form in two sessions: at first visit for validation, and after 7 days for test-retest reliability. For internal consistency, Cronbach's alpha was calculated. Convergent validity of the CHIQ with CH features and the results of questionnaires assessing anxiety, depression, stress, and quality of life was evaluated using Spearman's correlation coefficient. RESULTS: We included 181 patients subdivided in 96 patients with active eCH, 14 with cCH, and 71 with eCH in remission. The 110 patients with either active eCH or cCH were included in the validation cohort; only 24 patients with CH were characterized by a stable attack frequency after 7 days, and were included in the test-retest cohort. Internal consistency of the CHIQ was good with a Cronbach alpha value of 0.891. The CHIQ score showed a significant positive correlation with anxiety, depression, and stress scores, while showing a significant negative correlation with quality-of-life scale scores. CONCLUSION: Our data show the validity of the Italian version of the CHIQ, which represents a suitable tool for evaluating the social and psychological impact of CH in clinical practice and research.

Effectiveness of anti-CGRP monoclonal antibodies on central symptoms of migraine.

BACKGROUND: Clinical trials and observational studies with anti-calcitonin gene-related peptide antibodies poorly investigated their impact on migraine prodromal and accompanying symptoms. This information might help deciphering the biologics' pharmacodynamic and provide hints on migraine pathogenesis. Herein, we report the effects of erenumab, fremanezumab and galcanezumab on attack prodromal and accompanying symptoms and on neurological and psychiatric traits. . METHODS: An explorative, prospective, questionnaire-based study was completed by a cohort (n = 80) of patients with chronic migraine patients presenting a sustained reduction of ≥50% of Migraine Disability Assessment Score and ≥30% of monthly migraine days three months after anti-calcitonin gene-related peptide antibodies treatment. RESULTS: The majority of patients experienced a complete prevention of migraine symptoms without evidence of initial onset followed by attack abortion. Few patients reported the recurrence of prodromal (from 10% to 12.5%) or accompanying (from 1.3% to 8.8%) symptoms without headache. All patients with migraine with aura reported a decrease of aura incidence. Sleep changes (51.2%), increase in appetite (20.0%) and weight (18.8%) as well as a reduction in stress (45.0%), anxiety (26.3%), and panic attacks (15%) were also reported. CONCLUSION: Anti-calcitonin gene-related peptide antibodies seems to significantly impact brain functions of migraineurs, preventing not only migraine headache but also its anticipatory and accompanying symptoms.

Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized, double-blind, placebo-controlled dose-finding pilot study.

BACKGROUND: A novel formulation of diclofenac, complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubility enhancer, in a prefilled syringe for self-administered subcutaneous injection may overcome the limitations of acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes. METHODS: This multicentre, phase 2, double-blind, randomized, placebo-controlled, dose-finding pilot study evaluated the efficacy, safety and tolerability of three different doses (25/50/75 mg/1 mL) of subcutaneous diclofenac sodium in the treatment of an acute migraine attack in 122 subjects. The primary efficacy endpoint was the percentage of patients pain-free at 2 hours after the study drug injection. RESULTS: A significantly higher percentage of patients in the 50 mg diclofenac group 14 (46.7%) were pain-free at 2 hours when compared with placebo: 9 (29.0%) (p = 0.01). The 50 mg dose proved superior to placebo also in the majority of the secondary endpoints. The overall global impression favoured diclofenac vs placebo. There were no adverse events leading to study withdrawal. The majority of treatment-emergent adverse events were mild. CONCLUSIONS: The 50 mg dose of this novel formulation of diclofenac represents a valuable self-administered option for the acute treatment of migraine attacks.Trial registration: EudraCT Registration No. 2017-004828-29.

Predictors of sustained response and effects of the discontinuation of anti-calcitonin gene related peptide antibodies and reinitiation in resistant chronic migraine.

BACKGROUND AND PURPOSE: Guidelines for migraine prophylaxis suggest stopping medication after 6-12 months to reevaluate treatment appropriateness. The Italian Medicines Agency set a mandatory regulation to stop anti-calcitonin gene related protein (CGRP) pathway monoclonal antibody (anti-CGRP mAb) treatments for 3 months after 12 months of treatment. Herein, the effects of discontinuation and retreatment of anti-CGRP mAbs in resistant chronic migraine patients are assessed, evaluating predictive factors of sustained response. METHODS: This was a monocentric prospective cohort study, enrolling 44 severe (resistant to ≥3 preventive treatments) chronic migraine patients (all with medication-overuse), treated with erenumab (54.5%) or galcanezumab (45.5%) for 12 months, who discontinued treatment for 3 months and then restarted for 1 month. RESULTS: Overall, patients reported an increasing deteriorating trend during the 3 months of discontinuation. Monthly migraine days, number of analgesics, days with at least one analgesic used, a ≥50% response rate (reduction in monthly migraine days), and Migraine Disability Assessment Score and Headache Impact Test 6 total score, remained lower than baseline values, but increased compared to month 12 of treatment. All outcome measures decreased again during the month of retreatment. Patients who did not meet criteria for restarting treatment had a lower Migraine Disability Assessment Score (p = 0.03) and Headache Impact Test 6 (p = 0.01) score at baseline and better outcome measures during discontinuation compared to patients who restarted treatment. CONCLUSIONS: In most patients, the 3-month discontinuation of anti-CGRP mAbs resulted in progressive migraine deterioration that was rapidly reverted by retreatment. However, one-quarter of patients who reported better quality of life indices before treatment showed a sustained benefit during discontinuation and did not need retreatment.

Mental pain as a global person-centered outcome measure.

BACKGROUND: Mental pain has been proposed as a global person-centered outcome measure. The aim of this cross-sectional study was to test an essential requisite of such a measure, namely that mental pain incorporates independent contributions from a range of discrete but disparate outcome measures. METHODS: Two hundred migraine patients were assessed concerning migraine disability, psychosomatic syndromes, mental pain, depression, anxiety, and psychosocial dimensions. General linear models were tested to verify which measures would individually make unique contributions to overall mental pain. RESULTS: The final model, accounting for 44% of variance, identified that higher mental pain was associated with more severe depressive symptoms, higher migraine disability, lower well-being, and poorer quality of life. CONCLUSION: In this sample, mental pain was shown to behave as expected of a global outcome measure, since multiple measures of symptomatology and quality of life showed modest but significant bivariate correlations with mental pain and some of these measures individually made unique contributions to overall mental pain.

Galcanezumab effectiveness on comorbid cluster headache and chronic migraine: a prospective case series.

BACKGROUND: Cluster headache (CH) and migraine are recurrent painful primary cephalalgies, typically with different clinical appearance and some shared features, such as unilateral pain, common triggers and response to triptans and/or monoclonal antibodies against the calcitonin gene-related peptide (CGRP) pathway. Common pathophysiological mechanisms are proposed in CH and migraine, including the role of the trigeminal-vascular system with its most representative neuropeptide, CGRP. Very few case series have been conducted so far investigating anti-CGRP treatments in patients with comorbid CH and migraine, and no cases have been reported which assess both CH and chronic migraine outcomes. CASE SERIES: We describe 4 patients with both chronic migraine and cluster headache, with or without failure to preventive medications. Galcanezumab (240 mg loading dose, followed by 120 mg monthly) was used for at least a 3-month treatment, demonstrating improvement in both migraine and CH outcomes (i.e. migraine days, CH attacks, Headache Impact Test -6 item score, acute medications use), achieving sustained clinical benefit. No adverse events were reported. DISCUSSION AND CONCLUSION: Taking into account the role of CGRP in migraine and CH pathophysiology, a usually well-tolerated treatment with CGRP blockade could be a rationale-based option to treat patients with coexisting chronic migraine and cluster headache. Additional studies are needed to assess the role of anti-CGRP drugs in episodic and chronic CH treatment, as well as to establish correct timing and patient prerequisites to begin therapy.

Mental pain and pain-proneness in patients with migraine: results from the PAINMIG cohort-study.

BACKGROUND: Pain has been qualified under four categories: nociception, perception of pain, suffering, and pain behaviors. Most of the literature on migraine has devoted attention to the first two. The aim of the present cohort study was to investigate patients with migraine enrolled at a tertiary care unit to study suffering and mental pain and identify potential risk factors for migraine. METHODS: An observational cross-sectional study was carried out on patients with chronic migraine (CM) and episodic migraine (EM), and healthy subjects (HS). The three groups were matched for age and sex. A comprehensive assessment of migraine disability, pain, psychiatric disorders, psychosomatic syndromes, depressive and anxious symptoms, euthymia, psychosocial variables, mental pain, and pain-proneness (PP) was performed. RESULTS: Three hundred subjects were enrolled (100 CM, 100 EM, and 100 HS). Based on the multiple regression analyses, those presenting PP (social impairment: odds ratio [OR] = 3.59, 95% confidence interval [CI] = 1.14-11.29; depressive symptoms: OR = 3.82, 95% CI = 1.74-8.41) were more likely to be CM than HS. Those with higher levels of PP (social impairment: OR = 4.04, 95% CI = 1.60-10.22; depressive symptoms: OR = 2.02, 95% CI = 1.26-3.24) were more likely to be EM than HS. Those presenting higher levels of mental pain were more likely to be CM than EM (OR = 1.45, 95% CI = 1.02-2.07). CONCLUSION: Migraine is an unpleasant sensory and emotional experience associated with psychosocial manifestations that might contribute to the level of suffering of the individuals. Mental pain resulted to be the variable that most differentiated patients with CM from EM.

Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.

OBJECTIVES: A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH. METHODS: A prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded. RESULTS: Thirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30-150) to 16 (5-30), p < 0.001), in pain intensity (from 8.5 (8-9) to 5 (3-6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34-240) to 15 (3-28), p < 0.001). No misuse or diversion cases were observed. CONCLUSION: LDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.

Epidemiology and determinants of chronic migraine: A real-world cohort study, with nested case-control analysis, in primary care in Italy.

BACKGROUND: The proper identification of chronic migraine is one of the mainstays for general practitioners. This study therefore aims to assess the epidemiology and determinants of chronic migraine in primary care in Italy by testing five operational case definition algorithms. METHODS: Five case definition algorithms defining chronic migraine were developed to estimate the prevalence and incidence rate of chronic migraine in the Health Search database. For each algorithm, we conducted a nested case-control analysis to quantify the level of association between certain determinants and incident cases of chronic migraine. RESULTS: Considering a cohort of 1,091,032 patients (52% were females), the prevalence rate of chronic migraine increased from the first to the fifth case definition algorithm ranging from 0.03 to 0.28%. No 95% confidence interval overlapped the others, and every confidence interval reliably maintained 2% precision. Incidence rates showed a growing trend (0.008-0.056 per 100,000 person-years) as well. All case definition algorithms were able to capture sex (i.e. female) and nonsteroidal anti-inflammatory drug (NSAID) overuse as statistically significant determinants of incident cases of chronic migraine. Depression was associated with a statistically significant increase of incidence rate of chronic migraine only for two case definition algorithms. CONCLUSION: Our findings show that prevalence and incidence rate of chronic migraine are underestimated when compared with current literature. On the other hand, we found acceptable correctness of chronic migraine definition in the light of the association with well-known determinants.

Ultra-rapid brain uptake of subcutaneous sumatriptan in the rat: Implication for cluster headache treatment.

BACKGROUND: In spite of the substantial therapeutic efficacy of triptans, their site of action is still debated. Subcutaneous sumatriptan is the most efficacious symptomatic treatment for cluster headache (CH) patients, showing therapeutic onset within a few minutes after injection even in migraine patients. However, whether subcutaneous sumatriptan is able to reach the CNS within this short time frame is currently unknown. METHODS: Here, by means of liquid chromatography/mass spectrometry, we investigated peripheral and brain distribution of subcutaneous sumatriptan soon after injection in rats at a dose equivalent to that used in patients. Tissue sumatriptan contents were compared to those of oxazepam, a prototypical lipophilic, neuroactive drug. RESULTS: We report that sumatriptan accumulated within brain regions of relevance to migraine and CH pathogenesis such as the hypothalamus and the brainstem as soon as 1 and 5 minutes after injection. Notably, sumatriptan brain distribution was faster than that of oxazepam, reaching concentrations exceeding its reported binding affinity for 5HT1B/D receptors, and in the range of those able to inhibit neurotransmitter release in vivo. CONCLUSION: Our findings indicate that sumatriptan distributes within the CNS soon after injection, and are in line with prompt pain relief by parenteral sumatriptan in CH patients.

Criterion-related validity in a sample of migraine outpatients: the diagnostic criteria for psychosomatic research.

OBJECTIVE: The Diagnostic Criteria for Psychosomatic Research (DCPR) are those of psychosomatic syndromes that did not find room in the classical taxonomy. More recently, the DCPR were updated, called DCPR-revised (DCPR-R). The present study was conducted to test the criterion-related validity of the DCPR-R. METHODS: Two hundred consecutive subjects were enrolled at the Headache Center of Careggi University Hospital (Italy): 100 subjects had a diagnosis of chronic migraine (CM) and 100 had a diagnosis of episodic migraine (EM). Participants received a clinical assessment, which included the DCPR-revised Semi-Structured Interview (DCPR-R SSI), the Structured Clinical Interview for DSM-5 (SCID-5), and the psychosocial index (PSI). RESULTS: Forty-seven subjects (23.5%) had at least one DSM-5 diagnosis: major depressive disorder (8.5%; n = 17) and agoraphobia (7.5%; n = 15) were the most frequent. One hundred and ten subjects (55%) reported a DCPR-R diagnosis: allostatic overload (29%; n = 58) and type A behavior (10.5%; n = 21) were the most frequent. When the incremental validity of the DCPR system over the DSM system was tested using PSI subscales as the criterion variable, the DCPR-R increased up to 0.11-0.24 the amount of explained variance. Subjects with at least one DCPR-R diagnosis showed lower PSI well-being scores (p = .001), higher PSI stress scores (p < .001), and higher PSI psychological distress scores (p = .008) than subjects without a DCPR-R diagnosis. CONCLUSION: The DCPR-R showed a good criterion-related validity in migraine outpatients. Thus, they might be implemented, together with the DSM-5, in the assessment of migraine subjects.

Migraine-provoking substances evoke periorbital allodynia in mice.

BACKGROUND: Administration of endogenous mediators or exogenous chemicals in migraine patients provoke early headaches and delayed migraine-like attacks. Although migraine provoking substances are normally vasodilators, dilation of arterial vessels does not seem to be the sole contributing factor, and the underlying mechanisms of the delayed migraine pain are mostly unknown. Sustained mechanical allodynia is a common response associated with the local administration of various proalgesic substances in experimental animals and humans. Here, we investigated the ability of a series of endogenous mediators which provoke or do not provoke migraine in patients, to cause or not cause mechanical allodynia upon their injection in the mouse periorbital area. METHODS: Mechanical allodynia was assessed with the von Frey filament assay. Stimuli were given by subcutaneous injection in the periorbital area of C57BL/6J mice; antagonists were administered by local and systemic injections. RESULTS: Calcitonin gene related peptide (CGRP), but not adrenomedullin and amylin, pituitary adenylyl cyclase activating peptide (PACAP), but not vasoactive intestinal polypeptide (VIP), histamine, prostaglandin E2 (PGE2) and prostacyclin (PGI2), but not PGF2α, evoked a dose-dependent periorbital mechanical allodynia. The painful responses were attenuated by systemic or local (periorbital) administration of antagonists for CGRP (CLR/RAMP1), PACAP (PAC-1), histamine H1, PGE2 (EP4), and PGI2 (IP) receptors, respectively. CONCLUSIONS: The correspondence between substances that provoke (CGRP; PACAP, histamine, PGE2, PGI2), or do not provoke (VIP and PGF2α), migraine-like attacks in patients and periorbital allodynia in mice suggests that the study of allodynia in mice may provide information on the proalgesic mechanisms of migraine-provoking agents in humans. Results underline the ability of migraine-provoking substances to initiate mechanical allodynia by acting on peripheral terminals of trigeminal afferents.

Development and validation of the ID-EC - the ITALIAN version of the identify chronic migraine.

BACKGROUND: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. METHODS: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. RESULTS: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. CONCLUSIONS: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Long-Term Treatment with the Calcitonin Gene-Related Peptide Receptor Antagonist Erenumab in CADASIL: Two Case Reports.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of cerebral small vessel disease, caused by a mutation in the NOTCH3 gene on chromosome 19. The main clinical features include migraine (often with aura), early onset, recurrent subcortical ischemic strokes, mood disturbances, and cognitive impairment, frequently leading to dementia and disability with a reduction in life expectancy. Cerebral chronic global hypoperfusion, due to impaired cerebrovascular reactivity, seems to play a primary role in CADASIL. Migraine is the most common early feature of the disease, and to date, there are no consensus guidelines for treatment. Given the vasomodulatory influence of many antimigraine drugs, there is concern about their use in this disease. In particular, the calcitonin gene-related peptide (CGRP) system serves as a vasodilatory protective mechanism during cerebral and cardiac ischemia. Blocking this system could exacerbate ischemic events. Herein, we describe two CADASIL patients who were treated with the calcitonin gene-related peptide (CGRP) receptor antagonist erenumab for chronic migraine, reporting a significant reduction in the frequency of attacks and intensity of pain, and an improvement in quality of life without adverse effects.

TRPA1 and other TRP channels in migraine.

Ever since their identification, interest in the role of transient receptor potential (TRP) channels in health and disease has steadily increased. Robust evidence has underlined the role of TRP channels expressed in a subset of primary sensory neurons of the trigeminal ganglion to promote, by neuronal excitation, nociceptive responses, allodynia and hyperalgesia. In particular, the TRP vanilloid 1 (TRPV1) and the TRP ankyrin 1 (TRPA1) are expressed in nociceptive neurons, which also express the sensory neuropeptides, tachykinins, and calcitonin gene-related peptide (CGRP), which mediate neurogenic inflammatory responses. Of interest, CGRP released from the trigeminovascular network of neurons is currently recognized as a main contributing mechanism of migraine attack. The ability of TRPA1 to sense and to be activated by an unprecedented series of exogenous and endogenous reactive molecules has now been extensively documented. Several of the TRPA1 activators are also known as triggers of migraine attack. Thus, TRP channels, and particularly TRPA1, may be proposed as novel pathways in migraine pathophysiology and as possible new targets for its treatment.

Switching OnabotulinumtoxinA to Monoclonal Anti-CGRP Antibodies in Drug-Resistant Chronic Migraine.

BACKGROUND: OnabotulinumtoxinA (BTX-A) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (anti-CGRP mAbs) are approved drugs for chronic migraine (CM), a difficult-to-treat condition. Optimization of CM patient management by choosing the best options and determining appropriate time for switching or adding concomitant treatments are highly needed. OBJECTIVE: Evaluate clinical response to anti-CGRP mAbs in patients who switched from BTX-A due to ineffectiveness defined by different cut-offs and assess the retention rate, effectiveness, and safety of both drugs within the first 9 months of treatment. METHODS: A monocentric, cohort study, enrolling patients with CM, resistant to several preventive treatments, first treated with BTX-A and then with anti-CGRP mAbs with two observational phases of 9 months preceded by respective baseline. First, the retention rate and effectiveness of both treatments were measured in all patients. A second analysis assessed effectiveness in patients stratified according to <50 or <30% response rate to BTX-A. The absolute change from baseline in monthly headache days (MHDs), response rate, analgesic use, and persistence in medication overuse (MO) at 3, 6, and 9 months of treatment were recorded. Last observation carried forward (LOCF) analyses, including all patients and assuming no further changes after discontinuation, were performed for all outcomes. RESULTS: Of the 78 enrolled patients (80.8% female, and 89.7% with MO at baseline), 32 (41.0%) received erenumab, 32 (41.0%) galcanezumab, and 14 (18.0%) fremanezumab. Retention rate was 62.2 and 91.0% for BTX-A and 76.9 and 96.2%, for anti-CGRP mAbs at 3 and 9 months of treatment, respectively. At 9 months of treatment, 22.4% of BTX-A patients and 65.0% of anti-CGRP mAbs patients achieved a ≥50% response rate. Anti-CGRP mAbs reduced MHDs, AMN, and AMDs, and decreased the number of MO patients at 9 months. In patients stratified according to <50 or <30% response rate to BTX-A, response rate (≥50% response at 9 months) to anti-CGRP was 62.9 and 57.9%, respectively. LOCF analyses confirmed these findings. No serious adverse events (AEs) were recorded and only two patients discontinued treatment due to AEs. CONCLUSIONS: Difficult-to-treat CM patients who discontinued BTX-A and received anti-CGRP mAbs showed a substantial clinical improvement in migraine-related outcomes. Switching to an anti-CGRP mAb appears to be a viable option in patients with insufficient response after the first 2 cycles with BTX-A. The appropriate variables, cut-offs, and timing to define ineffectiveness and the best time to switch or combine therapies for difficult-to-treat CM need to be investigated further.

Long-Term Treatment Over 52 Weeks with Monthly Fremanezumab in Drug-Resistant Migraine: A Prospective Multicenter Cohort Study.

BACKGROUND: Real-world studies on fremanezumab, an anti-calcitonin gene-related peptide monoclonal antibody for migraine prevention, are few and with limited follow-up. OBJECTIVE: We aimed to evaluate the long-term (up to 52 weeks) effectiveness and tolerability of fremanezumab in high-frequency episodic migraine and chronic migraine. METHODS: This s an independent, prospective, multicenter cohort study enrolling outpatients in 17 Italian Headache Centers with high-frequency episodic migraine or chronic migraine and multiple preventive treatment failures. Patients were treated with fremanezumab 225 mg monthly. The primary outcomes included changes from baseline (1 month before treatment) in monthly headache days, response rates (reduction in monthly headache days from baseline), and persistence in medication overuse at months 3, 6, and 12 (all outcome timeframes refer to the stated month). Secondary outcomes included changes from baseline in acute medication intake and disability questionnaires scores at the same timepoints. A last observation carried forward analysis was also performed. RESULTS: A total of 90 patients who received at least one dose of fremanezumab and with a potential 12-month follow-up were included. Among them, 15 (18.0%) patients discontinued treatment for the entire population, a reduction in monthly headache days compared with baseline was reported at month 3, with a significant median [interquartile range] reduction in monthly headache days (- 9.0 [11.5], p < 0.001). A statistically different reduction was also reported at month 6 compared with baseline (- 10.0 [12.0]; p < 0.001) and at 12 months of treatment (- 10.0 [14.0]; p < 0.001). The percentage of patients with medication overuse was significantly reduced compared with baseline from 68.7% (57/83) to 29.6% (24/81), 25.3% (19/75), and 14.7% (10/68) at 3, 6, and 12 months of treatment, respectively (p < 0.001). Acute medication use (days and total number) and disability scores were also significantly reduced (p < 0.001). A ≥ 50% response rate was achieved for 51.9, 67.9, and 76.5% of all patients at 3, 6, and 12 months, respectively. Last observation carried forward analyses confirmed these findings. Fremanezumab was well tolerated, with just one patient discontinuing treatment because of adverse events. CONCLUSIONS: This study provides evidence for the real-world effectiveness of fremanezumab in treating both high-frequency episodic migraine and chronic migraine, with meaningful and sustained improvements in multiple migraine-related variables. No new safety issue was identified.