By Louise M. Klebanoff, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Prednisone, given at 100 mg for five days and then tapering by 20 mg every three days, is a safe and effective short-term prevention for episodic cluster headaches while waiting for longer-acting preventive agents to be initiated.

SOURCE: Obermann M, Nägel S, Ose C, et al. Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: A multicentre, double-blind, randomised controlled trial. Lancet Neurol 2021;20:29-37.

Cluster headache is a primary headache disorder characterized by attacks of severe, unilateral facial and head pain accompanied by trigeminal autonomic symptoms, with attacks lasting 15-180 minutes and occurring from once every other day to up to eight times a day in clusters lasting between one week and several months. Treatments for acute attacks include high-flow oxygen, triptans, and intranasal lidocaine. Preventive medications, such as verapamil and lithium, reduce the number of attacks and potentially terminate the cluster episode. However, they need to be titrated gradually to avoid side effects and can take several weeks to achieve efficacy. Although headache guidelines recommend treatment with oral corticosteroids to break the initial cluster episode while waiting for preventive medications to take effect, this recommendation has not been rigorously assessed. The purpose of this trial was to assess the safety and efficacy of prednisone 100 mg for the short-term prevention of episodic cluster headaches.

The study was a multicenter, randomized, double-blind, placebo-controlled trial performed at 10 specialized pain and headache centers throughout Germany. Eligible patients were age 18-65 years and met criteria for episodic cluster headache as defined by the International Classification of Headache Disorders. To avoid confounding data caused by spontaneous remission, the authors included patients whose prior cluster episodes lasted at least 30 days. Patients could use triptans, high-flow oxygen, intranasal lidocaine, ergotamine, and oral analgesics as needed. Patients were randomized to receive oral prednisone or placebo. Prednisone was given at a dose of 100 mg for five days and then tapered by 20 mg every three days. Oral verapamil was initiated at a dose of 40 mg three times a day at the same time and increased every three days to a maximum daily dose of 360 mg. Patients also received 20 mg of pantoprazole daily to prevent gastrointestinal side effects from corticosteroids.

Patients used diaries to record the number and severity of cluster attacks, associated autonomic symptoms, and the use of acute rescue medication. The primary endpoint was the mean number of cluster attacks within the first week of treatment compared with placebo. Over five years, the authors prescreened 157 patients and randomized 116 to participate in the study, 57 to the prednisone group and 59 to the placebo group. The mean number of attacks within the first week of treatment was 25% less in the prednisone group (7.1; standard deviation [SD] 6.5 vs. 9.5; SD 6.0; P = 0.002) vs. placebo. In addition to improvement in the primary endpoint, the prednisone group also performed better in terms of the number of cluster attacks after 28 days (15.6 vs. 20.2), the number of cluster attacks after seven days (3.9 vs. 5.1), and the number of days with cluster attacks at 28 days (8.8 vs. 11.0). After seven days, cluster attacks had ceased in 35% of the prednisone group vs. 7% of the placebo group. At least a 50% reduction in attack frequency at day 7 was seen in nearly 50% of the prednisone group vs. only 15% in the placebo group. The need for acute medication also was higher in the placebo group.

There were no significant differences in the frequency or severity of adverse events between the two groups. The Clinical Global Impression scale showed significant differences between groups, with 15% of patients in the prednisone group (but none in the placebo group) rated as “normal” at seven days.

COMMENTARY

This study supports the clinical impression and prior societal recommendations that prednisone, starting with 100 mg and with gradual reduction over 17 days, is of value in the management of acute cluster attacks. Patients treated with prednisone reported significantly fewer cluster attacks, with more than one-third reporting complete cessation of attacks after seven days, nearly one-half reporting at least a 50% reduction in attacks, and marked reduction in the number of days with cluster attacks as well as the need for acute medication. Prednisone, given at 100 mg for five days and then tapering by 20 mg every three days, is a safe and effective short-term prevention for episodic cluster while waiting for longer-acting preventive agents to be initiated. The study was limited to small numbers in each group because of funding difficulties and the challenges of recruiting patients who may have been exposed to the treatment medications previously. The results need to be interpreted with caution since many patients with cluster headache will experience spontaneous remissions; limiting the study to patients with prior cluster periods lasting more than 30 days offsets this concern. In future studies, oral prednisone could be compared with occipital nerve block and other long-term preventive agents.