Noninvasive vagus nerve stimulation (nVNS) may represent an effective acute intervention for episodic, but not chronic, cluster headache, according to the pooled analysis of 2 randomized double-blind sham-controlled trials published in Cephalalgia.

In this analysis, the data of 2 clinical trials, ACT1 and ACT2 ( identifiers: NCT01792817 and NCT01958125, respectively) — in which the efficacy of nVNS was examined in patients with episodic and chronic cluster headache — was pooled, as each study lacked sufficient power to determine the differential effect size for each type of cluster headache separately. Results from both the ACT1 and ACT2 studies indicated the effectiveness of nVNS for the acute treatment of episodic — but not chronic — cluster headache. Pooling of the data from both trials was permitted thanks to comparable study designs (ie, for the comparison of active vs sham stimulation and in data collection) and populations (ie, participants with episodic or chronic cluster headaches).

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Both trials differed in their primary outcome, with ACT1 examining the percentage of participants reporting improvements in pain intensity from moderate/severe/very severe to no/mild 15 minutes after using nVNS for the first time for the acute treatment of a cluster headache, and ACT2 examining the percentage of any attack in which pain intensity was reduced from 2-4 to 0 on a 5-point scale, also 15 minutes after treatment initiation. ACT1 and ACT2 also differed in the respective lengths of their double-blind and open-label phases and in their timing of treatment initiation.

The pooled number of participants (age ≥18 years) in the ACT1 and ACT2 trials was 225 (episodic, n=112; chronic, n=113), with 108 and 117 patients randomly assigned to receive nVNS or sham stimulation, respectively.

A greater percentage of participants with episodic cluster headache who were treated with nVNS vs sham stimulation reported improvements in pain intensity 15 minutes after their first attack (ACT1 primary end point; absolute difference: ACT1, 24%; P =.01; pooled populations, 27%; P <.01; but not in ACT2; P =.07), and a greater percentage reported being pain-free 15 minutes after any attack with nVNS vs sham stimulation (ACT2 primary end point; absolute difference: ACT1, 9%; P <.05; ACT2, 41%; P <.05; pooled, 22%; P <.01).

A greater percentage of participants with episodic cluster headache treated with nVNS vs sham stimulation reported being pain-free (absolute difference: pooled population, 18%; P =.01; ACT1, 14%; P =.05; ACT2, 28% P =.11;), or being pain-free or experiencing mild pain (absolute difference: ACT1, 19%; P =.04; ACT2, 49%; P =.02; pooled, 27%; P <.01), both 15 minutes after attack onset for ≥50% of attacks treated. Response rates ≥50% for freedom from or absence of pain 15 minutes after treatment initiation were also greater in patients treated with nVNS vs sham stimulation (absolute difference: ACT2, 26%; P <.01; pooled population, 14%; P =.01).

The occurrence of at least one adverse event was reported by 38 and 45 patients treated with nVNS and sham stimulation, respectively, including serious adverse events reported by one patient each in ACT1 and ACT2 (cluster headache exacerbation and pain in the lower abdomen/back, respectively). The adverse events most commonly reported by participants treated with nVNS were perioral muscle contraction during stimulation for the pooled population, lip or facial drooping/pooling/twitching in the ACT1 population, and irritation or paresthesia at the application site in the ACT2 population.

“nVNS offers several advantages over existing treatment options, including its ease and flexibility of use and its ability to be used for as many attacks as the patient experiences per day, without restrictions to daily number of treatments and co-medications,” noted the study authors.


de Coo IF, Marin JC, Silberstein SD, Friedman DI, Gaul C, McClure CK, et al. Differential efficacy of non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A meta-analysis [published online June 10, 2019]. Cephalalgia.