Treatment Of Cluster Headache Research Articles

Galcanezumab for episodic and chronic cluster headache

Cluster headache (CH) is ahighly debilitating headache disorder characterized by frequent attacks of excruciating unilateral pain accompanied by cranial autonomic symptoms. Calcitonin gene-related peptide (CGRP) is implicated in the pathophysiology of CH. Preventive efficacy and tolerability of the anti-CGRP antibody galcanezumab in patients with episodic (eCH) and chronic CH (cCH). Review of the study results and the challenges in developing drugs for the preventive treatment of CH. In two international multicenter phaseIII trials galcanezumab 300 mg given subcutaneously every 4weeks was compared with placebo. The double-blind study period (8weeks in eCH, 12weeks in cCK) was preceded by abaseline period in both trials. The primary endpoint was the reduction in weekly attack frequency. In the eCH trial, 106patients were randomized to either galcanezumab (n = 49) or placebo (n = 57). The mean weekly attack frequency during the first 3weeks decreased by 52% in the galcanezumab group compared with 27% in the placebo group (p = 0.036). In the cCH trial, 237patients were randomized to galcanezumab (n = 117) or placebo (n = 120). The primary endpoint was not met in this study. The reduction in mean weekly attack rate was 5.4 with galcanezumab versus 4.6 with placebo (p = 0.334). Galcanezumab was well tolerated in both studies. Galcanezumab had asignificant effect in the prevention of eCH attacks but not in cCH. Possible reasons for this discrepancy are discussed.

Challenges and complexities in designing cluster headache prevention clinical trials: A narrative review.

ObjectiveTo provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies.BackgroundCurrent guidelines for preventive treatment of CH are largely based on off‐label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995.Methods/ResultsRandomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of “cluster headache,” and manually reviewed. Cumulatively, there were 27 unique placebo‐controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo‐controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges.ConclusionsOptimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.

Comparative Impact of Pharmacological Therapies on Cluster Headache Management: A Systematic Review and Network Meta-Analysis.

It is important to find effective and safe pharmacological options for managing cluster headache (CH) because there is limited evidence from studies supporting the general efficacy and safety of pharmacological therapies. This systematic review and network meta-analysis (NMA) analyzed published randomized controlled trials (RCTs) to evaluate the efficacy and safety of pharmacological treatments in patients with CH. The PubMed and Embase databases were searched to identify RCTs that evaluated the efficacy and safety of pharmacological treatments for CH. Efficacy outcomes included frequency and duration of attacks, pain-free rate, and the use of rescue agents. Safety outcomes were evaluated based on the number of patients who experienced adverse events. A total of 23 studies were included in the analysis. The frequency of attacks was reduced (mean difference (MD) = −1.05, 95% confidence interval (CI) = −1.62 to −0.47; p = 0.0004), and the pain-free rate was increased (odds ratio (OR) = 3.89, 95% CI = 2.76–5.48; p < 0.00001) in the pharmacological treatment group, with a lower frequency of rescue agent use than the placebo group. Preventive, acute, and triptan or non-triptan therapies did not show significant differences in efficacy (p > 0.05). In the NMA, different results were shown among the interventions; for example, zolmitriptan 5 mg was more effective than zolmitriptan 10 mg in the pain-free outcome (OR = 0.40, 95% CI = 0.19–0.82; p < 0.05). Pharmacological treatment was shown to be more effective than placebo to manage CH with differences among types of therapies and individual interventions, and it was consistently shown to be associated with the development of adverse events. Thus, individualized therapy approaches should be applied to treat CH in real-world practice.

Effects of acute and preventive therapies for episodic and chronic cluster headache: A scoping review of the literature.

Cluster headache is the most common primary headache disorder of the trigeminal autonomic cephalalgias, and it is highly disabling. We undertake a scoping review to characterize therapies to prevent and acutely treat cluster headache, characterize trial methodology utilized in studies, and recommend future trial "good practices." We also assess homogeneity of studies and feasibility for future network meta-analyses (NMAs) to compare acute and preventive treatments for cluster headache. A priori protocol for this scoping review was registered and available on Open Science Forum. We sought studies that enrolled adult patients with cluster headache as identified by accepted diagnostic criteria. Both randomized controlled trials (RCTs) and observational studies (with a control group) were included. The interventions of interest were medications, procedures, devices, surgeries, and behavioral/psychological interventions, whereas comparators of interest were placebo, sham, or other active treatments. Outcomes were predefined; however, we did not exclude studies lacking these outcomes. A systemic search was conducted in Ovid Medline, Embase, and Cochrane. We performed a targeted search for conference abstracts from journals prominent in the field. We identified 56 studies: 45 RCTs, four studies only available in clinical trial registries, and seven observational studies. Of the 45 RCTs, 20 focused on acute therapies and 25 on preventive therapies. Overall, we determined that it is feasible to pursue a NMA for acute therapy focusing on 15 or 30-min headache reduction for acute trials, as we identified 11 trials in the combined population of patients with either episodic or chronic cluster headache (2 trials in populations with chronic cluster headache were also found). For preventive therapy of cluster headache, we identified trials with common outcomes that may be considered for NMA, however, as these trials had differences in treatment effect modifiers that could not be corrected, NMAs appear infeasible for this indication. We identified new studies looking at noninvasive vagal nerve stimulation, sphenopalatine ganglion stimulation, prednisone, and oxygen published since the most recent systematic review in the field, although these acute treatments were previously identified as effective. However, for calcitonin gene-related peptide (CGRP) monoclonal antibodies, galcanezumab demonstrated effectiveness in episodic cluster headache, but a lack of effectiveness in chronic cluster headache, and fremanezumab was not effective for episodic nor chronic cluster headache. This finding highlights that CGRP monoclonal antibodies may not show a class effect in cluster headache prevention and need to be considered individually. We describe the treatment landscape of cluster headache for both acute and preventive treatments. Last, we present the NMAs we will undertake in acute therapies of cluster headache.

Effects of cluster headache preventatives on mouse hypothalamic transcriptional homeostasis.

To investigate how cluster headache preventatives verapamil, lithium and prednisone affect expression of hypothalamic genes involved in chronobiology. C57Bl/6 mice were exposed to daily, oral treatment with verapamil, lithium, prednisone or amitriptyline (as negative control), and transcripts of multiple genes quantified in the anterior, lateral and posterior hypothalamus. Verapamil, lithium or prednisone did not affect expression of clock genes of the anterior hypothalamus (Clock, Bmal1, Cry1/2 and Per1/2). Prednisone altered expression of hypothalamic neuropeptides melanin-concentrating hormone and histidine decarboxylase within the lateral and posterior hypothalamus, respectively. The three preventatives did not affect expression of the neurohypophyseal hormones oxytocin and arginine-vasopressin in the posterior hypothalamus. Conversely, amitriptyline reduced mRNA levels of Clock, oxytocin and arginine-vasopressin. Data suggest that cluster headache preventatives act upstream or downstream from the hypothalamus. Our findings provide new insights on hypothalamic homeostasis during cluster headache prophylaxis, as well as neurochemistry underlying cluster headache treatment.

Clínica y fisiopatología de la cefalea en racimos. Acercamiento a la indicación de neuroestimulación combinada occipital y supraorbitaria

Cluster headache (CH) is included under section 3 - Trigeminal autonomic cephalalgias (TAC) of the International Headache Society (IHS) classification. It is one of the most frequent, painful and disabling primary headaches. Acute and preventive pharmacological treatments are often poorly tolerated and of limited effectiveness. Due to improved understanding of the pathophysiology of CH, neuromodulation devices are now considered safe and effective options for preventive and acute treatment of CH. In this paper, we review the information available to date, and present the case of a patient with disabling cluster headache highly resistant to medical treatment who underwent implantation of a peripheral nerve neurostimulation system to stimulate the supraorbital nerves (SON) and greater occipital nerve (GON) in our Pain Unit. We also review the diagnostic criteria for CH, the state of the knowledge on the pathophysiology of CH, and the role played by neuromodulation in treating this condition

Gamma Knife radiosurgery for the treatment of cluster headache: a systematic review.

Cluster headache (CH) is a severe trigeminal autonomic cephalalgia that, when refractory to medical treatment, can be treated with Gamma Knife radiosurgery (GKRS). The outcomes of studies investigating GKRS for CH in the literature are inconsistent, and the ideal target and treatment parameters remain unclear. The aim of this systematic review is to evaluate the safety and the efficacy, both short and long term, of GKRS for the treatment of drug-resistant CH. A systematic review of the literature was performed to identify all clinical articles discussing GKRS for the treatment of CH. The literature review revealed 5 studies describing outcomes of GKRS for the treatment of CH for a total of 52 patients (48 included in the outcome analysis). The trigeminal nerve, the sphenopalatine ganglion, and a combination of both were treated in 34, 1, and 13 patients. The individual studies demonstrated initial meaningful pain reduction in 60-100% of patients, with an aggregate initial meaningful pain reduction in 37 patients (77%). This effect persisted in 20 patients (42%) at last follow-up. Trigeminal sensory disturbances were observed in 28 patients (58%) and deafferentation pain in 3 patients (6%). Information related to GKRS for CH are limited to few small open-label studies using heterogeneous operative techniques. In this setting, short-term pain reduction rates are high, whereas the long-term results are controversial. GKRS targeted on the trigeminal nerve or sphenopalatine ganglion is associated to a frequent risk of trigeminal disturbances and possibly deafferentation pain.

Development and characterization of a novel mucoadhesive sol-gel suppository of sumatriptan: design, optimization, in vitroand ex vivo evaluation for rectal drug delivery.

Aim: Sumatriptan (ST) is used for the treatment of migraine and cluster headaches. However, it exhibits low oral bioavailability (15%) due to the high first-pass metabolism. The aim of this work was to formulate an ST rectal hydrogel. Methods: Hydrogels were formulated according to a Box-Behnken design using pluronic F-127 (PF-127) and chitosan as thermogelling and mucoadhesive agents, respectively. The rectal permeability was examined using a sheep rectal mucosa. Results: Among all the formulations, the hydrogel S2 showed satisfactory drug content (4.50%), gelling temperature (32°C), pH (6.41), viscosity (105 cP) and strength (15.90sec). Mucoadhesive strength was adequate to provide a prolonged residence time. The flux of hydrogel S2 was calculated to be 0.0003μg/cm2.min. Conclusion: The ST hydrogel can provide a potential opportunity to overcome the first pass metabolism and reduce drug dose.

Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

Cluster headache is a primary headache disorder and is the most prevalent of the trigeminal autonomic cephalalgias. Cluster headache significantly impacts those affected, necessitating early diagnosis and management. Despite unique clinical features, such as patients experiencing attacks in a circannual pattern and often with a circadian rhythm within bouts, cluster headache patients often are misdiagnosed, mismanaged and have a delay in diagnosis. Preclinical, neuroimaging and clinical studies have advanced our understanding of cluster headache pathophysiology. The trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamus are all involved in the pathophysiology of cluster headache. As our understanding of the pathophysiology of cluster headaches has evolved, new therapeutic options, such as calcitonin gene-related peptide monoclonal antibodies, non-invasive vagal nerve stimulation and sphenopalatine ganglion stimulation, have proved to have efficacy in the treatment of cluster headache. Herein, we aim to review developments to aid readers in their understanding of this debilitating disorder.

Neurology : what's new in 2021

In 2021, we assisted to the publication of new diagnostic criteria, classifications, and guidelines (CIDP, brain tumors, auto-immune encephalitis). Several studies helped to define the pharmacological management of focal and generalized epileptic seizures and epilepsy in pregnant women. The availability of biomarkers and the approval of immunotherapies are modifying the landscape of dementia management. Endovascular interventions without previous thrombolysis seems to be effective in anterior circulation acute ischemic stroke (AIS) and severe posterior circulation AIS. Neurologic complications of Sars-CoV-2 infection were further studied, as well as the efficacy of vaccines in immunosuppressed patients. New molecules and techniques show promising results for the treatment of migraine and cluster headache.

Sphenopalatine ganglion stimulation in the treatment of chronic refractory cluster headache. A preliminary multicenter study in Russia

To analyze the results of sphenopalatine ganglion stimulation in treatment of chronic headache. Medical histories of patients who underwent sphenopalatine ganglion stimulation in 4 clinical centers have been analyzed. The analysis included the type of pain and its characteristics, methods of surgery, CT, MRI, radiography before and after surgery. The follow-up data of patients with implanted pulse generators was collected in an outpatient clinic or by telephone review. The study included 15 patients with chronic refractory headache, including 14 with cluster headache and one female patient with features of trigeminal autonomic cephalgia without a clear definition of the type of pain. Trial stimulation was performed in 10 patients to determine analgesic effect. Among them stimulation was favorable in 7 cases, and 6 of them underwent pulse generator implantation. In total, 11 (73%) patients underwent implantation with a follow-up from 1 to 60 months. Among them only 6 (54%) patients use stimulation, the remaining 5 (46%) cases had device-related complications (migration, infection of system). Cluster headache has a significant improvement in long-term follow-up. Sphenopalatine ganglion stimulation may have high potential in the treatment of chronic drug-resistant cluster headache. The complication rate demonstrates that operative technique should be improved.

Pharmacokinetics study of chitosan-coated liposomes containing sumatriptan in the treatment of migraine.

Background:Sumatriptan is a routine medication in the treatment of migraine and cluster headache that is generally given by oral or parental routes. However, a substantial proportion of patients suffer severe side effects. The aim of this study was to investigate the physicochemical characterization and pharmacokinetic parameters of a novel delivery system for sumatriptan succinate (SS) using nanoliposomes (NLs) coated by chitosan (CCLs) to optimize the formulations to enhance its bioavailability.Methods:The new formulation was used to minimize drug particle size and extend its release and bioavailability. The mean particle size and entrapment efficiency for NLs and CCls were optimized and the formulations with better characteristics were chosen for in vivo studies. The concentration-time profile of intravenous SS, intranasal SS, SS-NLs, and CCLs were examined in a rabbit model.Results:The results demonstrated that CCLs were absorbed more rapidly from nasal drops containing chitosan compared to those of SS and SS-NLs as indicated by a shorter tmax, and a higher Cmax in both states. A comparison of the AUC (0-240 min) values revealed that chitosan improved the extent of SS absorption for CCLs formulation. The results of the present study indicated that loading SS into the liposome and coating with chitosan improves drug absorption and a large amount of the drug can be efficiently delivered into the systemic circulation.Conclusion:The liposomal and chitosan formulations of SS had better kinetic behavior than the soluble form in the animal model.

Oxygen Therapy in Cluster Headache, Migraine, and Other Headache Disorders

Oxygen therapy (OT) can relieve head pain in certain primary headache disorders, including cluster headache (CH). The exact underlying mechanism is currently uncertain, but suggested mechanisms include inhibition of the trigeminoautonomic reflex, modulation of neurotransmitters, and cerebral vasoconstriction. OT is the standard for acute treatment of CH, but patients with CH often experience considerable difficulties accessing home OT due to problems with insurance coverage. Inhalation of 100% oxygen at 6–12 L/min for 15–30 min using a non-rebreather face mask is one of the most effective acute therapies for CH, but several trials have indicated the superiority of higher oxygen flow rates of up to 15 L/min and/or using a demand-valve oxygen mask that can produce very high flow rates. Two randomized controlled trials have demonstrated the efficacy of OT in migraine, but obtaining reliable evidence is considered difficult because of different inhalation protocols, varying outcome measures, and small samples. There are some reports on the efficacy of OT as an adjuvant therapy in hypnic headache, primary headache in the emergency department, and even postdural puncture headache. The goal of this review article is to expand the knowledge regarding the use of oxygen in the treatment of headache disorders.

Drug Treatment of Cluster Headache.

Cluster headache belongs to the group of trigeminal autonomic headaches. This review summarizes drug therapy of cluster attacks and prophylactic treatment. Neurostimulation methods are not addressed. The therapy for acute cluster attacks includes inhalation of 100% oxygen, subcutaneous administration of sumatriptan, and intranasal application of sumatriptan or zolmitriptan. Bridging therapy, which is used until oral prophylactic therapy is effective, is performed either with oral prednisolone or with a pharmacological block of the major occipital nerves. Best documented drugs for preventive treatment of cluster headache are verapamil and lithium, and possibly effective drugs are gabapentin, topiramate, divalproex sodium, and melatonin. The efficacy of monoclonal antibodies to the calcitonin gene-related peptide so far has been only demonstrated for episodic cluster headache. Several drug therapies are being investigated including ketamine, onabotulinumtoxinA, lysergic acid, and sodium oxybate.

TVNS in the management of headache and pain.

First clinical observations of the therapeutic effect of vagus nerve stimulation were of patients who were treated for refractory epilepsy with a fully implanted vagus nerve stimulator, who also reported an improvement of their migraine and cluster headache. With the development of non-invasive vagus nerve stimulation, first clinical studies concerning a possible therapeutic effect in migraine and cluster headache were performed. In a controlled study, transcutaneous cervical vagus nerve stimulation (tcVNS) showed a significant but limited effect in acute treatment of a migraine attack. There was no significant prophylactic effect in episodic migraine. Concerning cluster headache, there was a clear beneficial effect in the prophylaxis of chronic cluster headache and in the attack treatment in episodic cluster headache. There are fewer studies in the literature on the effect of transcutaneous auricular vagus nerve stimulation (taVNS), with a partial overlap with studies on electrical ear acupuncture. In a small controlled clinical trial, there was a significant effect of taVNS in the prevention of chronic migraine. In less defined clinical studies, there were some positive signs that the method may be beneficial in chronic back pain and in unspecific gastro-intestinal pain in adolescents. Based on the available evidence, it is probable that vagus nerve stimulation can have a clinically meaningful influence on pain syndromes, but there are still several questions (e.g. frequency of the stimulation; duration of the stimulation; differential effects of auricular vagus stimulation and cervical vagus stimulation) to answer before vagus stimulation can be used widely in the clinic.

Accuracy of Electrode Position in Sphenopalatine Ganglion Stimulation in Correlation With Clinical Efficacy

Sphenopalatine ganglion (SPG) stimulation is an efficient treatment for cluster headache. The target for the SPG microstimulator in the pterygopalatine fossa lies between the vidian canal and foramen rotundum, ideally two contacts should be placed in this area. However, placement according to the manufacturers recommendations is frequently not possible. It is not known whether a suboptimal electrode placement interferes with postoperative outcomes. SPG stimulation was performed in 13 patients between 2015 and 2018 in a single center. Lead location was determined by intraoperative computed tomography scan and correlated with the planned lead position as well as clinical data and stimulation parameters. Patients with a reduction of 50% or more in pain intensity or frequency were considered responsive. Eleven patients (84.6%) responded to SPG stimulation with eight being frequency responders (61.5%). In seven cases, there were less than two electrodes between vidian canal and foramen rotundum, there was no significant correlation with negative stimulation results (p=0.91). The mean distance of lead location between pre- and postoperative images did not correlate with clinical outcomes (p=0.84) and was even bigger in responders (4.91 mm vs. 4.53 mm). The closest electrode contact to the vidian canal was in the stimulation area in all but one patient, regardless of its overall distance to canal. The distance of the closest electrode to the vidian canal was, however, not significantly correlated to the percentage of frequency (p=0.68) or intensity reduction (p=0.61). There was no significant correlation regarding aberrations of lead position from the planned position with clinical outcome. However, this study might be underpowered to detect such a correlation. The closest electrode contact to the vidian canal was in the stimulation area in all but one patient in the final programming. This indicates that, overall, the lead location does play a crucial role in SPG stimulation for cluster headache.

Localization of the Sphenopalatine Ganglion Within the Pterygopalatine Fossa on Computed Tomography Angiography—A Potential Role in the Setting of Sphenopalatine Ganglion Microstimulator Implantation

A recent approach to treatment of cluster headaches (CH) employs a microstimulator device for on-demand neuromodulation of the sphenopalatine ganglion (SPG) during an acute CH attack. A precise anatomical localization of the SPG within the pterygopalatine fossa (PPF) is optimal in order to position the SPG electrode array. This study aims to investigate a novel approach for SPG localization using computed tomography angiographic studies (CTA). Two independent observers identified the location of the SPG on 54 computed tomography angiographic studies (CTA) and measured its position relative to the vidian canal (VC). The qualitative confidence of identification, morphology, position within the PPF and its relation to vascular structures were also recorded. The SPG was detectable in 88% of cases with a variable position. The most frequent positions were superior (56%) and lateral (99%) relative to the VC with a mean (±SD) craniocaudal distance of 0.34 mm (±1.38) and a mean mediolateral distance of 3.04 mm (±1.2). However, in a considerable proportion of cases, the SPG was identified inferiorly to the VC (33%). Interobserver and intraobserver agreement for SPG location were moderate and strong respectively. Since localization of SPG on CTAs is feasible and reproducible, it has future clinical potential to aid placement, optimal positioning and individualized programming of the electrode array.

Non-invasive vagus nerve stimulation for treatment of cluster headache: a retrospective review of prescribing in England

Background/Aims Beginning in April 2019, non-invasive vagus nerve stimulation was included in the NHS Innovation and Technology Payment programme. The programme guaranteed reimbursement of at least a 3-month course of treatment using gammaCore, through a prescription refill card, authorised by a headache specialist for patients with cluster headache who reported a clinically meaningful benefit. This study evaluated prescribing and refill trends to assess the use of gammaCore in England since the beginning of this programme. Methods Data regarding gammaCore prescriptions and refills from 1 April 2019 to 31 December 2020 were collected and tabulated. Patients were categorised into three groups: those who initiated gammaCore therapy under the programme (new starters), those who were prescribed ≥1 refill, and those who were prescribed ≥2 refills. One refill corresponds to 3 months of gammaCore therapy. Results In total, 52 NHS sites submitted 2092 prescriptions for gammaCore devices, including 655 for new starters. Among new starters, 46.3% received ≥1 refill and 30.9% received ≥2 refills. Those who started using gammaCore after its inclusion in the Innovation and Technology Payment programme received up to seven refills during the data collection period, representing 21 months of therapy. Conclusions This is one of the largest clinical audits of patients with cluster headache. Patients' continued use of gammaCore treatment through multiple 3-month refills in this audit suggests that non-invasive vagus nerve stimulation is efficacious, tolerable and practical for patients with cluster headache.

Cluster Headache: Clinical Characteristics and Opportunities to Enhance Quality of Life.

Cluster headache is a highly disabling primary headache disorder characterized by severe pain and autonomic features. We present the existing body of literature on psychological factors associated with cluster headache and recommendations to address gaps in current clinical care with regards to psychological treatments for cluster headache. People with cluster headache often endorse depressive symptoms, are more likely than the general population to report suicidal ideation and behaviors, and experience significantly decreased quality of life. Psychological treatments such as Acceptance and Commitment Therapy may be particularly valuable for patients with cluster headache given that they are transdiagnostic in nature and can therefore simultaneously address the disease burden and common psychiatric comorbidities that present. Greater understanding of the debilitating nature of cluster headache and behavioral interventions that seek to reduce the burden of the disease and improve the quality of life of people with cluster headache is paramount.

Greater occipital nerve injection in cluster headache: Which protocol to choose? A comparison study

Several Greater Occipital Nerve (GON) injections protocols are described for treatment of cluster headache (CH), and it is uncertain which leads to better results. Aim of this study is to compare two of most widely-accepted GON injections protocols: repeated suboccipital steroid injections and single GON anaesthetic blockade (GONB).