Greater occipital nerve injection with methylprednisolone as transitional therapy in episodic cluster headache: Results from an RCT.

Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study

BackgroundMany patients with cluster headache (CH) are inadequately controlled by current treatment options. Non-invasive vagus nerve stimulation (nVNS) is reported to be effective in the management of CH though some studies suggest that it is ineffective.ObjectiveTo assess the safety and efficacy of nVNS in chronic cluster headache (CCH) patients.MethodWe prospectively analysed data from 40 patients with refractory CCH in this open-label, observational study. Patients were seen in tertiary headache clinics at the National Hospital for Neurology and Neurosurgery and trained to use nVNS as preventative therapy. Patients were reivewed at one month and then three-monthly from onset. The primary endpoint was number of patients achieving ≥50% reduction in attack frequency at 3 months. A meta-analysis of all published studies evaluating the efficacy of nVNS in CCH was also conducted. We searched MEDLINE and EMBASE for all studies investigating the use of nVNS as a preventive or adjunctive treatment for CCH with five or more participants. Combined mean difference and responder proportions with 95% confidence intervals (CI) were calculated from the included studies.Results17/40 patients (43%) achieved ≥50% reduction in attack frequency at 3 months. There was a significant reduction in monthly attack frequency from a baseline of 124 (±67) attacks to 79 (±63) attacks in month 3 (mean difference 44.7; 95% CI 25.1 to 64.3; p < 0.001). In month 3, there was also a 1.2-point reduction in average severity from a baseline Verbal Rating Scale of 8/10 (95% CI 0.5 to 1.9; p = 0.001). Four studies, along with the present study, were deemed eligible for meta-analysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month.ConclusionThis study highlights the potential benefit of nVNS in CCH, with significant reductions in headache frequency and severity. To better characterise the effect, randomised sham-controlled trials are needed to confirm the beneficial response of VNS reported in some, but not all, open-label studies.

Among cephalgias, cluster headache (CH) is the rarest and the most disabling, explaining the appellation of "suicide headache." Up to 20% of chronic CH reveals to be resistant to pharmacological treatments, in which case interventional procedures should be considered. Many reports evaluated invasive approaches and a wide strand of research is dedicated to the sphenopalatine ganglion. Our paper will now be focused on providing an overview on modern applications on the sphenopalatine ganglion (SPG), their outcomes, and their feasibility in terms of risks and benefits. The group reviewed the international literature systematically for procedures targeting the sphenopalatine ganglion and its branches for episodic and chronic CH, including block, stimulation, radiofrequency, stereotactic radiosurgery, and vidian neurectomy. Seventeen articles fixed our inclusion criteria. Comparing the outcomes that have been analyzed, it is possible to notice how the most successful procedure for the treatment of refractory chronic and episodic CH is the SPG block, which reaches respectively 76.5% and 87% of efficacy. Radiofrequency has a wide range of outcomes, from 33 to 70.3% in CCH. Stimulation of SPG only achieved up to 55% of outcomes in significant reduction in attack frequency in CCH and 71% in ECH. Radiosurgery and vidian neurectomy on SPG have also been analyzed. Generally, ECH patients show better response to standard medical therapies; nevertheless, even this more manageable condition may sometimes benefit from interventional therapies mostly reserved for CCH. First results seem promising and considering the low frequency of side effects or complications, we should think of expanding the indications of the procedures also to those conditions. Outcomes certainly suggest that further studies are necessary in order to understand which method is the most effective and with less side effects. Placebo-controlled studies would be pivotal, and tight collaboration between neurologists and otorhinolaryngologists should also be central in order to give correct indications, which allow us to expect procedures on the SPG to be an effective and mostly safe method to control either refractory ECH or CCH.

Infiltration of the greater occipital nerve (GON) with local anaesthetics and corticosteroids is a treatment option for cluster headache. We retrospectively analysed the efficacy and safety of 121 GON injections in 60 patients with episodic or chronic cluster headache over a period of 4 years. Almost 80% of the infiltrations were at least partially effective (reduction of attack frequency, duration or severity) and 45% resulted in a complete response (no further attacks). The effect was maintained for 3.5 weeks on average in chronic cluster headache. In episodic cluster headache, the effect lasted for most of the bout. In 18 infiltrations, transient side effects were reported, such as local pain, steroid effects (facial oedema, sleeping disorders, acne), bradycardia or syncope. Our data show that GON infiltration is a valuable and safe option in the clinical setting to treat patients suffering from cluster headache, especially for the episodic form of the disorder.

BackgroundEpisodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene–related peptide, may be a preventive treatment for cluster headache.MethodsWe enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month. The primary end point was the mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after receipt of the first dose. The key secondary end point was the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. Safety was also assessed.ResultsRecruitment was halted before the trial reached the planned sample size of 162 because too few volunteers met the eligibility criteria. Of 106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57 to receive placebo. The mean (±SD) number of cluster headache attacks per week in the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 in the placebo group. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; P=0.04). The percentage of patients who had a reduction of at least 50% in headache frequency at week 3 was 71% in the galcanezumab group and 53% in the placebo group. There were no substantial between-group differences in the incidence of adverse events, except that 8% of the patients in the galcanezumab group had injection-site pain.ConclusionsGalcanezumab administered subcutaneously at a dose of 300 mg once monthly reduced the weekly frequency of attacks of episodic cluster headache across weeks 1 through 3 after the initial injection, as compared with placebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.)

To investigate our experience with oral steroid and greater occipital nerve (GON) injection with steroid as transitional treatments for cluster headache. Cluster headache is a primary headache disorder characterized by multiple episodes of intense unilateral pain with autonomic features. During cluster headache attacks, transitional therapies are useful while prophylactic dosages are initiated or increased. There are limited data comparing the efficacy of oral versus injected transitional treatments. We retrospectively reviewed charts for patients evaluated with cluster headache at our center and captured episodes of transitional therapy utilized from 1995 to 2014. Treatment benefit was categorized into complete, partial, or no response. Forty-three patients received transitional therapy over a total of 151 encounters, of which 140 were available for analysis. Encounters featured oral steroids (81, 57.9%) and GON injection (59, 42.1%). Of the 40 patients with treatment response data available, 24 patients received only one type of transitional therapy and 16 patients received both therapies. More encounters featuring oral steroids versus GON injections led to at least a partial response (82.7% vs 64.4%) and to a lesser extent a complete response (50.6% vs 35.6%). Among 16 patients treated with both therapies, 8 (50%) responded to both and 6 (37.5%) responded only to oral steroids. Our single-center, retrospective data suggest the majority of patients with cluster headache responded to both prednisone and GON injections for transitional treatment, with a higher response to oral steroids. Our results may inform study design for a randomized trial, which is warranted.

Background Verapamil is recommended as a first-line preventive for episodic and chronic cluster headache, however, its use is limited by a wide range of adverse events. From clinical practice at a tertiary headache centre, we have observed that the initiation of verapamil may be associated with headache worsening. The aim of this service evaluation was to examine whether verapamil initiation was associated with headache worsening, and whether these exacerbations may be attributed to comorbid migraine in some patients. Methods Patients with a diagnosis of cluster headache from June 2014 to December 2023 were identified from the tertiary headache centre at King's College Hospital, London. Data including age, sex, headache phenotype and headache frequency was collected retrospectively in a cross-sectional design through the use of clinic letters followed by a telephone interview. A Wilcoxon signed-rank test was used to compare number of cluster headache attacks per day pre- and post-verapamil administration. A negative binomial generalized linear model was used to interrogate the relationship between the number of attacks post-verapamil and age, sex, verapamil dosing, comorbid migraine and baseline number of attacks. Results Of 168 patients included, the mean age was 31 years, 73% were male, 46% of patients had chronic cluster headache and 51% had comorbid migraine. During the latest ictal period, the median (interquartile range) frequency of cluster headache attacks per day was 3 (2–5) for the entire sample. The presence of comorbid migraine increased the likelihood of headache exacerbation by verapamil by an odds ratio of 1.616 (95% confidence interval: 1.059–2.465, χ21 = 4.955, P = 0.026). No differences were observed in the frequency of shadow attacks amongst those with comorbid migraine ( n = 54/85, 64%) versus patients without migraine ( n = 48/83, 58%) (Mann-Whitney U = 3728, z = 0.754, P = 0.451). No effect was seen on monthly migraine days pre- and post-verapamil administration ( P = 0.141). Adverse events were reported in 62 of 109 (57%) of patients taking verapamil with the most common being PR interval prolongation (15.6%), lower limb oedema (8.3%), worsened headache (6.4%) and fatigue (6.4%). Conclusions It is likely that the association of cluster headache and migraine is more common than generally thought and co-existence may go under-recognised. Our results show comorbid migraine increased the likelihood of headache exacerbation during the initiation of verapamil. In patients with headache worsening, a dual diagnosis of migraine alongside cluster headache should be considered.

ObjectiveTwo phase 3 galcanezumab trials were conducted in Europe and North America to analyze the reduction of weekly cluster headache (CH) attack frequency in populations with episodic and chronic CH. The current study aims to illustrate prospectively recorded baseline clinical data from these trials and to identify possible predictors of response.MethodsPatients (aged 18–65 years) met The International Classification of Headache Disorders 3rd edition-beta criteria for CH. Attacks were evaluated using an electronic headache diary for 7-day (episodic) or 14-day (chronic) eligibility assessments before patients were randomized 1:1 to monthly subcutaneous galcanezumab 300 mg or placebo.ResultsData were collected from 106 patients with episodic and 237 with chronic CH. Overall, the mean age [standard deviation] was 45.4 [11.0] years; patients were predominantly White (84.5%), male (75.8%), and European (77.6%). Patients with episodic CH reported 17.5 [10.0] attacks/week; patients with chronic CH reported 18.8 [10.2] attacks/week. The average pain severity score (range 0–4) was 2.5 [0.7] for episodic CH and 2.7 [0.7] for chronic CH. Higher attack frequency was a possible predictor of response to galcanezumab; potential negative predictors of response were greater attack severity and duration.ConclusionThis large dataset of patients with CH provides reliable systematically and prospectively collected information on disease characteristics. The analysis in episodic CH underscores potential predictors of response worth considering for future CH trial design.Clinical Trial RegistrationClinicalTrials.gov, identifiers: NCT02397473 and NCT02438826.

To conduct an individual subject meta-analysis of available controlled studies of zolmitriptan nasal spray in the acute treatment of cluster headache. Two double-blind, placebo-controlled, randomized, crossover studies of zolmitriptan nasal spray in the acute treatment of cluster headache, with similar patient populations, protocol designs, doses, and clinical endpoints have been published. In both double-blind studies, each patient was to treat 3 attacks, 1 with placebo, 1 with zolmitriptan 5 mg, and 1 with zolmitriptan 10 mg in a randomized, crossover manner. Headache intensity was rated on a 5-point scale (none to very severe). The primary endpoint was headache relief at 30 minutes post dose: reduction from moderate, severe, or very severe pain to mild or none. A multilevel, random-effects, logistic regression model was used to analyze the data. A total of 121 patients (100 male; 64.5% with episodic cluster headache) provided efficacy data for at least 1 attack. Zolmitriptan 5 mg and 10 mg were significantly more effective at providing headache relief at 30 minutes post treatment than placebo (odds ratio 3.48; 95% confidence interval 1.49-8.10 and odds ratio 8.68; 95% confidence interval: 3.35-22.5, respectively). For episodic cluster headache, response rates were 35.6%, 51.7%, and 73.7% for placebo, zolmitriptan 5 mg (odds ratio 2.5; P = .06 vs placebo), and 10 mg (odds ratio 9.9; P < .001 vs placebo), respectively. For chronic cluster headache, response rates were 17.2%, 41.9%, and 40.7% for placebo, zolmitriptan 5 mg (odds ratio 8.1; P = .035), and 10 mg (odds ratio 7.6; P = .046), respectively. Zolmitriptan was well tolerated in both studies with no serious adverse events reported. Zolmitriptan nasal spray at a dose of 5 mg and 10 mg is efficacious in the acute treatment of episodic and chronic cluster headache.

BackgroundInjections targeting the occipital nerve are used to reduce headache attacks and abort cluster bouts in cluster headache patients. There is no widely accepted agreement over the optimal technique of injection, type and doses of steroids and/or anesthetics to use, as well as injection regimens. The aim of this study was to verify the effectiveness and safety of greater occipital nerve long-acting steroid injections in the management of episodic and chronic cluster headache.MethodsWe conducted a prospective observational cohort study on episodic (ECH) and chronic cluster headache patients (CCH). ECH were included in the study at the beginning of a cluster period. Three injections with 60 mg methylprednisolone were performed on alternate days. We registered the frequency and intensity of attacks three days before and 3, 7 and 30 days after the treatment, the latency of cluster relapse, adverse events, scores evaluating anxiety (Zung scale), depression (Beck’s Depression Scale) and quality of life (Disability Assessment Schedule II, 12-Item Self-Administered Version). Primary outcome was the interruption of the cluster after the three injections. Responders conducted a follow-up period of 12 months.ResultsWe enrolled 60 patients, 47 with ECH and 13 with CCH. We observed a complete response in 47.8% (22/46) of episodic and 33.3% (4/12) of chronic patients. Moreover, a partial response (reduction of at least 50% of attacks) was obtained in further 10.8% (5/46) of episodic and in 33.3% (4/12) of chronic patients at 1 month. Median pain-free period was of 3 months for CCH responders. Only mild adverse events were reported in 38.3% (23/58) cases.ConclusionsWe suggest three greater occipital nerve injections of 60 mg methylprednisolone on alternate days as useful therapy in episodic and chronic cluster headache. This leads to a long pain-free period in chronic forms. Adverse effects are mild and support its use as first choice.Trial registrationThe study was inserted in AIFA observational studies register.

Cluster headache (CH) is a primary headache and considered as one of the worst pains known to man. The sphenopalatine ganglion (SPG) plays a pivotal role in cranial autonomic symptoms associated with pain. Lesioning procedures involving the SPG and experimental acute SPG stimulation have shown some degree of efficacy with regard to CH. A neuromodulation device, chronically implanted in the pterygopalatine fossa, has been specifically designed for acute on-demand SPG stimulation. In a pilot placebo-controlled study in 28 patients suffering from refractory chronic CH, alleviation of pain was achieved in 67.1% of full stimulation-treated attacks compared to 7% of sham stimulation-treated attacks (p<0.0001). Long-term results (24 months; 33 patients) confirmed the efficacy of SPG stimulation as an abortive treatment for CH attacks. Moreover, 35% of the patients observed a >50% reduction in attack frequency, suggesting that repeated use of SPG stimulation might act as a CH-preventive treatment. Globally, 61% of the patients were acute responders, frequency responders, or both, and 39% did not respond to SPG stimulation. The safety of SPG microstimulator implantation procedure was evaluated in a cohort of 99 patients; facial sensory disturbances were observed in 67% of the patients (46% of them being transient), transient allodynia in 3%, and infection in 5%. SPG stimulation appears as a promising innovative, efficient, and safe therapeutic solution for patients suffering from severe CH. It has shown its efficacy in aborting CH attacks compared to placebo stimulation, suggesting that it is particularly adapted for CH patients who are not sufficiently improved by abortive treatments such as sumatriptan and oxygen. However, further studies comparing SPG stimulation with standard abortive and/or preventive CH treatments will be necessary to define more precisely its place within the management of severe chronic and/or episodic CH.

To evaluate the efficacy and tolerability of oral zolmitriptan 5 mg and 10 mg and placebo in cluster headache. A multicenter, double-blind, randomized, three-period, crossover, outpatient study. Adult patients received placebo and zolmitriptan 5 mg and 10 mg orally for the acute treatment of episodic or chronic cluster headache. Headache intensity was rated by a five-point scale: none, mild, moderate, severe, or very severe. Patients only treated moderate to very severe headaches. The primary efficacy measure was headache response (two-point or greater reduction from baseline in the cluster headache rating scale) at 30 minutes. Secondary efficacy measures included proportion of patients with initial headache relief within 15 and 30 minutes, mild or no pain at 30 minutes, meaningful headache relief, and use of escape medication. A total of 124 patients took at least one dose of study medication, with 73% having episodic and 27% chronic cluster headache. For the primary endpoint, there was a treatment-by-cluster-headache-type interaction (p = 0.0453). Therefore, results are presented separately for chronic and episodic cluster headache. In patients with episodic cluster headache, the difference between zolmitriptan 10 mg and placebo at 30 minutes reached significance (47% versus 29%; p = 0.02). Mild or no pain at 30 minutes was reported by 60%, 57%, and 42% patients treated with zolmitriptan 10 mg, zolmitriptan 5 mg, and placebo (both p </= 0.01 versus placebo). For all other secondary endpoints, zolmitriptan 10 mg was significantly superior to placebo in episodic cluster headache patients, whereas zolmitriptan 5 mg was significantly superior to placebo for three of the four secondary endpoints. In patients with chronic cluster headache, response rates following zolmitriptan 5 mg or 10 mg were not significantly different from placebo at any endpoint. Zolmitriptan 5 mg and 10 mg were well tolerated. Oral zolmitriptan is efficacious in episodic cluster headache.

Vagus Nerve Stimulation for the Acute Treatment of Cluster Headache

Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care.

A 29-year-old man with medically refractory right-sided chronic cluster headache presented with increased attack frequency. As a bridging therapy, we considered a greater occipital nerve (GON) injection with corticosteroids and local anesthetic. Delving through his childhood medical records, it came to light he had an incidental right cerebellopontine angle dermoid excised. He could not recall the details of this; therefore, plain skull X-ray (figure 1) and head CT (figure 2) were performed. Neuroimaging is required before proceeding with GON injection if there is any suggestion of past neurosurgical intervention. There is a risk of causing loss of consciousness with GON injections into nonintact skull.1,2