Intranasal Ketamine for Acute Cluster Headache Attacks

Results From a Proof-of-concept Open-label Trial

Anja S. Petersen MD; Adam S. Pedersen BMEd; Mads C. J. Barloese MD, PhD; Per Holm PharmD, PhD; Ole Pedersen PharmD, PhD; Rigmor H. Jensen MD, DMSc; Agneta H. Snoer MD, PhD


Headache. 2022;62(1):26-35. 

In This Article

Abstract and Introduction


Objective: To investigate the safety and efficacy of intranasal ketamine for the treatment of a single cluster headache (CH) attack.

Background: Acute treatment options for patients with CH who have an insufficient response to oxygen and triptans are limited. Intranasal ketamine has anecdotally been successful in treating a CH attack.

Methods: We conducted an open-label pilot study enrolling 23 patients with chronic CH (International Classification of Headache Disorders, 3rd edition), and of these, 20 patients treated a single CH attack with intranasal ketamine. Under in-hospital observation, patients received 15 mg of intranasal ketamine every 6 min a maximum of five times. The primary endpoint was a 50% reduction in pain intensity within 15 min after initiating treatment.

Results: The primary endpoint was not met; 15 min after the first ketamine administration, the mean reduction in pain intensity was 1.1 (95% confidence interval [CI]: −0.6 to 2.7, p = 0.188) on the numeric rating scale (NRS), equivalent to a 15% reduction in pain intensity. However, 30 min after the first application, the pain intensity was reduced by 59% on an 11-point NRS (mean difference: 4.3, 95% CI: 2.4–6.2, p < 0.001, N = 16) and 11 out of 16 (69%) scored 4 or below on the NRS. Four patients received rescue medication 15 min after the first ketamine application and were therefore excluded from the analysis at 30 min. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No serious adverse events were identified during the trial.

Conclusion: Intranasal ketamine may be an effective acute treatment for CH at 30 min but should be tested in a larger controlled design. Patients and physicians should be conscious of the abuse potential of ketamine.


Acute treatment of cluster headache (CH) attacks usually consists of subcutaneous or intranasal triptans and inhaled oxygen.[1] Many patients benefit greatly from these first-line treatments; however, 20%–30% of patients are not adequately relieved by triptans and oxygen.[2,3] Trials of the triptans and oxygen have primarily been conducted in the episodic patient group, and large clinical series have demonstrated that patients with chronic CH (cCH) experience less effects from triptans and oxygen.[3] A few alternative therapies exist such as subcutaneous octreotide,[4] intranasal application of lidocaine or cocaine,[5] neurostimulation of the sphenopalatine ganglion[6] or the vagus nerve.[7] However, noninvasive vagus stimulation has no documented effect in cCH and is not available for all patients and the sphenopalatine device is, despite a previous well-documented effect, currently unavailable.[8] Octreotide use is hampered by long-term side effects.[9] Cocaine is obviously hindered by the abuse potential, and lidocaine was rated ineffective in more than half of the population.[2,10] In clinical practice, if oxygen and triptans are insufficient, then the treatment options are limited; thus, new treatments of CH are warranted especially for patients with cCH who are severely burdened.

Ketamine (R,S-2-chlorophenyl)-2-(methylamino)-(cyclohexanone hydrochloride) has been used since the 1970s and is currently used as an anesthetic and analgesic for chronic pain.[11] Esketamine (S-ketamine) has been approved in the United States and the European Union as an intranasal spray for the treatment of severe depression.[12] Case-based evidence indicates that intranasal-applied ketamine may be effective in the treatment of an acute CH attack.[13–15]

Based on the available literature, we hypothesized that intranasal ketamine is an effective acute treatment for CH attacks. The aim of this proof-of-concept study was to evaluate the effect and safety of intranasal ketamine as a potential acute treatment for CH attacks in patients with cCH.