Review: More Research Needed on Ketamine Treatment for Migraine

More research is needed to better understand the potential therapeutic benefits of ketamine among migraineurs, concluded authors of a systematic review and meta-analysis.

Results of a systematic review published in the Journal of Dental Anesthesia and Pain Medicine indicate more research is needed to assess the efficacy of ketamine in treating acute and chronic refractory migraines and other primary headaches (HAs) using intranasal and subcutaneous routes.

Migraine is the second leading cause of disability worldwide, and although numerous interventional and preventive treatments exist for the condition, these can result in varying degrees of efficacy, induce unwanted adverse events, and contribute to medication overuse headache.

These factors open a window of opportunity for alternative migraine treatments like ketamine, “an N-methyl-D-aspartate receptor (NMDAR) antagonist that acts on the central nervous system (CNS) and acts on other CNS receptors,” the researchers explained.

“The water and lipid solubility of ketamine allows for good bioavailability and multiple administration routes, including the intravenous (IV), intramuscular, oral, rectal, subcutaneous (SC), epidural, and intranasal routes,” they added.

Adverse events associated with ketamine administration can include laryngeal spasms and transient apnea, gastrointestinal, and cardiovascular effects, but they depend on the administration route, speed, and dosage. Hallucinations, dissociative anesthesia, and repeated anesthesia and analgesia leading to tolerance have also been reported.

Additional studies revealed that ketamine yielded benefits in other pain conditions, and recently, investigators showed a controlled dose of the substance improved cognitive function, making those in suicidal crises less likely to harm themselves.

Due to the interest in evaluating novel therapeutic options for primary HA management to improve quality of life, reduce the strain on emergency departments, and avoid lost work production, investigators carried out a systematic review and meta-analysis. Specifically, they sought “to determine the efficacy of ketamine compared to active intervention or placebo as a therapeutic agent for migraines and other primary HAs.”

All studies included were randomized controlled trials (RCTs) conducted on human participants. A total of 5 studies were included in the qualitative synthesis and 3 in the meta-analysis. Participant ages ranged from 18 to 65 years and the number of participants ranged from 17 to 54 (total N = 193). Studies were conducted in the United States, the United Kingdom, and Italy.

Two studies were determined to have an unclear risk of bias and 3 had a high risk of bias. “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” researchers concluded.

In addition, “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.” They continued, “in one trial, subcutaneous ketamine was superior to saline in migraine severity reduction; however, (IV) ketamine was inferior to IV prochlorperazine and diphenhydramine in another study.”

Among participants who received ketamine, feelings of unreality, fatigue, and nausea were among the most reported adverse events.

One investigation did show SC-administered ketamine resulted in statistically significant relief over saline placebo. Another showed intranasal ketamine improved the severity of migraine with aura, but not the duration in hours, compared with intranasal midazolam, the authors explained.

Additional studies with long-term follow-up are warranted to better understand the impact of ketamine on migraine severity and should also include patients with chronic or refractory migraine and other primary HAs. “Once the efficacy and the side effect profile of ketamine are established with additional research and follow-up, it may become a valuable tool in the management of migraine and other primary HAs,” the authors concluded.

“The studies included in this systematic review did not show ketamine to be uniformly superior to traditional treatments; however, varying amounts of benefits have been reported,” they said.


Chah N, Jones M, Milord S, Al-Eryani K, Enciso R. Efficacy of ketamine in the treatment of migraines and other unspecified primary headache disorders compared to placebo and other interventions: a systematic review. J Dent Anesth Pain Med. Published online October 1, 2021. doi:10.17245/jdapm.2021.21.5.413