Effects of acute and preventive therapies for episodic and chronic cluster headache: A scoping review of the literature

Background Cluster headache is the most common primary headache disorder of the trigeminal autonomic cephalalgias, and it is highly disabling. Objective We undertake a scoping review to characterize therapies to prevent and acutely treat cluster headache, characterize trial methodology utilized in studies, and recommend future trial good practices. We also assess homogeneity of studies and feasibility for future network meta-analyses (NMAs) to compare acute and preventive treatments for cluster headache. Methods A priori protocol for this scoping review was registered and available on Open Science Forum. We sought studies that enrolled adult patients with cluster headache as identified by accepted diagnostic criteria. Both randomized controlled trials (RCTs) and observational studies (with a control group) were included. The interventions of interest were medications, procedures, devices, surgeries, and behavioral/psychological interventions, whereas comparators of interest were placebo, sham, or other active treatments. Outcomes were predefined; however, we did not exclude studies lacking these outcomes. A systemic search was conducted in Ovid Medline, Embase, and Cochrane. We performed a targeted search for conference abstracts from journals prominent in the field. Results We identified 56 studies: 45 RCTs, four studies only available in clinical trial registries, and seven observational studies. Of the 45 RCTs, 20 focused on acute therapies and 25 on preventive therapies. Overall, we determined that it is feasible to pursue a NMA for acute therapy focusing on 15 or 30-min headache reduction for acute trials, as we identified 11 trials in the combined population of patients with either episodic or chronic cluster headache (2 trials in populations with chronic cluster headache were also found). For preventive therapy of cluster headache, we identified trials with common outcomes that may be considered for NMA, however, as these trials had differences in treatment effect modifiers that could not be corrected, NMAs appear infeasible for this indication. We identified new studies looking at noninvasive vagal nerve stimulation, sphenopalatine ganglion stimulation, prednisone, and oxygen published since the most recent systematic review in the field, although these acute treatments were previously identified as effective. However, for calcitonin gene-related peptide (CGRP) monoclonal antibodies, galcanezumab demonstrated effectiveness in episodic cluster headache, but a lack of effectiveness in chronic cluster headache, and fremanezumab was not effective for episodic nor chronic cluster headache. This finding highlights that CGRP monoclonal antibodies may not show a class effect in cluster headache prevention and need to be considered individually. Conclusions We describe the treatment landscape of cluster headache for both acute and preventive treatments. Last, we present the NMAs we will undertake in acute therapies of cluster headache.

Automated summary

This study characterized therapies for preventing and acutely treating cluster headache, assessed trial methodology, and evaluated the feasibility of future network meta-analyses. While a NMA for acute therapy appears feasible, it may be challenging for preventive therapy due to differences in treatment effects. New studies on various treatments were identified, highlighting the need to consider individual effectiveness in cluster headache prevention.