Intranasal Ketamine Effective in Cluster Headache

Steve Cimino

January 20, 2022

Intranasal ketamine may be a viable treatment option for acute cluster headache attacks, a pilot study has found, though it did not reduce pain intensity as quickly as initially anticipated.

"In clinical practice, intranasal ketamine might be a valuable tool for severely affected patients with insufficient response or intolerance to current first-line treatment," wrote Anja S. Petersen, MD, of the Danish Headache Center at Rigshospitalet-Glostrup (Denmark) and her coauthors. The study was published online ahead of print in Headache.

To assess ketamine's safety and efficacy in treating cluster headache attacks, the researchers launched a single-center, open-label, proof-of-concept study of 23 Danish patients with chronic cluster headache. Their average age was 51, 70% were males, and their mean disease duration was 18 years. Twenty of the participants suffered a spontaneous attack while under in-hospital observation and were treated with 15 mg of intranasal ketamine every 6 minutes to a maximum of five times.

Fifteen minutes after ketamine was administered, mean pain intensity (±SD) was reduced from 7.2 (±1.3) to 6.1 (±3.1) on an 11-point numeric rating scale, equivalent to a 15% reduction and well below the primary endpoint of a 50% or greater reduction. Only 4 of the 20 participants had a reduction of 50% or more, and 4 patients chose rescue medication at 15 minutes. However, at 30 minutes pain intensity was reduced by 59% (mean difference 4.3, 95% confidence interval, 2.4-6.2, P > 0.001), with 11 out of 16 participants scoring a 4 or below.

Eight of the 20 participants reported feeling complete relief from the ketamine nasal spray, while 6 participants reported feeling no effects. Half of the patients said they preferred ketamine to oxygen and/or sumatriptan injection. Seventeen patients (83%) reported side effects, but 12 of them classified their side effects as "few." No serious adverse events were identified, with the most common adverse events being dizziness, lightheadedness, nausea/vomiting, and paresthesia.

Debating Ketamine's Potential for Cluster Headache Patients

"I'm not crazy about the prospects," said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., in an interview. "It was an admirable proof-of-concept trial, and well worth doing. These are desperate patients. But if the aim was to decrease pain intensity within 15 minutes for cluster patients without side effects, this clearly did not do that," Dr. Tepper said.

"In a sense, this study was to evaluate whether glutamate might be a target for chronic cluster headache, to determine if blocking NMDA glutamate receptors by ketamine would be effective," Dr. Tepper said. "And I must say, I'm not very impressed."

He noted his concerns about the study – including 30 minutes being an "unacceptable" wait for patients undergoing a cluster attack, the 20% of patients who required a rescue at 15 minutes, and the various side effects that come with ketamine in nasal form – and said the results did not sway him to consider ketamine a practical option for cluster headache patients.

"You add all of that up, and I would say this was an equivocal study," he said. "There might be enough there to be worth studying in episodic cluster rather than chronic cluster; there might be enough to consider a randomized, placebo-controlled trial. But it's not something that I would ring the bell at Wall Street about."

"The acute treatment of a patient with chronic cluster headache is a real problem for us headache specialists," added Alan Rapoport, MD, professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, in an interview. "Cluster headache is probably the worst pain we deal with; women who've gone through childbirth say that cluster headache is worse. So it's very reasonable to have tried."

"It's not an impressive finding," he said, "but it does indicate that there's some value here. Maybe they need to change the dose; maybe they need to get it in faster by doing something tricky like combining the drug with another substance that will make it attach to the nasal mucosa better. I urge them to study it again, and I hope that they come up with better results the next time, because what they attempted to study is absolutely vital."

The authors acknowledged their study's limitations, including a homogeneous patient population and the lack of placebo-controlled verification of effect after 30 minutes. They added, however, that a pilot study like this provides "critical information and paves the way for subsequent placebo-controlled studies." They also admitted that "daily usage [of ketamine] seems suboptimal" because of the potential of patients becoming addicted.

The study was funded by CCH Pharmaceuticals. Several authors reported receiving speaker's fees and being subinvestigators in trials run by various pharmaceutical companies, including CCH Pharmaceuticals.

This article originally appeared on, part of the Medscape Professional Network.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.