The last search was carried out in March 2024. The initial search resulted in 252 hits. After removal of duplicates, two independent reviewers screened the literature. In the case of diverging assessment, a third reviewer was consulted.

Five publications could be isolated that investigated the effect of ketamine on cluster headache. One publication on the use of ketamine in patients with refractory headaches included two cases with cluster headache; however, as no specific data were given for these two patients, we excluded this publication [30]. Therefore, four publications remained for further analysis [31,32,33,34]. The study flow chart is displayed in Fig. 1. The study characteristics are summarized in Table 2.

All included publications were case series. In total, 68 patients were reported to be treated with ketamine for cluster headache. No controlled studies are available yet.

In 2016, Granata et al. [31] published an observational study of 29 patients (2 women) with refractory cluster headache treated with ketamine. Sixteen patients had a diagnosis of episodic cluster headache and 13 had a diagnosis of chronic cluster headache. The patients were treated with intravenous R/S ketamine 0.5 mg*kg−1. Depending on the success of the therapy, the infusions were repeated up to four times. To prevent possible side effects, one third of the patients received 2.5 mg midazolam i.v. before ketamine was infused.

The treatment was well tolerated by all patients, and only mild or well-treatable side effects occurred. These included mild derealization, transient hypertension, bradycardic phases and mild to severe fatigue.

As a result of the therapy, 54% of patients with chronic cluster headache were free of attacks, with the effect lasting between 3 to 18 months. In all patients with episodic cluster headache, a termination of the episode was achieved.

Moisset et al. [32] published a case report on two patients whom they treated with ketamine and magnesium. Patient 1 was 45 years old at the time of treatment. He had been suffering from cluster headache for 6 years, with the disease having taken on a chronic form for 1 year. In an outpatient setting, the patient received a single dose of ketamine 0.5 mg*kg−1 in an infusion over 2 h. In addition, he was infused with 3 g magnesium sulfate within 30 min. The patient did not experience any side effects during this therapy. The next day, the patient was in complete remission, which lasted for 6 weeks. After these 6 weeks, the patient again had 6–10 attacks daily, which were successfully treated by electrical stimulation of the greater occipital nerve.

Patient 2 was 28 years old. This patient also received ketamine and magnesium sulfate in an outpatient setting the same way as patient 1, which improved his symptoms. The daily attacks were reduced by 50%. The remaining attacks were treated with oxygen only. Since then, the patient has received an infusion of ketamine and magnesium sulfate every 8 weeks.

In 2020, Moisset et al. [33] published data from a retrospective case series including 17 patients (14 men). All patients had been diagnosed with chronic cluster headache before, were > 18 years old and had suffered from the disease for at least 1 year. They were all treatment-refractory to at least three different preventive methods. All patients had an average of more than two attacks per day. Treatment with ketamine took place in a day clinic setting. The patients received a single dose of ketamine (0.5 mg*kg−1) as an infusion over 2 h. In addition, 3 g magnesium sulfate was infused over 30 min. The primary endpoint was the overall difference in the frequency of mean daily attacks between days 7 and 8 after the ketamine-magnesium infusion compared to the mean daily attacks for 2 weeks prior to the treatment. The main secondary endpoint was the proportion of patients with a ≥ 50% reduction in the frequency of daily acute episodes on days 7 and 8 post-infusion.

The number of daily attacks before the infusion was 4.3 ± 2.4. Seven and 8 days after a single infusion of the ketamine-magnesium combination, the number of daily attacks decreased clinically significantly (– 2.75 [95% CI: – 4.0 to – 1.75], P < 0.001) to 1.3 ± 1.0 attacks per day, corresponding to a reduction of 63.2% overall and 78.4% in responders. The analgesic effect started 1 to 6 (median = 3) days after infusion and lasted 2 to 68 (median = 4) weeks. Of these 17 patients, 13 (76.5%; 95% CI 56.3–96.6) had a ≥ 50% reduction in the frequency of daily episodes. In seven patients, the headaches disappeared completely (between 75 and 100% reduction), and in six patients the burden was reduced by at least 50%, measured by the average number of attacks per day. Of the four patients who did not respond to treatment, two showed no response within the first week and two experienced a reduction of 20.0–33.3% but failed to meet the study’s criteria for success.

None of the patients experienced hallucinations during the infusion, and although transient sedation was common (7/17 or 41.2%), none of the patients showed debilitating sedation 1 hour after the end of infusion. No bradycardia or high blood pressure was observed.

In 2021, Petersen et al. [34] published an open study investigating the effect of intranasal ketamine on acute cluster headache attacks. For this purpose, 23 patients diagnosed with chronic cluster headache were selected. Participants received 15 mg of ketamine every 6 min for a maximum of five doses, resulting in a maximum dose of 75 mg. Ketamine was only administered for attacks with an intensity of at least 6 on an 11-point numerical pain rating scale, where 0 is no pain and 10 is the worst pain imaginable. Patients received at least three doses of ketamine 6 min apart, with possibility of two additional administrations. However, if a patient was pain free or almost pain free (defined as NRS < 4), no further ketamine was administered. All participants were offered oxygen and/or sumatriptan as rescue medication 15 min after the first ketamine administration. The main finding of this study is that ketamine may be effective for acute cluster headache. After 15 min, the mean reduction of pain intensity was 15%, after 30 min 69%. Furthermore, their data suggest that intranasal application at the dosage used is probably safe from severe side effects.

Ten patients were included in this case series. Of these, eight identified as male and two as female. Both patients with episodic cluster headache (n = 6) and chronic cluster headache (n = 4) were included. The mean time since the first diagnosis was 12 ± 6.9 years. Patients’ characteristics are summarized in Table 3. Patients received an average of 4.1 ± 1.7 S-ketamine infusions with a mean frequency of 2.4 ± 1.3 infusions per week. The total number of infusions ranged from one to seven. The study results are summarized in Table 4.

All patients except two reported a complete pain-free interval. The duration however varied considerably, ranging from 1 to 26 months. Both non-responders suffered from chronic cluster headache, resulting in a success rate of 100% in the episodic cluster headache and in 50% in chronic cluster headache population. No side effects were reported.