Efficacy and safety of galcanezumab as chronic cluster headache preventive treatment under real world conditions: Observational prospective study.

BACKGROUND: Calcitonin gene-related peptide has shown to play a central role in cluster headache (CH) pathophysiology. A clinical trial with galcanezumab was carried out in chronic cluster headache (CCH) but did not meet its primay endpoint. However, its off-label use in patients with CCH refractory to other therapies could be considered. We aimed to asses the efficacy and safety of galcanezumab as CCH preventive treatment in a real-life setting. METHODS: An observational study was conducted. Patients with CCH who received at least one dose of 240 mg of galcanezumab. RESULTS: Twenty-one patients who tried a mean of 6.3 ± 1.9 preventive therapies, including onabotulinumtoxinA in 90.5%. At baseline, the median of frequency was 60 (37.5-105) monthly attacks with 10 (8.3-10) points in pain intensity (Numerical Rating Scale). After one month, the frequency decreased to 31 (10.5-45) (p = 0.003) with 8.5 (8-9.5) intensity (p = 0.007); 10 (47.6%) patients were 50% responders of whom four (19%) were 75% responders. Of the 15 patients with 3 months of follow-up, seven (46.6%) reduced their frequency by 50% and four (26.6%) by 75%, with 40 (10-60) monthly attacks (p = 0.07) and pain intensity of 8 (5-10) (p = 0.026). Some 52% patients experienced adverse events, mostly mild. CONCLUSIONS: In our cohort of refractory CCH, galcanezumab was effective in almost 50% of patients. This finding supports individual off-label treatment attempts.

Open label experience of repeated OnabotulinumtoxinA injections towards the sphenopalatine ganglion in patients with chronic cluster headache and chronic migraine.

BACKGROUND: A novel technique for injection of OnabotulinumtoxinA (BTA) towards the sphenopalatine ganglion (SPG) has shown promise in refractory chronic migraine (CM) and chronic cluster headache (CCH). Open label safety and efficacy data are presented here. METHODS: Patients with refractory CM or CCH who had received at least one injection and completed headache diaries were included. Efficacy was defined as ≥50% reduction in moderate-to-severe headache days for CM, or ≥50% reduction in attack frequency for CCH, at weeks five to eight. RESULTS: Over 261 injections, there were 123 adverse events (AE), of which one was serious. Most (93%) AEs were mild and all were transient. The 50% response to one injection was 81% for CM and 69% for CCH. The response gradually reduced over subsequent months for CM but stayed between 55% and 67% for CCH. Repeated injections were beneficial. CONCLUSIONS: Injections resulted in improvement for both groups and was maintained with repeated injections. Repeat injection after three months may be beneficial in CM. Adverse events were not uncommon, but universally transient, presumably as a result of the mechanism of action of BTA. Repeated BTA injection towards the SPG could be an effective treatment for refractory CM and CCH. Larger, randomised, placebo-controlled trials are required.

CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity.

OBJECTIVE: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). BACKGROUND: CCH is an excruciating and difficult-to-treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited. METHODS: In this small open-label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow-up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose. RESULTS: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow-up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = -0.81), implicating this neural pathway in treatment response. CONCLUSION: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.

Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions.

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies. MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment. CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

One-year prevalence of cluster headache, hemicrania continua, paroxysmal hemicrania and SUNCT in Norway: a population-based nationwide registry study.

BACKGROUND: There is lack of population-based studies evaluating the prevalence of paroxysmal hemicrania, hemicrania continua and short-lasting unilateral neuralgiform headache attacks. OBJECTIVES: The aim of this study was to investigate the gender-specific 1-year prevalence of cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks. METHODS: A nationwide study was conducted from January 1 2022 and December 31 2022 by linking diagnostic codes from Norwegian Patient Registry and prescription of relevant drugs from Norwegian Prescription Database on an individual basis. The 1-year prevalence with 95% confidence intervals (CI) of cluster headache, paroxysmal hemicrania, hemicrania continua and short-lasting unilateral neuralgiform headache attacks are estimated based on the combination of diagnostic codes, prescription of drugs and corresponding reimbursement codes. RESULTS: Among 4,316,747 individuals aged ≥ 18 years, the 1-year prevalence per 100,000 was 14.6 (95% CI 13.5-15.8) for cluster headache, 2.2 (95% CI 1.8-2.7) for hemicrania continua, 1.4 (95% CI 1.0-1.8) for paroxysmal hemicrania, and 1.2 (95% CI 0.8-1.4) for short-lasting unilateral neuralgiform headache attacks. For all the trigeminal autonomic cephalalgies, cluster headache included, the prevalence was higher for women than men. CONCLUSIONS: In this nationwide register-based study, we found a 1-year prevalence per 100,100 of 14.6 for cluster headache, 2.2 for hemicranias continua, 1.4 for paroxysmal hemicranias, and 1.2 for short-lasting unilateral neuralgiform headache attacks. This is the first study reporting higher prevalence of cluster headache for women than men.

Induction of cluster headache after opening of adenosine triphosphate-sensitive potassium channels: a randomized clinical trial.

ABSTRACT: Activation of adenosine triphosphate-sensitive potassium (K ATP ) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches. Over 2 distinct experimental days, participants underwent a continuous 20-minute infusion of levcromakalim, a K ATP channel opener, or a placebo (isotonic saline), followed by a 90-minute observational period. The primary outcome was comparing the incidence of cluster headache attacks within the postinfusion observation period between the levcromakalim and placebo groups. Six of 10 participants (60%) with episodic cluster headaches in bout experienced attacks after levcromakalim infusion, vs just 1 of 10 (10%) with placebo ( P = 0.037). Among those in the remission phase, 1 of 15 participants (7%) reported attacks after levcromakalim, whereas none did postplacebo ( P = 0.50). In addition, 5 of 17 participants (29%) with chronic cluster headache had attacks after levcromakalim, in contrast to none after placebo ( P = 0.037). These findings demonstrate that K ATP channel activation can induce cluster headache attacks in participants with episodic cluster headaches in bout and chronic cluster headache, but not in those in the remission period. Our results underscore the potential utility of K ATP channel inhibitors as therapeutic agents for cluster headaches.

Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

Clomiphene treatment may be effective in refractory episodic and chronic cluster headache / Tratamento de 15 casos episódicos e crônicos de cefaleia em salvas de difícil controle com clomifeno

ABSTRACT Objective To describe the evolution of 15 patients who were treated for difficult-to-control episodic and chronic cluster headaches with clomiphene. Methods Clomiphene treatment was used for seven chronic and eight episodic cluster headache patients. The chronic patients were refractory to the medication being used, and the episodic patients, in addition to being resistant to conventional medication, had longer cluster headache periods, exceeding the average time of previous cluster cycles. Our main analysis was of the time to pain-free, complete remission, and the length of pain-free time and complete remission. Results Clomiphene was used for 45-180 days. The average time to being pain-free was 15 days and cluster remission was up to 60 days. The average time between being pain-free until cluster remission was 26 days. Conclusions Clomiphene treatment was significantly efficient. It interrupted chronicity in all patients, suggesting the capability of changing the pattern of attacks. It proved to be safe and well tolerated.

RESUMO Objetivo Descrever a evolução de 15 casos de cefaleia em salvas de difícil controle, episódicos e crônicos, tratados com clomifeno. Métodos Foram tratados 7 casos crônicos e 8 episódicos. Os crônicos, refratários aos medicamentos preventivos em uso e os episódicos, além de refratários, apresentaram salva mais longa que as anteriores. Foram analisados o tempo para a ausência das crises, fim da salva e o tempo entre os dois parâmetros. Resultados O clomifeno foi usado por 45 a 180 dias. A média de tempo para a remissão das crises foi de 15 dias e da salva foi de 60 dias. A média entre o fim das crises e da salva foi de 26 dias. Conclusão O clomifeno foi eficaz em ambos os padrões. Foi capaz de interromper a cronicidade em todos os casos, o que sugere uma ação neuromodulatória capaz de mudar o padrão das crises. Mostrou-se seguro e bem tolerado.

Abordaje diagnóstico y terapéutico de la cefalea en racimos (cluster headache): aplicación de un modelo de análisis de decisión / Diagnostic and therapeutic approach to cluster headache: application of a decision-making analysis model

Introducción: Las ciencias de la decisión conforman el conjunto de técnicas y teorías surgido del método cuantitativo y matemático dirigido al auxilio de una toma de decisiones con criterio aplicable a varias disciplinas y en los más variados contextos, donde la multicausalidad y la influencia de múltiples factores hace difícil la elección de una decisión unívoca, dado que la incertidumbre es el patrón común situacional. Se presenta a continuación el caso concreto de un paciente de 50 años portador de una cefalea en racimos, en el que se aplica el análisis de decisión de abordaje diagnóstico-terapéutico, y se elige la conducta a seguir basándose en esta metodología. Objetivos: Aplicar este modelo de análisis de la decisión a un problema clínico individual: un paciente de 50 años, portador de una cefalea en racimos o acuminada. Demostrar que en este caso clínico puntual, ante varias opciones diagnósticas y terapéuticas, el intervencionismo antálgico es una de las herramientas más efectivas y elegidas por los pacientes, teniendo en cuenta aspectos tales como la evidencia científica de respaldo de cada alternativa, la calidad de vida de los pacientes con dolor crónico no oncológico de tipo invalidante y el uso de una metodología concreta para la toma de decisión. Material y métodos: Aplicación de un análisis de decisión diagnóstico (terapéutico concreto), presentando un caso clínico real de cefalea en racimos. Búsqueda bibliográfica en Medline y OVID. Para la formulación de los valores umbrales, el análisis de sensibilidad y la graficación del árbol de decisión se utilizó el paquete estadístico STATA - DATA TREE AGE 3.5. Como outcome principal se determinó la expectativa de vida ajustada por calidad (medida en QALYs)...

Introduction: The science of decision-making is a set of techniques and theories arising from the quantitative and mathematic method, aimed at assisting in decision-making with criterion, applicable to many disciplines and numerous different contexts in which multi-causality and the influence of multiple factors make the choice of an unequivocal decision difficult, as uncertainty is the common pattern of the situation. Following is the case history of a 50-year-old patient suffering from cluster headaches; the analysis of decision-making as to the diagnostic-therapeutic approach is applied and the choice of conduct is based on this methodology. Objectives: To apply this decision-making analysis model to a clinical problem: a 50-year-old patient with cluster or acuminate headaches. To prove that in this specific clinical case, faced with different diagnostic and therapeutic options, antalgic interventionism is one of the most effective tools and is chosen by patients, taking into account aspects such as scientific backing proof of each alternative, quality of life of patients with chronic non-oncology invalidating pain and the use of a specific methodology for making the decision. Material and methods: Application of a diagnostic decision analysis, with a real clinical case of cluster headaches. Bibliographic research in Medline and OVID. To formulate threshold values, the sensitivity analysis and graphing the decision tree, the STATA - DATA TREE AGE 3.5 was used. As main outcome, the life expectancy adjusted by quality (measured in QALYs) was determined. Results: Once the sequence of the analysis was developed, the model firmly showed that the best diagnosis prognosis decision is to make a best diagnosis-prognosis block with local anesthetics and, should it be positive, to proceed to denervate the sphenoid-palatine ganglion by radiofrequency...

Introdução: As ciências da decisão conformam um conjunto de técnicas e teorias surgido do método quantitativo e matemático direcionado ao auxílio de uma tomada de decisão criteriosa, aplicável a diversas disciplinas e nos mais variados contextos, onde a multicausalidade e a influencia de múltiplos fatores torna difícil a escolha de uma decisão unívoca, já que a incerteza é o padrão situacional genérico. Apresenta-se o caso de um paciente de 50 anos, portador de cefaléia em cacho, em que foi aplicado o processo de análise de decisão de abordagem diagnóstica-terapêutica, sendo escolhida a conduta a seguir tomando como base esta metodologia. Objetivos: Aplicar este modelo de análise de decisão a um problema clínico individual: um paciente de 50 anos, portador de uma cefaléia em cacho ou acuminada. Provar que neste caso clínico particular, a intervenção antálgica, diante de várias opções diagnósticas e terapêuticas, é uma das ferramentas mais eficazes e escolhidas pelos pacientes, considerando aspectos tais como a evidência científica de apoio a cada alternativa, a qualidade de vida dos pacientes com dor crônica não oncológica incapacitante e o uso de uma metodologia concreta para a tomada de decisão. Material e métodos: Aplicação de uma análise de decisão diagnóstica (terapêutica concreta), apresentando um caso clínico real de cefaléia em cacho. Busca bibliográfica na Medline e na OVID. Para a formulação dos valores limiares, a análise de sensibilidade e a representação gráfica da árvore de decisão, foi utilizado o pacote estatístico STATA - DATA TREE AGE 3.5. Como outcome principal, determinou-se a expectativa de vida ajustada à qualidade (medida em QALYs). Resultados: Desenvolvida a seqüência da análise, o modelo mostra, de forma contundente, que a melhor decisão diagnóstica-terapêutica é o bloqueio diagnóstico-prognóstico com anestésicos locais, e caso esse bloqueio seja satisfatório, fazer a denervação por radiofreqüência do ganglio esfenopalatino...

Cluster-tic syndrome: report of five new cases

The so-called short lasting primary headaches include heterogenic entities that can be divided between those without pronounced autonomic activation and those where this activation is evident, which includes the cluster-tic syndrome. We report five new cases with age closer to the trigeminal neuralgia's one, and concomitance of cluster headache and trigeminal neuralgia, which is less frequent in the literature. We also discuss briefly the pathophysiology of these clinical entities, suggesting that the trigeminus nerve is a common pathway of pain manifestation.

Síndrome da cefaléia em salvas-nevralgia do trigêmeo: a propósito de dois casos / Cluster-tic syndrome: two case reports

Säo relatados 2 casos da síndrome da cefaléia em salvas - nevralgia do trigêmeo. O primeiro caso, um paciente eque apresentava crises do tipo trigeminal, do lado direito da face, acompanhadas de sinais autonômicos homolaterais do tipo lacrimejamento, coriza, congestão ocular, ptose palpebral parcial. As crises eram espontâneas durante o dia. Aperiodicidade dos surtos era de aproximadamente 6 meses. Houve alívio dos sintomas quando da utilizaçäo de carbamazepina, na dose de 800 mg por dia. No segundo caso, o paciente apresentava dor excruciante, do tipo nevrálgico, do lado esquerdo da face, acompanhada de lacrimejamento,conjestäo ocular, ptose palpebral parcial, rinorréia, fotofobia e fonofobia. A periodicidade dos surtos era de aproximadamente 12 meses. O exame neurológico revelou "zonas de gatilho" na primeira e segunda divisöes do nervo trigêmeo. O paciente foi tratado com verapamil (160 mg/dia) e prednisona (60 mg/dia), com melhora da dor. A revisäo da literatura mostrou o relato de 37 casos, divididos em dois grupos de pacientes. No primeiro grupo, os pacientes apresentavam surtos de cefaléia em salvas e nevralgias do trigêmeo ocorrendo em tempos diferentes. No segundo grupo, com apenas 9 casos, os quadros clínicos se sobrepöem do ponto de vista temporal, à semelhança dos casos aqui apresentados.