CGRP receptor antagonists (gepants).

Small molecule calcitonin gene-related peptide (CGRP) receptor antagonists are commonly referred to as gepants. The first generation of gepants provided the first line of evidence of CGRP-mediated antimigraine medication in 2004-2011. However, further development was halted due to either lack of oral availability or concerns of hepatotoxicity. More than 15 years later, the first second generation of gepants, ubrogepant and rimegepant, are now approved for the acute treatment of migraine with or without aura. Furthermore, a novel and promising third-generation gepant, zavegepant, has recently been approved as well. In this chapter, we review the evidence supporting the effectiveness, safety, and tolerability of gepants for the acute treatment of migraine. Furthermore, we discuss the potential limitations and future directions of this class of migraine-specific medication.

Excellent Response to OnabotulinumtoxinA: Different Definitions, Different Predictors.

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle.

Comparing the relative and absolute effect of erenumab: is a 50% response enough? Results from the ESTEEMen study.

BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. METHODS: ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. RESULTS: Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. CONCLUSIONS: The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.

Is There a Gender Difference in the Response to onabotulinumtoxinA in Chronic Migraine? Insights from a Real-Life European Multicenter Study on 2879 Patients.

INTRODUCTION: Migraine is mostly a female disorder because of its lower prevalence in men. Less than 20% of patients included in the available studies on migraine treatments are men; hence, the evidence on migraine treatments might not apply to men. The aims of the present study were to provide reliable information on the effectiveness of onabotulinumtoxinA (BT-A) for chronic migraine in men and to compare clinical benefits between men and women. METHODS: We performed a pooled patient-level gender-specific analysis of real-life data on BT-A for chronic migraine of patients followed-up to 9 months. We reported the 50% responder rates during each BT-A cycle, defined as percentage of reduction in monthly headache days (MHDs) compared to baseline, along with 75% and 30% responder rates. We also reported the mean decrease in MHDs and in days of acute medication use (DAMs) during each BT-A cycle as compared to baseline. We also evaluated the reasons for stopping the treatment within the third cycle. RESULTS: We included an overall cohort of 2879 patients, 522 of whom (18.1%) were men. In men, 50% responder rates were 27.7% during the first BT-A cycle, 29.2% during the second, and 35.6% during the third cycle; in women, the corresponding rates were 26.6%, 33.5%, and 41.0%. In the overall cohort, responder rates did not differ between men and women during the first two cycles; during the third cycle, the distribution was different (P < 0.001) mostly because of higher rates of treatment stopping and non-responders in men. In the propensity score matched cohort, the trend was maintained but lost its statistical significance. Both men and women had a significant decrease in MHDs and in DAMs with BT-A treatment (P < 0.001). There were no gender differences in those changes with the only exception of MHD decrease which, during the third cycle, was lower in men than in women (7.4 vs 8.2 days, P = 0.016 in the overall cohort and 9.1 vs 12.5 days, P = 0.009 in the propensity score matched cohort). At the end of follow-up, 152 men and 485 women stopped BT-A treatment (29.1% vs 20.6%; P < 0.001). The relative proportion of patients stopping treatment because of inadequate response (less than 30% decrease in MHDs from baseline) was higher in men than in women (42.8% vs 39.6%), while the proportion of patients stopping because of adverse events was higher in women than in men (5.6% vs 0%; P = 0.031). CONCLUSIONS: Our pooled analysis suggests that the response to BT-A is significant in both men and women with a small gender difference in favor of women. Men tended to stop the treatment more frequently than women. We emphasize the need for more gender-specific data on migraine treatments from randomized controlled trials and observational studies.

Early Management of OnabotulinumtoxinA Treatment in Chronic Migraine: Insights from a Real-Life European Multicenter Study.

INTRODUCTION: OnabotulinumtoxinA (BT-A) quarterly was the first treatment approved specifically for chronic migraine (CM). It is unclear whether three cycles are better than two to assess early BT-A response. METHODS: We performed a retrospective analysis on real-life prospectively collected data in 16 European headache centers. All the centers provided data on patients treated with BT-A for CM over the first three cycles of treatment. For each treatment cycle we defined patients as "good responders" if reporting a ≥ 50% reduction in monthly headache days compared with the three months before starting BT-A, "partial responders" if reporting a 30-49% reduction in monthly headache days, and "non-responders" if reporting a < 30% reduction in monthly headache days or stopping the treatment before the third cycle. RESULTS: We included 2879 patients. Seven hundred and eighty-four (64.6%) of the 1213 patients reporting a good response during the first and/or the second cycle had a good response during the third cycle; 309 (49.3%) of the 627 patients reporting a partial response (but no good response) during the first and/or the second cycle had a good response during the third cycle; only 65 (6.3%) of the 1039 patients who did not respond during both the first two cycles achieved a good response during the third cycle. Multivariate analyses showed that partial or good response during the first or the second cycle were independently associated with good response during the third cycle. CONCLUSIONS: Our data suggest that patients with CM responding to BT-A during the first two cycles will likely benefit from the third cycle of treatment, while the probability that non-responders to the first two cycles start responding during the third cycle is low. These results can help guide the individual decision to stop or continue treatment after the second cycle in patients who have not responded to the first two cycles.

Gender Differences in 3-Month Outcomes of Erenumab Treatment-Study on Efficacy and Safety of Treatment With Erenumab in Men.

Objective: We reported gender-specific data on the efficacy and safety of erenumab, a monoclonal antibody antagonizing the calcitonin gene-related peptide (CGRP) receptor. Methods: Our pooled patient-level analysis of real-world data included patients treated with erenumab and followed up for 12 weeks. We considered the following outcomes at weeks 9-12 of treatment compared with baseline: 0-29%, 30-49%, 50-75%, and ≥75% responder rates, according to the decrease in monthly headache days (MHDs), rate of treatment stopping, change in MHDs, monthly migraine days (MMDs), monthly days of acute medication and triptan use, and Headache Impact Test-6 (HIT-6) score from baseline to weeks 9-12. Outcomes were compared between men and women by the chi-squared test or t-test, as appropriate. An analysis of covariance (ANCOVA) was performed to identify factors influencing the efficacy outcomes. Results: We included 1,410 patients from 16 centers, of which 256 (18.2%) were men. Men were older than women and had a lower number of MHDs at baseline. At weeks 9-12, compared with baseline, 46 (18.0%) men had a ≥75% response, 75 (29.3%) had a 50-74% response, 35 (13.7%) had a 30-49% response, and 86 (33.6%) had a 0-29% response, while 14 (5.5%) stopped the treatment. The corresponding numbers for women were 220 (19.1%), 314 (27.2%), 139 (12.0%), 402 (34.8%), and 79 (6.8%). No gender difference was found in any of the outcomes. The ANCOVA showed that gender did not influence the efficacy of outcomes. Conclusion: We found that erenumab is equally safe and effective in men compared with women after 12 weeks.

Safety and Efficacy of Melatonin in Chronic Tension-Type Headache: A Post-Marketing Real-World Surveillance Program.

INTRODUCTION: Tension-type headache (TTH) is the most prevalent primary headache. Every year, about 2-3% of patients with TTH progress to chronic TTH with daily or near-daily headache, warranting preventive treatment. The treatment of chronic TTH is complex and very often associated with significant tolerability issues. To date, melatonin has been studied in only a few small uncontrolled trials. The aim of this surveillance program was to evaluate the efficacy of melatonin (Melaxen®) in patients with TTH and disruption of circadian rhythms in real-world practice. METHODS: Sixty-one patients with chronic TTH were enrolled. After the 30-day baseline period, patients took 3 mg of melatonin at bedtime for 30 days with a follow-up period of another 30 days. VAS pain intensity assessments, Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), HIT-6 and Levin sleep quality scores were obtained at the baseline visit, at month 1, and month 2. RESULTS: A significant decrease in the number of headache days per month, VAS pain intensity, HAM-A, HAM-D and HIT-6 scores, and an improvement in sleep quality were observed throughout the study. No treatment-emergent adverse events were reported. CONCLUSIONS: Melatonin is an effective and safe alternative for the treatment of chronic TTH.

Wear-Off of OnabotulinumtoxinA Effect Over the Treatment Interval in Chronic Migraine: A Retrospective Chart Review With Analysis of Headache Diaries.

OBJECTIVE: To quantify wear-off of the response to OnabotulinumtoxinA (OnabotA) treatment over the treatment cycle in chronic migraine at group and individual level. BACKGROUND: OnabotA administered quarterly is an effective treatment for chronic migraine. However, some patients report that headache recurs before the scheduled follow-up injection. METHODS: In this retrospective chart review performed in 6 university outpatient centers or private practices specialized in headache treatment, 112 patients with a ≥30% response to OnabotA who completed headache diaries over 13 weeks after OnabotA treatment were included (age [mean ± SD] 45 ± 12 years, 82% female, headache days/month at baseline 24 ± 6). RESULTS: Compared to weeks 5 to 8 after injection, headache days/week increased significantly in weeks 12 (+0.52 ± 1.96, 95% CI [0.15, 0.88], P < .009) and 13 (+1.15 ± 1.95, CI[0.79, 1.52], P < .001), demonstrating significant wear-off of the OnabotA effect. Similarly, acute medication days/week significantly increased in weeks 12 (0.38±1.67, CI [0.06, 0.69], P ≤ .027) and 13 (+0.83 ± 1.76, CI [0.49, 1.16], P < .001). At an individual level, 57 patients (51%) showed ≥30% wear-off by weeks 12 and 13, and 28 patients (25%) showed ≥30% wear-off already by weeks 10 and 11. Age, gender, OnabotA dose or cycle number, or headache center did not predict individual wear-off. CONCLUSIONS: These data show that in clinical practice, on average the response of chronic migraine patients to OnabotA injection shows a clinically significant wear-off from week 12 after treatment. About 25% of the patients experience wear-off even by weeks 10 and 11. It must be noted that wear-off detected in a real-world study on OnabotA responders can be due to wear-off of a pharmacological OnabotA effect or a placebo effect, or to regression to the mean effects. This wear-off phenomenon may negatively affect quality of life of chronic migraine patients under OnabotA treatment. The best way to counteract wear-off remains to be determined.

Sleep Disorders and Headache: A Review of Correlation and Mutual Influence.

The review is devoted to the complex relationship between headache and sleep disorders. The shared neuroanatomical structures of the nervous system involved in pain perception and sleep are shown, and mechanisms of comorbidity between headaches and sleep disorders are considered. Various types of headaches in the continuum of the sleep-wake cycle are described. Both pharmacological and non-pharmacological approaches to treatment are examined in detail, with the biochemical basis of the drug action.

Interdisciplinary approach to chronic pain management.

Chronic pain is a significant and costly problem all over the world. Despite significant progress in identifying the best treatment approaches, there are still significant obstacles that must be overcome in order for the treatment to be truly beneficial. There is evidence to support the cost-effectiveness of interdisciplinary treatment programs for patients with chronic pain. Creating an interdisciplinary service is not easy and certainly is much more complicated than simply placing different services in one clinic. However, when such interdisciplinary programs are instituted, they increase the effectiveness of chronic pain management significantly; bring satisfaction to doctors and are economically attractive (interdisciplinary treatment programs for patients suffering from pain not only provide the best clinical treatment, but are also the most cost-effective in the long run).

Cognitive impairment in chronic migraine: a cross-sectional study in a clinic-based sample.

Cognitive impairment has been described in all phases of a migraine attack and interictally. However, the prevalence and phenotype of such impairment in chronic migraine (CM) have not yet been studied. OBJECTIVES: The aim of this study was to evaluate both the prevalence of the objective cognitive deficit in patients with CM and the factors underlying its etiology. METHODS: 144 patients with CM and 44 age-matched patients with low-frequency episodic migraine (EM) (a maximum of 4 headache days per month) participated in this study. Neuropsychiatric characteristics were measured with the HADS Hospital Anxiety and Depression Scale. Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and the Perceived Deficits Questionnaire (PDQ-20). RESULTS: Compared to EM, CM subjects demonstrated higher subjective and objective cognitive impairment across all tests. CM patients had 4 times higher odds of achieving a RAVLT score in the lower quartile range compared to EM (Odds Ratio [OR] 3.8; 95% confidence interval [95%CI] 1.5‒9.6; р=0.005). In the MoCA, CM patients demonstrated the most striking impairment in memory/delayed recall (65.3%), attention (46.5%), abstraction (30.6%), and language (27.1%). Chronic headache and level of education, but not gender, depression or anxiety, were independent predictors of cognitive impairment. CONCLUSIONS: Cognitive impairment is prevalent in the CM population during their mildest possible pain and may be caused by a central sensitization. Timely preventive treatment of EM is warranted.

Cognitive impairment in chronic migraine: a cross-sectional study in a clinic-based sample / Comprometimento cognitivo na enxaqueca crônica: um estudo transversal em uma amostra clínica

Abstract Cognitive impairment has been described in all phases of a migraine attack and interictally. However, the prevalence and phenotype of such impairment in chronic migraine (CM) have not yet been studied. Objectives: The aim of this study was to evaluate both the prevalence of the objective cognitive deficit in patients with CM and the factors underlying its etiology. Methods: 144 patients with CM and 44 age-matched patients with low-frequency episodic migraine (EM) (a maximum of 4 headache days per month) participated in this study. Neuropsychiatric characteristics were measured with the HADS Hospital Anxiety and Depression Scale. Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and the Perceived Deficits Questionnaire (PDQ-20). Results: Compared to EM, CM subjects demonstrated higher subjective and objective cognitive impairment across all tests. CM patients had 4 times higher odds of achieving a RAVLT score in the lower quartile range compared to EM (Odds Ratio [OR] 3.8; 95% confidence interval [95%CI] 1.5‒9.6; р=0.005). In the MoCA, CM patients demonstrated the most striking impairment in memory/delayed recall (65.3%), attention (46.5%), abstraction (30.6%), and language (27.1%). Chronic headache and level of education, but not gender, depression or anxiety, were independent predictors of cognitive impairment. Conclusions: Cognitive impairment is prevalent in the CM population during their mildest possible pain and may be caused by a central sensitization. Timely preventive treatment of EM is warranted.

Resumo O comprometimento cognitivo foi descrito em todas as fases de um ataque de enxaqueca, de maneira intermitente. Entretanto, a prevalência e o fenótipo desse comprometimento na enxaqueca crônica (EC) não foram estudados. Objetivos: O objetivo deste estudo foi avaliar a prevalência do déficit cognitivo objetivo em pacientes com EC e fatores subjacentes à sua etiologia. Métodos: 144 pacientes com CM e 44 pacientes pareados por idade com enxaqueca episódica (EE) de baixa frequência (máximo de 4 dias de dor de cabeça por mês) foram incluídos. As características neuropsiquiátricas foram medidas pela Hospital Anxiety and Depression Scale (HADS). A função cognitiva foi avaliada por meio da Montreal Cognitive Assessment (MoCA), o Digit Symbol Substitution Test (DSST), o Rey Auditory Verbal Learning Test (RAVLT) e o Perceived Deficits Questionnaire (PDQ-20). Resultados: Em comparação com a EE, os indivíduos com EC demonstraram um comprometimento cognitivo subjetivo e objetivo maior em todos os testes. Os pacientes com CM tiveram 4 vezes mais chances de alcançar um escore RAVLT na faixa quartil inferior, em comparação com EE (Odds Ratio [OR] 3,8; intervalo de confiança de 95% [IC95%] 1,5‒9,6; p=0,005). No MoCA, os pacientes com EC demonstraram o maior prejuízo na memória/atraso na recordação (65,3%), atenção (46,5%), abstração (30,6%) e linguagem (27,1%). Dor de cabeça crônica e nível de escolaridade, mas não o sexo, depressão ou ansiedade, foram preditores independentes de comprometimento cognitivo. Conclusões: O comprometimento cognitivo é prevalente na população com enxaqueca crônica mesmo durante uma dor muito leve e pode ser causado pela sensibilização central. O tratamento preventivo oportuno da enxaqueca episódica se faz necessário.

Headache service quality: evaluation of quality indicators in 14 specialist-care centres.

BACKGROUND: The study was a collaboration between Lifting The Burden (LTB) and the European Headache Federation (EHF). Its aim was to evaluate the implementation of quality indicators for headache care Europe-wide in specialist headache centres (level-3 according to the EHF/LTB standard). METHODS: Employing previously-developed instruments in 14 such centres, we made enquiries, in each, of health-care providers (doctors, nurses, psychologists, physiotherapists) and 50 patients, and analysed the medical records of 50 other patients. Enquiries were in 9 domains: diagnostic accuracy, individualized management, referral pathways, patient's education and reassurance, convenience and comfort, patient's satisfaction, equity and efficiency of the headache care, outcome assessment and safety. RESULTS: Our study showed that highly experienced headache centres treated their patients in general very well. The centres were content with their work and their patients were content with their treatment. Including disability and quality-of-life evaluations in clinical assessments, and protocols regarding safety, proved problematic: better standards for these are needed. Some centres had problems with follow-up: many specialised centres operated in one-touch systems, without possibility of controlling long-term management or the success of treatments dependent on this. CONCLUSIONS: This first Europe-wide quality study showed that the quality indicators were workable in specialist care. They demonstrated common trends, producing evidence of what is majority practice. They also uncovered deficits that might be remedied in order to improve quality. They offer the means of setting benchmarks against which service quality may be judged. The next step is to take the evaluation process into non-specialist care (EHF/LTB levels 1 and 2).

Evidence of persistent central sensitization in chronic headaches: a multi-method study.

The aim of this study was to investigate central sensitization (CS) in chronic headaches and compare this phenomenon between chronic migraine (CM) and chronic tension-type headache (CTTH). We recruited 69 patients with chronic headaches and 18 control subjects. Questionnaires of headache history, allodynia and the Hospital Anxiety and Depression scale were administered. We recorded thresholds for pinprick and pressure pain, blink (BR) and nociceptive flexion reflex (NFR) R3 component coupled with wind-up ratios. Thresholds for pressure and pinprick pain, BR and NFR R3 were lower and wind-up ratios higher in patients. No differences of CS parameters between CM and CTTH were observed. CS is persistent and prevalent in patients with various types of chronic headache. CS levels are unrelated to the predominant side of pain, disease duration or depression. Neither is CS related to the headache type, suggesting similar mechanisms of headache chronification and chronicity maintaining and possibly explaining clinical similarity of various forms of chronic headache.