Adjunctive oral prednisone appears to significantly reduce cluster headache attacks, new research shows.
Results of the multicenter, randomized, double-blind trial show that patients who received the steroid had 25% fewer attacks in the first week of therapy compared to their counterparts who received placebo.
In addition, more than a third of patients in the prednisone group were pain free, and for almost half, headache frequency was reduced by at least 50% at day 7 of treatment.
These findings provide clear evidence that prednisone, in conjunction with the use of verapamil, is effective in cluster headache, lead author Mark Obermann, MD, director, Center for Neurology, Asklepios Hospitals Seesen, and associate professor, University of Duisburg-Essen, Germany, told Medscape Medial News.
The key message, he added, is that all patients with cluster headache should receive prednisone at the start of an episode.
The study was published online November 24 in The Lancet Neurology.
Cluster headaches are intense unilateral attacks of facial and head pain. They last 15 to 180 minutes and predominantly affect men. They are accompanied by trigeminal autonomic symptoms and are extremely painful.
"They're referred to as 'suicide headaches' because the pain is so severe that patients often report they think about killing themselves to get rid of the pain," said Obermann.
The cause is unclear, although there's some evidence that the hypothalamus is involved. The headaches sometimes follow a "strict circadian pattern," said Obermann. He noted that the attacks might occur over a few weeks or months and then not return for months or even years.
An estimated 1 in 1000 people experience cluster headache, but the condition is underrecognized, and research is scarce and poorly funded. Previous research does show that the calcium channel blocker verapamil, which is used to treat high blood pressure, is effective in cluster headache. However, it takes about 14 days to work and has to be slowly titrated because of cardiac side effects, said Obermann.
For these reasons, international guidelines recommend initiating short-term preventive treatment with corticosteroids to suppress, or at least lessen, cluster headache attacks until long-term prevention is effective.
Although some clinicians treat cluster headaches with corticosteroids, others don't because of a lack of evidence that shows they are effective.
"There's no evidence whatsoever on what the correct dose is or whether it helps at all. This is the gap we wanted to close," said Obermann.
The study included 116 adult patients with cluster headache from 10 centers who were experiencing a cluster headache episode and were not taking prophylactic medication.
The trial only included patients who had had an attack within 30 days of their current episode. The investigators included this restriction to reduce the possibility of spontaneous remission, which is "a big problem" in cluster headache trials, he said.
To confirm that episodes were cluster headache attacks, patients were also required to have moderate to severe pain, indicated by a score of at least 5 on a numerical rating scale in which 0 indicates no pain and 10 indicates the worse imaginable pain.
Participants were allowed to use treatments for acute attack, but these therapies were limited to triptans, high-flow oxygen, intranasal lidocaine, ergotamine, and oral analgesics.
Patients were randomly assigned to receive oral prednisone (n = 53) or placebo (n = 56). The study groups were matched with respect to demographic and clinical characteristics.
Prednisone was initiated at 100 mg/d for 5 days and was then tapered by 20 mg every 3 days in the active treatment group.
All patients also received oral verapamil at a starting dose of 40 mg three times per day. The dose was increased every 3 days by 40 mg to a maximum of 360 mg/d.
All participants received pantoprazole 20 mg to prevent the gastric side effects of prednisone. An attack was defined as a unilateral headache of moderate to severe intensity. The study lasted 28 days.
The study's primary outcome was the mean number of cluster headache attacks during the first week of treatment with prednisone vs placebo.
The mean number of attacks during the first week of treatment was 7.1 in the prednisone group and 9.5 in the placebo group, for a difference of –2.4 attacks (95% CI, –4.8 to –0.03; P = .002).
"This might not sound like much," but reducing the number of daily attacks from, say, eight to six "really makes a difference because the attacks are so painful," said Obermann.
The prednisone group also came out on top for a number secondary outcomes. After the first 7 days, attacks ceased in 35% of the prednisone group, vs 7% in the placebo group.
"Clear Evidence" of Efficacy
About 49% of patients who took prednisone reported a reduction of at least 50% in attack frequency at day 7. By comparison, 15% of patients who received placebo reported such a reduction. The number of cluster attacks at day 28 was less in the prednisone group than in the patients who received placebo.
With respect to treatment effect, the difference between prednisone and placebo gradually lessened over time "in parallel to the verapamil dose reaching its therapeutic effect," the investigators note. "Therefore, attack frequency reduction slowly converged between groups," they add.
The study results provide "clear evidence" and should reassure clinicians that short-term prednisone early in a cluster headache attack is effective, said Obermann.
Adverse events (AEs), which included headache, palpitations, dizziness, and nausea, were as expected and were similar in the two groups. There were only two severe AEs, both of which occurred in participants in the placebo group.
Obermann said the investigators were surprised that so many patients in the study were taking analgesics. "Analgesics don't work in cluster headache; they just don't work in this kind of pain," he said.
He noted that prednisone exposure of study patients spanned only 19 days and amounted to only 1100 mg, which he believes is safe.
The prednisone dose used in the study is "what most clinicians use in clinical practice," although there have been reports of success using 500 mg of intravenous prednisone over 5 days, said Obermann.
He added that it would be "interesting to see if 50 mg would be just as good" as a starting dose.
Potential limitations of the study include the fact that the majority of participants were White, so the findings may not be generalizable to other populations.
In an accompanying editorial, Anne Ducros, MD, PhD, professor of neurology and director of the Headache Center, Montpellier University Hospital, Montpellier, France, says the study provides "strong and long-awaited evidence supporting the use of oral steroids as a transitional treatment option."
The trial "raises many topics for future research," one of which is the long-term safety of prednisone for patients with cluster headache, says Ducros. She notes that use of high-dose steroids once or twice a year for 15 years or more "has the potential for severe systemic toxic effects," such as corticosteroid-induced osteonecrosis of the femoral head.
Other questions about corticosteroid use for patients with cluster headache remain. These include understanding whether these agents provide better efficacy than occipital nerve injections and determining the optimal verapamil regimen, she notes.
In addition, the risk for oral steroid misuse needs to be studied, she says. She notes that drug misuse is common among patients with cluster headache.
Despite these questions, the results of this new study "provide an important step forward for patients with cluster headache, for whom safe and effective transitional therapies are much needed," Ducros writes.
Obermann has received fees from Sanofi, Biogen, Novartis, Teva Pharmaceuticals, and Eli Lilly and grants from Allergan and Heel Pharmaceuticals outside of this work. Ducros has received fees from Amgen, Novartis, Teva, and Eli Lilly; grants from the Programme Hospitalier de Recherche Clinique and from the Appel d'Offre Interne of Montpellier University Hospital; and nonfinancial support from SOS Oxygene.
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Cite this: 'Clear Evidence' Oral Steroid Effective for 'Suicide Headache' - Medscape - Dec 01, 2020.