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

Summary

Background

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.

Methods

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).

Findings

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.

Interpretation

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.

Funding

The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

Introduction

Cluster headache is a highly disabling brain disorder, typically characterised by frequent attacks (up to eight times per day lasting 15–180 min) of excruciating, unilateral periorbital pain and ipsilateral facial autonomic symptoms, with or without restlessness.1, 2 Up to 20% of patients with cluster headache have chronic cluster headache, with no or only short (<3 months) attack-free periods, in contrast to patients who have the episodic form.²

Research in context

Evidence before this study

We searched PubMed on Jan 21, 2021, with the keywords “chronic cluster headache”, “cluster headache”, and “occipital nerve stimulation”, without restrictions to language or publication year. Reviews were excluded. Of 72 returned items, we selected all peer-reviewed papers that reported cluster headache attack frequency or intensity at least 1 month after implantation. Papers on burst or extra-occipital stimulation protocols were excluded. In the case of neurostimulation for refractory headache, only data from patients with cluster headache were considered.We identified 15 publications, from ten unique study populations, which fulfilled all selection criteria. Because of the wide heterogeneity of the baseline data, inclusion criteria, outcome measures, and follow-up time, a formal meta-analysis was not feasible. Instead, global results were summarised and presented as unbalanced means and range across studies. All studies were small, uncontrolled, and open-label and included in total 274 participants. Baseline periods were short (2–4 weeks). Not all main outcomes were available for all participants. All studies showed positive outcomes. Follow-up durations were highly variable, both between studies and within studies between participants. Mean reduction in attack frequency was 50% (range –25 to –80). Mean proportion of participants with more than 50% reduction in attack frequency was 62% (range 53–100). Mean change in headache intensity was 19% (range –49 to 8).

Added value of this study

Occipital nerve stimulation (ONS) showed promising results in small, uncontrolled, open-label studies. To the best of our knowledge, this is the first randomised, double-blind, controlled study to evaluate the clinical effects of ONS in a large population with medically intractable chronic cluster headache (MICCH). Because ONS induces local paraesthesia, complicating placebo comparison, we compared 100% ONS with 30% ONS. Both stimulation protocols were associated with similarly rapid and long-term sustained halving of the attack frequency. Half the participants achieved more than 50% reduction in attack frequency, and the attack intensity decreased by a third. More than 90% of participants would recommend ONS to other patients with MICCH.The abrupt, marked, and up to 2 years of sustained improvement in symptoms after ONS treatment following a highly stable, 12-week, pre-treatment baseline observation period in patients with an unremitting history of highly disabling MICCH over many years, strongly supports a therapeutic effect of ONS, rather than a placebo effect. Moreover, known drivers for placebo response were unlikely to have had a substantial role. Finally, our results are in line with those of earlier small case series.

Implications of all the available evidence

ONS, even at low intensity, is a highly effective last-resort preventive treatment of chronic cluster headache not responding to conventional preventive medication. Our data will be useful for a broad range of health-care providers caring for patients with headache and pain in general. The results should also stimulate further biophysical and biomedical research to improve understanding of the underlying mechanisms of ONS and neuromodulation in general, to improve stimulation protocols, and to improve trial designs for testing treatment efficacy.

Attacks can be stopped with administration of subcutaneous sumatriptan or 100% oxygen inhalation. However, most patients also need preventive therapy.² Up to 15% of patients with chronic cluster headache are refractory or intolerant to preventive medications, meaning that they have medically intractable chronic cluster headache (MICCH).3, 4 MICCH is a profoundly disabling disorder, particularly if attacks also occur at night and disturb sleep. Some patients even attempt to end their life by suicide.⁵

Invasive hypothalamic stimulation has shown promising efficacy in small studies without a control group (these have been reviewed elsewhere),6, 7 but was sometimes associated with fatal complications.⁸ Moreover, although effective in migraine⁹ and episodic cluster headache,¹⁰ the monoclonal antibodies to calcitonin-gene-related peptide or its receptor were not effective in chronic cluster headache,11, 12 underscoring the high unmet need for effective preventive treatment of this devastating disease.

Occipital nerve stimulation (ONS) is an invasive, non-destructive, reversible potential preventive treatment. Stimulation leads with electrodes are implanted subcutaneously bi-occipitally and connected to an implantable pulse generator (IPG; a battery-powered micro-electronic device that delivers electronic stimulation to the nervous system) that has been placed subcutaneously in the abdominal or gluteal region.¹³ The treatment rationale is based on human and animal studies showing convergence of cervical, somatic trigeminal, and dural trigeminovascular afferents on second-order nociceptors in the brainstem.² Small uncontrolled studies have shown promising results.14, 15, 16, 17, 18, 19, 20, 21, 22 Evidence from controlled studies is, however, scarce, primarily because ONS causes occipital paraesthesia,²³ which complicates the feasibility of masked placebo-controlled trials.

Therefore, we compared the effects of 100% versus 30% of the individually accepted electrical dose of ONS in a randomised, double-blind study.¹³ Both intensities were hypothesised to cause similar paraesthesia, mitigating the risk of unmasking, while also showing differential efficacy, as has been described for a range of neurostimulation modalities.24, 25, 26, 27

Our study aimed to expand the preventive treatment options for patients with MICCH, further understanding of the mode of action of ONS and how it can be investigated in clinical trials, and further understanding of neurostimulation in general.