Both 100% and 30% intensity occipital nerve stimulation can substantially reduce attack frequency in patients with medically intractable chronic cluster headaches, according to research results published in TheLancet Neurology.
Occipital nerve stimulation, a preventive treatment for medically intractable chronic cluster headaches, has demonstrated promising results in previous small, uncontrolled trials. In the current study, researchers sought to “expand the preventive treatment options” for this patient population. Researchers also hoped to determine the mode of action of occipital nerve stimulation and assess how it might be investigated in future clinical research.
The current study (ClinicalTrials.gov identifier NCT01151631) was an investigator-initiated, international, multicenter, randomized, double-blind, phase 3, electrical dose-controlled clinical trial, incorporating 4 study periods: a 12-week period for baseline observation, a run-in period with device implantation and 10-day 10% occipital nerve stimulation, and a 24-week randomized, double-blind treatment period with a stepwise increase in treatment intensity.
Adult participants with at least 4 medically intractable chronic cluster headaches per week were enrolled at 7 hospitals in the Netherlands, Belgium, Germany, and Hungary. After the baseline period, participants were randomly assigned in a 1:1 ratio to either 100% or 30% of the individually accepted occipital nerve stimulation dose.
The primary study outcome was mean attack frequency per week in the final 4 weeks of the masked study period, weeks 21 to 24 after the run-in period. Secondary outcomes included mean attack frequency for each 4-week period, weekly mean attack intensity, the proportion of participants with more than a 50% reduction in mean attack frequency at weeks 24 and 48 vs baseline, and patient satisfaction at weeks 24 and 48, among other outcomes.
The cohort included 150 patients who were enrolled between 2010 and 2017; after the 12-week baseline period, 131 patients were randomly assigned to a treatment group (100% group, n=65; 30% group, n=66). The majority of patients (n=122) were from Dutch centers. Within each treatment group, 1 participant was lost to follow-up.
At baseline, weekly mean attack frequencies were skewed, with some participants reporting a high frequency of attacks. For most, though, individual mean attack frequencies were stable throughout the baseline observation period.
After treatment onset, median weekly mean attack frequency was 7.38 (interquartile range [IQR], 2.50-18.50), representing a median decrease of -5.21 (IQR, 11.18 to -0.19). In the 100% group, the median decrease was -4.08 (IQR, -11.92 to -0.25), while the median decrease was -6.50 (IQR, -10.83 to -0.08) in the 30% group. No difference in decrease was noted between weeks 21 and 24 vs baseline (-2.42; 95% CI, -5.17 to 3.33).
During the first 4 weeks of treatment, median weekly mean attack frequency across the entire study population had “already reduced,” according to researchers. Median relative change in the total study population between weeks 21 and 24 was -42.56% (IQR, -80.05 to -1.80); median changes of -41.06 and -46.00 were recorded in the 100% and 30% groups, respectively.
During the open-label phase, median weekly mean attack frequency “did not increase much further,” and there were no significant differences reported between study sites. Roughly half of the study population experienced at least a 50% reduction in mean attack frequency between weeks 21 to 24 and 45 to 48.
In total, 7 participants were attack free during weeks 1 through 4, 9 were attack free during weeks 21 to 24, and 16 were attack free during weeks 45 to 48.
At baseline, investigators found that mean attack intensities were “highly stable” through 12 weeks in most participants. In the total population, weekly mean attack intensity decreased over the study period with similar results in both groups.
By week 24, approximately 91% of participants stated that they would recommend occipital nerve stimulation to other patients, and 74% of them were willing to “strongly recommend” the treatment. Only 5% of participants would not recommend it, and 5% had a neutral opinion.
By week 48, 97% of participants were willing to recommend occipital nerve stimulation, with 73% strongly recommending the treatment.
Overall, mean physical health summary score increased from 52 to 58 between baseline and week 24, with a further increase to 62 at 48 weeks. Mean mental health summary scores also increased, from 50 to 58 to 61 at the same time points. Results were similar between groups.
Researchers recorded 59 serious adverse events in 46 participants. Of these events, 35 serious adverse events that occurred in 31 participants were hardware related, including the replacement of empty implantable pulse generators (IPGs) or electrode or lead dislocation, failure, or fracture. The most severe adverse event took place in a patient with multiple vascular risk factors; this patient experienced a right-middle cerebral artery transient ischemic attack 1 month and 15 days after implantation. This event, however, was determined to be unrelated to the procedure or device.
Study limitations include a lengthy patient enrollment period due to insurance reimbursement issues, the use of circumstantial evidence to determine efficacy, and the lowering of prespecified treatment intensities in 20 patients in the 100% treatment group due to patient discomfort.
“Although the results of our study did not show a difference in treatment response between the different groups, circumstantial evidence suggests that [occipital nerve stimulation] is an effective, well-tolerated, and safe last-resort therapy for [medically intractable chronic cluster headaches], even at electrical doses that are lower than those currently recommended in the field of neurostimulation,” the researchers wrote.
Disclosure: This clinical trial was supported by Medtronic. Please see the original reference for a full list of authors’ disclosures.
Wilbrink LA, de Coo IF, Doesborg PGG, et al; for the ICON study group. 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. Lancet Neurol. 2021;20(7):515-525. doi: 10.1016/S1474-4422(21)00101-0