Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial

doi:10.1016/S1474-4422(19)30322-9

The Lancet Neurology

Volume 18, Issue 12, December 2019, Pages 1081-1090

https://doi.org/10.1016/S1474-4422(19)30322-9 Get rights and content

Summary

Background

Chronic cluster headache is the most disabling form of cluster headache. The mainstay of treatment is attack prevention, but the available management options have little efficacy and are associated with substantial side-effects. In this study, we aimed to assess the safety and efficacy of sphenopalatine ganglion stimulation for treatment of chronic cluster headache.

Methods

We did a randomised, sham-controlled, parallel group, double-blind, safety and efficacy study at 21 headache centres in the USA. We recruited patients aged 22 years or older with chronic cluster headache, who reported a minimum of four cluster headache attacks per week that were unsuccessfully controlled by preventive treatments. Participants were randomly assigned (1:1) via an online adaptive randomisation procedure to either stimulation of the sphenopalatine ganglion or a sham control that delivered a cutaneous electrical stimulation. Patients and the clinical evaluator and surgeon were masked to group assignment. The primary efficacy endpoint, which was analysed with weighted generalised estimated equation logistic regression models, was the difference between groups in the proportion of stimulation-treated ipsilateral cluster attacks for which relief from pain was achieved 15 min after the start of stimulation without the use of acute drugs before that timepoint. Efficacy analyses were done in all patients who were implanted with a device and provided data for at least one treated attack during the 4-week experimental phase. Safety was assessed in all patients undergoing an implantation procedure up to the end of the open-label phase of the study, which followed the experimental phase. This trial is registered with ClinicalTrials.gov, number NCT02168764.

Findings

Between July 9, 2014, and Feb 14, 2017, 93 patients were enrolled and randomly assigned, 45 to the sphenopalatine ganglion stimulation group and 48 to the control group. 36 patients in the sphenopalatine ganglion stimulation group and 40 in the control group had at least one attack during the experimental phase and were included in efficacy analyses. The proportion of attacks for which pain relief was experienced at 15 min was 62·46% (95% CI 49·15–74·12) in the sphenopalatine ganglion stimulation group versus 38·87% (28·60–50·25) in the control group (odds ratio 2·62 [95% CI 1·28–5·34]; p=0·008). Nine serious adverse events were reported by the end of the open-label phase. Three of these serious adverse events were related to the implantation procedure (aspiration during intubation, nausea and vomiting, and venous injury or compromise). A fourth serious adverse event was an infection that was attributed to both the stimulation device and the implantation procedure. The other five serious adverse events were unrelated. There were no unanticipated serious adverse events.

Interpretation

Sphenopalatine ganglion stimulation seems efficacious and is well tolerated, and potentially offers an alternative approach to the treatment of chronic cluster headache. Further research is need to clarify its place in clinical practice.

Funding

Autonomic Technologies.

Introduction

Cluster headache is a trigeminal autonomic cephalalgia.¹ It has an episodic subtype, in which patients go at least 3 months attack free and without treatment during any 12-month period, and a chronic subtype, in which patients have no such break from treatment. Acute attacks of cluster headache can typically occur from every second day to eight times a day, in association with cranial autonomic features ipsilateral to the pain.² Roughly 20% of all patients with cluster headache have the chronic subtype.³ The 1-year combined population prevalence of episodic and chronic cluster headache is estimated to be 0·1%.⁴ Acute attacks can occur with clockwork-like regularity, including attacks that frequently awaken patients from sleep.⁵ Remarkably, acute cluster headache attacks are considered to be the worst pain that human beings experience.⁶

Patients with chronic cluster headache need both preventive and acute treatment options. Options for acute attacks include triptans, serotonin 5-HT_1B and 5-HT_1D receptor agonists³, and inhaled oxygen.⁷ Triptans have cardiovascular contraindications⁸ that are important in cluster headache, which affects three times as many men as women and is common in people older than 50 years with a history of cigarette smoking.⁴ The mainstay of preventive treatment in chronic cluster headache is high-dose verapamil (up to 960 mg daily), which has well recognised side-effects, including cardiac arrthymias.⁹ Non-invasive neuromodulation approaches to treatment of acute cluster headache have been developed in the form of non-invasive vagal nerve stimulation, but this treatment did not work in patients with chronic cluster headache in two separate studies.10, 11 Invasive neuromodulation approaches, such as occipital-nerve stimulation,12, 13 have been used with some efficacy, but no controlled trial data are available. Deep-brain stimulation¹⁴ has also been used in chronic cluster headache, with patients accepting the associated risk of death¹⁵ to avoid further attacks.

Research in context

Evidence before this study

We searched Embase and MEDLINE with the terms “cluster headache” and “trigeminal autonomic cephalalgias” for articles published in English up to Jan 31, 2019. We also hand searched abstracts from meetings of the International Headache Society, American Headache Society, Migraine Trust, and European Headache Federation from the past 10 years. Chronic cluster headache is a highly disabling primary headache disorder that is often refractory to treatment. We identified one previous small blinded phase 2 study of sphenopalatine ganglion stimulation (CH-1), in which the therapy was efficacious compared with an inactive sham. This finding raised the question of whether efficacy would be maintained in a trial with adequate blinding. A limitation of our search strategy is that unreported negative trial results might not have been identified.

Added value of this study

This well blinded study provides further evidence that stimulation of the sphenopalatine ganglion in patients with chronic cluster headache can both control acute cluster headache attacks and diminish the frequency of attacks over time.

Implications of all the available evidence

The evidence from this trial, together with long-term safety data from the CH-1 study, suggests that sphenopalatine ganglion stimulation could be a promising option for management of chronic cluster headache.

An important component of the pathophysiology of acute cluster headache attacks is activation of the trigeminal–autonomic reflex,¹⁶ which accounts for the cranial autonomic features, such as lacrimation, conjunctival injection, nasal congestion, aural fullness, and periorbital oedema. The outflow pathway for these symptoms traverses the facial nerve (ie, the seventh cranial nerve) and synapses in the sphenopalatine ganglion,¹⁷ which is located in the pterygopalatine fossa.¹⁸ On the basis of this anatomy and clinical experience, the sphenopalatine ganglion was postulated to be a therapeutic target,19, 20, 21 and a sphenopalatine ganglion stimulator was subsequently developed and studied. In the first phase 2 trial,²² which included 32 patients with chronic cluster headache, the sphenopalatine ganglion stimulator was compared with a sham with no stimulation and a subperception stimulus in a randomised crossover design. In the sphenopalatine ganglion stimulator group, pain relief at 15 min was experienced in 67% of attacks, compared with 7% of attacks in both the sham and subperception treatment groups. 36% of participants in the sphenopalatine ganglion stimulator group also reported a 50% or greater reduction in attack frequency.²² However, this study was limited by its small size and the use of a no-perception sham.

Building on this previous study, we sought to establish the safety and efficacy of sphenopalatine ganglion neurostimulation for the acute treatment of attacks in patients with chronic cluster headache in a trial with better blinding.

Section snippets

Study design and participants

We did a randomised, sham-controlled, parallel group, double-blind, safety and efficacy study at 21 headache centres in the USA. Eligible participants were aged 22 years or older and had chronic cluster headaches² (at least four attacks per week, on the side of their dominant headache laterality) that were judged by investigators and participants to be either previously or currently inadequately controlled with available therapies (in terms of both prevention and treatment of acute attacks).

Results

Between July 9, 2014, and Feb 14, 2017, 93 patients were included and randomly assigned, 45 to the sphenopalatine ganglion stimulation group and 48 to the control group (figure 3). Table 1 shows participant demographics. 17 patients, nine in the sphenopalatine ganglion stimulation group and eight in the control group, had no acute attacks during the experimental phase. The remaining 76 participants treated at least one attack during the experimental phase of the trial and used the

Discussion

In this randomised, double-blind, sham-controlled, parallel group study, we showed that sphenopalatine ganglion stimulation in patients with chronic cluster headache relieved acute attacks within 15 min significantly more often than sham stimulation. Ancillary analyses provided some evidence that more patients had pain relief and freedom from pain at 15 min and sustained pain relief at 1 h after at least 50% of attacks with sphenopalatine ganglion stimulation than with sham treatment. Although

Data sharing

The data reported here are proprietary to the sponsor, Autonomic Technologies, and there are no plans to make the individual patient data or aggregate data publicly available.

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A prospective open label 2–8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache
2023, eBioMedicine
We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety.
ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals.
Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8–6.3), two (5.1; 3.5–7.6) and five years (4.1; 3.0–5.5) compared to baseline (16.2; 14.4–18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68–0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70–0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year⁻¹ [0.28–0.41]). We didn't find predictive factors for effectiveness.
ONS is a safe, well-tolerated and long-term effective treatment for MICCH.
The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.
Primary headache disorders: From pathophysiology to neurostimulation therapies
2023, Heliyon
Primary headache disorders including migraine, cluster headache, and tension-type headache are among the most common disabling diseases worldwide. The unclear pathogenesis of primary headache disorders has led to high rates of misdiagnosis and limited available treatment options. In this review, we have summarized the pathophysiological factors for a better understanding of primary headache disorders. Advances in functional neuroimaging, genetics, neurophysiology have indicated that cortical hyperexcitability, regional brain dysfunction, central sensitization and neuroplasticity changes play vital roles in the development of primary headache disorders. Moreover, we have also discussed a series of neurostimulation approaches with their stimulation mechanism, safety and efficacy for prevention and treatment of primary headache disorders. Noninvasive or implantable neurostimulation techniques show great promise for treating refractory primary headache disorders.
Transnasal endoscopy-guided percutaneous access to the sphenopalatine ganglion for neurostimulation in the treatment of primary headache: operative technique and feasibility
2023, Brazilian Journal of Otorhinolaryngology
Citation Excerpt :
Recent research with implantable microstimulators showed that 68% of patients experienced clinically relevant improvement in their symptoms during the study, achieving relief during at least 50% of episodes treated with full stimulation, as well as a reduction of at least 50% in episode frequency compared to baseline.1 Ancillary analyses demonstrated that more patients had pain relief and/or resolution within 15 min and sustained pain relief for 1 h in at least 50% of episodes comparing stimulator versus sham treatment.2 THE Intellis-97716 system® (Medtronic, Dublin, Ireland) was designed to treat lower-back and sciatic pain by spinal neurostimulation.
Cluster headache is considered a trigeminal autonomic cephalalgia and may present with characteristic symptoms of sympathetic/parasympathetic activation on the affected side of the face, such as nasal discharge, tearing, and conjunctival injection. Invasive therapies targeting the sphenopalatine ganglion have been performed in these headache syndromes and can have a medication-sparing effect, especially in refractory, difficult-to-manage cases. The gate control theory of pain suggests that electric pulses delivered to nerve tissues can modulate neuronal activity, thus aiding in management of nociceptive or neuropathic pain, and studies have demonstrated the efficacy and safety of sphenopalatine ganglion neurostimulation. Within this context, we sought to assess the feasibility of a new surgical technique for neurostimulation of the sphenopalatine ganglion in a cadaver dissection model.
The technique was developed through dissection of two cadaver heads. We divided the procedure into two stages: an endonasal endoscopic approach to expose the sphenopalatine ganglion and confirm electrode placement, and a cervicofacial approach to introduce the electrode array and position the internal pulse-generator unit. Computed tomography was performed to confirm implant placement at the end of the procedure.
The pulse-generator unit was successfully placed through a retroauricular incision, as is already standard for cochlear implant placement. This should reduce the incidence of perioperative sequelae, especially pain and swelling in the oral region, which are a common complication of previous approaches used for this purpose. Control imaging confirmed proper electrode placement. The device used in this study allows the patient to modulate the intensity of the stimulus, reducing or even obviating the need for drug therapy.
The novel technique described herein, based on percutaneous access guided by transmaxillary endoscopy, can provide great precision in electrode array positioning and decreased perioperative morbidity, combining the advantages of endoscopic approaches with those of the retroauricular route.
3.
The Sphenopalatine Ganglion: Associated Illnesses and Therapeutic Modalities
2022, Peripheral Nerve Stimulation: A Comprehensive Guide
The sphenopalatine ganglion is the largest gray matter structure outside of the central nervous system. This ganglion acts as a nexus for the autonomic nervous system of the head. Sympathetic fibers pass through and parasympathetic fibers synapse in the ganglion. Autonomics arising from the ganglion go on to targets in the nose, palate, pharynx, and lacrimal structures. Given the intersection of sensory and autonomic nerves, clinicians have sought to treat cluster headaches and sphenopalatine neuralgia first by blocks at the sphenopalatine ganglion and now by stimulation. Recently clinicians have also advocated for treatment of spinal headaches by blockade of the sphenopalatine ganglion. Although our understanding of the illnesses associated with the sphenopalatine ganglion has increased, this structure is being further researched, and new treatments associated with the sphenopalatine ganglion are likely to arise in the future.
Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial
2021, The Lancet Neurology
Citation Excerpt :
The ICON study also has many strengths. First, the baseline period is considerably longer than usual (2–4 weeks at most).10,33,40,44 This extended period allowed for a more accurate estimation of the attack frequency at baseline and showed that there was no spontaneous decrease in attack frequency in the first 12 weeks after inclusion (but before treatment onset), rendering regression to the mean or Hawthorne effects unlikely.
Occipital nerve stimulation (ONS) has shown promising results in small uncontrolled trials in patients with medically intractable chronic cluster headache (MICCH). We aimed to establish whether ONS could serve as an effective treatment for patients with MICCH.
The ONS in MICCH (ICON) study is an investigator-initiated, international, multicentre, randomised, double-blind, phase 3, electrical dose-controlled clinical trial. The study took place at four hospitals in the Netherlands, one hospital in Belgium, one in Germany, and one in Hungary. After 12 weeks’ baseline observation, patients with MICCH, at least four attacks per week, and history of being non-responsive to at least three standard preventive drugs, were randomly allocated (at a 1:1 ratio using a computer-generated permuted block) to 24 weeks of occipital nerve stimulation at either 100% or 30% of the individually determined range between paraesthesia threshold and near-discomfort (double-blind study phase). Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy. In weeks 25–48, participants received individually optimised open-label ONS. The primary outcome was the weekly mean attack frequency in weeks 21–24 compared with baseline across all patients and, if a decrease was shown, to show a group-wise difference. The trial is closed to recruitment (ClinicalTrials.gov NCT01151631).
Patients were enrolled between Oct 12, 2010, and Dec 3, 2017. We enrolled 150 patients and randomly assigned 131 (87%) to treatment; 65 (50%) patients to 100% ONS and 66 (50%) to 30% ONS. One of the 66 patients assigned to 30% ONS was not implanted and was therefore excluded from the intention-to-treat analysis. Because the weekly mean attack frequencies at baseline were skewed (median 15·75; IQR 9·44 to 24·75) we used log transformation to analyse the data and medians to present the results. Median weekly mean attack frequencies in the total population decreased from baseline to 7·38 (2·50 to 18·50; p<0·0001) in weeks 21–24, a median change of –5·21 (–11·18 to –0·19; p<0·0001) attacks per week. In the 100% ONS stimulation group, mean attack frequency decreased from 17·58 (9·83 to 29·33) at baseline to 9·50 (3·00 to 21·25) at 21–24 weeks (median change from baseline –4·08, –11·92 to –0·25), and for the 30% ONS stimulation group, mean attack frequency decreased from 15·00 (9·25 to 22·33) to 6·75 (1·50 to 16·50; –6·50, –10·83 to –0·08). The difference in median weekly mean attack frequency between groups at the end of the masked phase in weeks 21–24 was –2·42 (95% CI –5·17 to 3·33). In the masked study phase, 129 adverse events occurred with 100% ONS and 95 occurred with 30% ONS. None of the adverse events was unexpected but 17 with 100% ONS and eight with 30% ONS were labelled as serious, given they required brief hospital admission for minor hardware-related issues. The most common adverse events were local pain, impaired wound healing, neck stiffness, and hardware damage.
In patients with MICCH, both 100% ONS intensity and 30% ONS intensity substantially reduced attack frequency and were safe and well tolerated. Future research should focus on optimising stimulation protocols and disentangling the underlying mechanism of action.
The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.
Occipital nerve stimulation in medically intractable chronic cluster headache
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ArticlesSafety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Lancet

Lancet

Lancet Neurol

J Auton Nerv Syst

Int J Oral Maxillofac Surg

Brain Res

Brain Res

Neurosci Lett

A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic features, including new cases

Brain

The International classification of headache disorders, 3rd edn (beta version)

Cephalalgia

Cluster Headache

BMJ

Sleep and chronobiology in cluster headache

Cephalalgia

Cluster headache: Investigating severity of pain, suicidality, personal burden, access to effective treatment, and demographics among a large International survey sample

Cephalalgia

High flow oxygen for treatment of cluster headache. A randomized trial

JAMA

Consensus statement: cardiovascular safety profile of triptans (5-HT1B/1D Agonists) in the acute treatment of migraine

Headache

Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy

Neurology

Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study

Headache

Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study

Cephalalgia

Stereotatic stimulation of the posterior hypothalamic gray matter in a patient with intractable cluster headache

N Engl J Med

Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action

Brain

The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural influences on the cerebral circulation

J Cereb Blood Flow Metab

Anatomy of the human body

The role of the sphenopalatine (or Meckle's) ganglion in nasal headaches

NY Med J

Sphenopalatine ganglion radiofrequency ablation for the management of chronic cluster headache

Headache

Articles
Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial

Consensus statement: cardiovascular safety profile of triptans (5-HT_1B/1D Agonists) in the acute treatment of migraine