Efficacy of ketamine in the treatment of migraines and other unspecified primary headache disorders compared to placebo and other interventions: a systematic review

Abstract

Background Migraine headaches are the second leading cause of disability worldwide and are responsible for significant morbidity, reduction in the quality of life, and loss of productivity on a global scale. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of ketamine on migraines and other primary headache disorders compared to placebo and other active interventions, such as midazolam, metoclopramide/diphenhydramine, and prochlorperazine/diphenhydramine. Methods An electronic search of databases published up to February 2021, including Medline via PubMed, EMBASE, Web of Science, and Cochrane Library, a hand search of the bibliographies of the included studies, as well as literature and systematic reviews found through the search was conducted to identify randomized controlled trials (RCTs) investigating ketamine in the treatment of migraine/headache disorders compared to the placebo. The authors assessed the risk of bias according to the Cochrane Handbook guidelines. Results The initial search strategy yielded 398 unduplicated references, which were independently assessed by three review authors. After evaluation, this number was reduced to five RCTs (two unclear risk of bias and three high risk of bias). The total number of patients in all the studies was 193. Due to the high risk of bias, small sample size, heterogeneity of the outcomes reported, and heterogeneity of the comparison groups, the quality of the evidence was very low. One RCT reported that intranasal ketamine was superior to intranasal midazolam in improving the aura attack severity, but not duration, while another reported that intranasal ketamine was not superior to metoclopramide and diphenhydramine in reducing the headache severity. In one trial, subcutaneous ketamine was superior to saline in migraine severity reduction; however, intravenous (I.V.) ketamine was inferior to I.V. prochlorperazine and diphenhydramine in another study. Conclusion Further double-blind controlled studies are needed to assess the efficacy of ketamine in treating acute and chronic refractory migraines and other primary headaches using intranasal and subcutaneous routes. These studies should include a long-term follow-up and different ketamine dosages in diagnosed patients following international standards for diagnosing headache/migraine.

Trial protocol for a multicenter randomized controlled trial to assess the efficacy and safety of intravenous ketamine for chronic daily headaches: the “KetHead” trial

“…Despite recent evolutions in the pharmacological and interventional management of CDH patients, many patients remain refractory to these treatments and/or cannot afford them. Recent evidence shows that infusions of ketamine in high doses and a prolonged duration of treatment could have a positive effect on refractory chronic pain [ 10 ], but the quality of evidence for efficacy in CDH is low [ 17 ].…”

“…The incidence of reported ketamine-induced adverse effects in the recent literature is high, regardless of the type of administration or dose, and has mostly included psychomimetic effects. Most adverse effects were mild and resolved after decreasing the dose or ending the treatment [ 17 ].…”

“…Recently, ketamine administered through IV and other routes has been investigated for its role in refractory headaches in observational studies [11][12][13] and a few small randomized controlled trials (RCT) [14][15][16]. This evidence suggests analgesic benefit, but it is of low quality, and there is considerable heterogeneity across the studies in terms of indications, dose, and route of administration of ketamine and the pain-associated domains that have been assessed [17]. Recent evidence also shows that infusions of ketamine 1 mg kg −1 h −1 are associated with greater and sustained pain relief as compared to only a bolus and or low-dose infusion regimens [8,10,17].…”

“…Recently, ketamine administered through IV and other routes has been investigated for its role in refractory headaches in observational studies [ 11 – 13 ] and a few small randomized controlled trials (RCT) [ 14 – 16 ]. This evidence suggests analgesic benefit, but it is of low quality, and there is considerable heterogeneity across the studies in terms of indications, dose, and route of administration of ketamine and the pain-associated domains that have been assessed [ 17 ]. Recent evidence also shows that infusions of ketamine 1 mg kg −1 h −1 are associated with greater and sustained pain relief as compared to only a bolus and or low-dose infusion regimens [ 8 , 10 , 17 ].…”

Real-world study of intranasal ketamine for use in patients with refractory chronic migraine

“…8 To date, several randomized control trials (RCTs) have been published on subanesthetic ketamine infusion for headache management. 9 Since 2000, Thomas Jefferson University Hospital has been using subanesthetic ketamine infusions for multiple chronic pain conditions, including chronic regional pain syndrome and headache. We published several retrospective cohort studies demonstrating ketamine infusion's potential utility in managing rCM.…”