Safety and efficacy of occipital nerve stimulation as treatment of chronic cluster headache: an investigator-initiated, double-blind, randomized, placebo-controlled study

Occipital nerve stimulation has shown promising results in attack prevention in patients with chronic cluster headache, but evidence from controlled trials is scarce. Conventional (tonic) occipital nerve stimulation elicits paresthesia, hampering blinded comparison to placebo. Using paresthesia-free burst occipital nerve stimulation, we conducted a randomized, placebo-controlled trial. The study is an investigator-initiated, double-blind, randomized, placebo-controlled clinical trial involving participants with chronic cluster headache. It comprised a four-week baseline, a 12-week trial with transcutaneous electrical nerve stimulation, occipital nerve stimulator implantation, a 12-week randomized, double-blind burst occipital nerve stimulation treatment period, and a 12-week open-label tonic occipital nerve stimulation treatment period. The primary outcomes were safety and the proportion of participants reporting a ≥30% reduction in attack frequency in the randomized and open-label trial phases. Participants were enrolled between August 2021 and October 2023. 116 chronic cluster headache patients were assessed for eligibility. Sixty-five were excluded, and 51 entered baseline observation. Before occipital nerve stimulator implantation and randomization, an additional 13 were excluded. Thirty-eight participants underwent occipital nerve stimulator implantation and were randomly assigned to burst occipital nerve stimulation (n = 19) or placebo (n = 19). After the randomized trial phase, the proportion of ≥30% responders was 18.81% (95%CI 0.28%–37.87%) in the burst occipital nerve stimulation group and 50.02% (95%CI 26.87%–73.09%) in the placebo group. The likelihood of reaching the primary endpoint was 31.20% (95%CI 1.29%–61.23%, p = 0.042) higher in the placebo group. After the open-label phase, 42.09% (95%CI 19.91%–64.34%) in the burst occipital nerve stimulation group and 51.11% (95%CI 27.32%–74.88%) in the placebo group had ≥30% frequency reduction. In total, 20 adverse events were registered; eight were treatment-related serious adverse events. The most common adverse event was temporary occipital dysesthesia in eight participants. Occipital nerve stimulation reduced attack frequency but was not superior to placebo. The treatment had an acceptable safety profile and was well-tolerated. The results call for attention to sufficient placebo control when planning further studies. The trial is registered at clinicaltrials.gov (identifier NCT05023460).Study registration date: July 27th 2021.