Preventive treatment of refractory chronic cluster headache: systematic review and meta-analysis.

BACKGROUND: Preventive treatment for refractory chronic cluster headache (rCCH) is challenging and many therapies have been tried. OBJECTIVE: To study what could be considered the therapy of choice in rCCH through a systematic review and meta-analysis. METHODS: This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in PROSPERO (ID CRD42021290983). A systematic search was performed in MEDLINE, Embase, Cochrane, clinicaltrials.gov, and the WHO's-International-Clinical-Trials-Registry-Platform. Studies on the preventive treatment for rCCH as defined by the European Headache Federation consensus statement were included. A meta-analysis of the pooled response rate was conducted for the different therapies. RESULTS: Of 336 results, 45 were eligible for inclusion. Most articles studied the effect of neuromodulation as a preventive treatment for rCCH. The most studied neuromodulation technique was occipital nerve stimulation (ONS), with a pooled response rate in the meta-analysis of 57.3% (95% CI 0.481-0.665). Deep brain stimulation (DBS) was the second most studied treatment with a pooled response rate of 77.0% (95% CI 0.594-0.957). DBS results were more heterogeneous than ONS, which could be related to the different stimulation targets in DBS studies, and reported more serious adverse events than in ONS studies. The remaining therapies (anti-CGRP pathway drugs, warfarin, ketamine-magnesium infusions, serial occipital nerve blocks, clomiphene, onabotulinum toxin A, ketogenic diet, sphenopalatine ganglion radiofrequency or stimulation, vagus nerve stimulation, percutaneous bioelectric current stimulation, upper cervical cord stimulation, and vidian neurectomy) present weaker results or have less quality of evidence. CONCLUSIONS: The results of this systematic review and meta-analysis suggest that ONS could be the first therapeutic strategy for patients with rCCH based on the current evidence.

Cluster headache: state of the art of pharmacological treatments and therapeutic perspectives.

Cluster headache (CH) is the most common form of trigeminal autonomic cephalalgia. Current treatments have several limitations, and new drugs are required. This article first briefly reviews present acute and preventive treatments in CH, their mechanism of action and limitations, then describes the state of the art in recent clinical drug trials since 2015, and ends with a critique of trials in the CH field. Research is limited by lack of knowledge of pathophysiology and lack of animal models. In the past 5 years, no brand-new treatment has emerged, but promising drugs, such as CGRP(R) antibodies, are under study. According to the literature and guidelines, clinicians and researchers should be aware of many limitations in study protocols: concomitant medication, patient sample size, patients' protocol compliance, and study designs that tend to restrict patient recruitment.

Neuromodulation for the Acute and Preventive Therapy of Migraine and Cluster Headache.

Headache disorders are among the most common and disabling medical conditions worldwide. Pharmacologic acute and preventive treatments are often insufficient and poorly tolerated, and the majority of patients are unable to adhere to their migraine treatments due to these issues. With improvements in our understanding of migraine and cluster headache pathophysiology, neuromodulation devices have been developed as safe and effective acute and preventive treatment options. In this review, we focus on neuromodulation devices that have been studied for migraine and cluster headache, with special attention to those that have gained food and drug administration (FDA) clearance. We will also explore how these devices can be used in patients who might have limited pharmacologic options, including the elderly, children, and pregnant women.

[Positioning of headache units in the field of neurology: the importance of OnabotulinumtoxinA and other therapies in the treatment of headaches]. / Posicionamiento de las unidades de cefalea en el ambito de la neurologia: la importancia de la OnabotulinumtoxinA y otras terapias en el tratamiento de la cefalea.

Chronic migraine is a disease that affects 0.5-2.5% of the population, depending on the statistics that are analysed and the definition of chronic migraine that is used. It is extraordinarily disabling, since it does not allow the sufferer to carry out any of their scheduled personal, professional or social activities, and it has a great impact on the patients' quality of life, as measured on disability, quality of life and impact on daily activities scales. Yet, nowadays there are treatments that have proven to be effective in cases of chronic migraine, such as OnabotulinumtoxinA. It is a treatment that is well tolerated and with a high rate of efficacy. Yet it is not only a therapeutic tool, but in the world of headaches it has also opened up the doors to invasive treatments, to the learning of techniques and, in short, to placing headaches in referral units that are usually located in tertiary care hospitals. Furthermore, it has also helped to overcome the idea that patients with headache should be visited exclusively by primary care physicians or general neurologists. This is an opportunity to redefine the field of study and the care for headaches that must be seized. In the future, this is going to be complemented by novel treatments with neurostimulation and probably with monoclonal antibodies against the calcitonin gene-related peptide. A revolution has begun in our knowledge and capacity to act. It is our duty to give it the importance and usage it deserves both for our patients and for us as specialists.

TITLE: Posicionamiento de las unidades de cefalea en el ambito de la neurologia: la importancia de la OnabotulinumtoxinA y otras terapias en el tratamiento de la cefalea.La migraña cronica es una enfermedad que afecta al 0,5-2,5% de la poblacion segun las estadisticas que se analicen y la definicion de migraña cronica que se adopte. Es extraordinariamente incapacitante, ya que no permite realizar las actividades personales, profesionales o sociales programadas, y tiene un gran impacto sobre la calidad de vida de los pacientes, medido en escalas de discapacidad, calidad de vida e impacto en la actividad diaria. Sin embargo, actualmente se dispone de tratamientos que han demostrado eficacia en la migraña cronica, como la OnabotulinumtoxinA. Es un tratamiento bien tolerado y con una tasa de eficacia elevada. Pero no es solo una herramienta terapeutica, sino que ha abierto las puertas en el mundo de la cefalea a la realizacion de tratamientos invasivos, al aprendizaje de tecnicas y, en definitiva, a situar la cefalea en unidades de referencia ubicadas, habitualmente, en hospitales de tercer nivel. Ademas, ha ayudado a eliminar el concepto de que los pacientes con cefalea deben ser atendidos exclusivamente por medicos de atencion primaria o neurologos generales. Esta es una oportunidad que debe aprovecharse para redimensionar el campo del estudio y asistencia de la cefalea. En el futuro, esto va a complementarse con novedosos tratamientos con neuroestimulacion y, probablemente, con anticuerpos monoclonales contra el peptido relacionado con el gen de la calcitonina. Se ha iniciado una revolucion en nuestro conocimiento y capacidad de actuacion. Es nuestro deber darle la importancia y uso que se merecen tanto para nuestros pacientes como para nosotros como especialistas.

[Therapeuetic aspects of cluster headache in the practical clinical site].

The therapeutic procedures of cluster headache begin from the precise diagnose. Because cluster headache is usually accompanied with teeth pain and/or neck pain, some patients aren't able to consult adequate medical institutions. In this lecture I showed the some male and female patients as examples. The female patient was suffered from menstruation related migraine in her period of cluster headache. From the view point of treatment, preventive medicines are essential. They not just reduce severity and also improve the length of headache-period. Suitable preventive medicines may avoid the whole severe attacks. We reported therapeutic experiences of valproate, gabapentin and amitriptyline with verapamil in 2010 at general meeting of Societas Neurologica Japonica. Steroids are not indispensable. As for triptans rapid-type one are usually used. If the attacks are severe, sumatriptan subcutaneous injection kit (SSI) needs to be introduced. The expert nurses who are skilled in the procedures of SSI improve both patients' adherence and therapeutic efficiency. We held a first educational meeting of SSI in Tokyo 2012. Because cluster headache is formidable, the integrated therapy which is composed of precise diagnosis, preventive medicine and adequate medicines for headache attacks is essential and needed.

Management of cluster headache.

The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated unilateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment and prophylactic treatment. In ECH and CCH the attacks can be treated with oxygen (12 L/min) or subcutaneous sumatriptan 6 mg. For both oxygen and sumatriptan there are two randomized, placebo-controlled trials demonstrating efficacy. In both ECH and CCH, verapamil is the prophylactic drug of choice. Verapamil 360 mg/day was found to be superior to placebo in one clinical trial. In clinical practice, daily doses of 480-720 mg are mostly used. Thus, the dose of verapamil used in cluster headache treatment may be double the dose used in cardiology, and with the higher doses the PR interval should be checked with an ECG. At the start of a cluster, transitional preventive treatment such as corticosteroids or greater occipital nerve blockade can be given. In CCH and in long-standing clusters of ECH, lithium, methysergide, topiramate, valproic acid and ergotamine tartrate can be used as add-on prophylactic treatment. In drug-resistant CCH, neuromodulation with either occipital nerve stimulation or deep brain stimulation of the hypothalamus is an alternative treatment strategy. For most cluster headache patients there are fairly good treatment options both for acute attacks and for prophylaxis. The big problem is the diagnosis of cluster headache as demonstrated by the diagnostic delay of 7 years. However, the relatively short-lasting attack of pain in one eye with typical associated symptoms should lead the family doctor to suspect cluster headache resulting in a referral to a neurologist or a headache centre with experience in the treatment of cluster headache.

Cluster headache--acute and prophylactic therapy.

Cluster headache (CH) pain is the most severe of the primary headache syndromes. It is characterized by periodic attacks of strictly unilateral pain associated with ipsilateral cranial autonomic symptoms. The majority of patients have episodic CH, with cluster periods that typically occur in a circannual rhythm, while 10% suffer from the chronic form, with no significant remissions between cluster periods. Sumatriptan injection or oxygen inhalation is the first-line therapy for acute CH attacks, with the majority of patients responding to either treatment. The calcium channel blocker verapamil is the drug of choice for CH prevention. Other drugs that may be used for this purpose include lithium carbonate, topiramate, valproic acid, gabapentin, and baclofen. Transitional prophylaxis, most commonly using corticosteroids, helps to control the attacks at the beginning of a cluster period. Peripheral neural blockade is effective for short-term pain control. Recently, the therapeutic options for refractory CH patients have expanded with the emergence of both peripheral (mostly occipital nerve) and central (hypothalamic) neurostimulation. With the emergence of these novel treatments, the role of ablative surgery in CH has declined.

Pharmacotherapy of cluster headache.

IMPORTANCE OF THE FIELD: Cluster headache belongs to the trigemino-autonomic cephalgias and is one of the most devastating idiopathic pain syndromes. Despite its extreme severity and its prevalence of about 0.1%, little attention has been paid to this painful syndrome by either basic or clinical research. AREAS COVERED IN THIS REVIEW: All clinical trials on the acute and prophylactic drug treatment of cluster headache are reviewed, including review articles and book chapters. WHAT THE READER WILL GAIN: The treatment of cluster headache is based on acute and prophylactic drug treatment. Oxygen inhalation, subcutaneous or intranasal sumatriptan, and intranasal zolmitriptan are recommended to stop an attach. For prophylaxis, verapamil is drug of first choice. Other drugs efficacious in cluster headache are steroids, lithium, some anticonvulsants and methysergide. Recently, interventional procedures have been studied for the treatment of refractory cluster headache. In the future, new anticonvulsants and unconventional ways of immunotherapy should be evaluated. TAKE HOME MESSAGE: In most cases, cluster headache can be treated sufficiently (i.e., with sufficient quality of life) by an individual concept of acute and prophylactic drug treatment.

Cluster headache: pharmacological treatment and neurostimulation.

Cluster headache is a primary headache syndrome that is characterized by excruciatingly severe, strictly unilateral attacks of orbital, supraorbital or temporal pain, which last 15-180 min and are accompanied by ipsilateral autonomic manifestations (e.g. lacrimation and rhinorrhea). The attacks typically occur with circadian rhythmicity, being experienced at fixed hours of the day or night. In episodic cluster headache, attacks usually occur daily in 6-12-week bouts (cluster periods) followed by remission periods. In chronic cluster headache there is no notable remission. Cluster headache attacks reach full intensity very quickly and abortive agents need to be administered without delay. The pathophysiology of cluster headache is imperfectly understood and treatment has so far been mainly empirical. However, neuroimaging studies have prompted the successful use of hypothalamic stimulation to treat the condition. More recently, the less invasive technique of occipital nerve stimulation has shown promise in drug-refractory chronic cluster headache. This Review discusses both acute and preventive treatments for cluster headache and includes suggestions of how to use the available medications. The rationale, study results and selection criteria for neurostimulation procedures are also summarized, as are the disadvantages of these procedures.

Cluster headache and lifestyle habits.

Cluster headache (CH) has traditionally been associated with certain anthropometric features, personality traits, and lifestyle features. This article focuses on lifestyle features in patients with CH. Especially excessive smoking and alcohol consumption have been ascribed to patients with CH. Despite country-specific habits and a time trend, smoking is much more prevalent among CH patients compared with the general population. Although excessive alcohol consumption was reported in early studies, this was not corroborated more recently. On the contrary, patients with CH seem to avoid alcohol, particularly during active phases, likely due to its ability to trigger attacks. Present studies are purely descriptive. Thus, the associations sketched give no information about the long-term effects of smoking or alcohol consumption on the course of CH.

[Treatment of cluster headache]. / Traitement de l'algie vasculaire de la face.

Management of cluster headache has greatly changed in recent years although most of the drugs used have not received approval for this indications. Subcutaneous injections of sumatriptan has been found to be remarkable effective for acute episodes. This drug continues to exhibit efficacy for long periods of use up to several months and has no serious adverse effects if used according to recommendations. Nasal administration of oxygen (not approved for this indication in France) continues to be an adjuvant treatment for patients with a contraindication for sumatriptan or for those with more than two acute episodes per day. Other treatments are under debate. Prophylactic first intention verapamil (not approved in France for this indication) could be useful. Lithium (not approved in France for this indication) could also be helpful, particularly for certain clinical forms. Other options are discussed.

Preventive effects of hyperbaric oxygen in cluster headache.

The effect of a 2-week course of hyperbaric oxygen on both the duration and frequency of cluster headache attacks was tested in four patients suffering from chronic cluster headache with no clear response to pharmacological treatments. Two patients (two courses in one case) dramatically improved while on hyperbaric oxygen treatment, this positive response remaining for 2 and 31 days posttreatment. Case 3 only improved in frequency, while the remaining patient showed no benefit. These findings suggest that daily hyperbaric oxygen treatment can be used as a transient preventive treatment for desperate cluster headache sufferers.

Preventative effect of repeated nasal applications of capsaicin in cluster headache.

Preliminary studies have shown that repeated nasal applications of capsaicin prevented the occurrence of cluster headache attacks. The present study was designed to verify the difference in efficacy of treatment with nasal capsaicin, depending on the side of application. Fifty-two patients affected by episodic form were divided into 2 groups, one receiving the treatment on the same side where the attacks occurred (ipsilateral side), the other on the controlateral side. Eighteen patients with a chronic form alternately received both ipsilateral and controlateral treatments. Seventy percent of the episodic patients, treated on the ipsilateral side, showed a marked amelioration whereas no improvement was noted in the patients treated on the contralateral side. The efficacy of ipsilateral treatment was emphasized by the results obtained in chronic patients. However, in these patients, the maximum period of amelioration lasted no more than 40 days. The difference between the effects of the 2 treatments (contralateral and ipsilateral) was statistically significant in both episodic and chronic sufferers. The efficacy of repeated nasal applications of capsaicin in cluster headache is congruent with previous reports on the therapeutic effect of capsaicin in other pain syndromes (post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia) and supports the use of the drug to produce a selective analgesia.