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.

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.

Burning mouth syndrome (BMS) is a chronic oral disorder of unknown etiology which presents therapeutic challenges. Alpha-lipoic acid (ALA) has been studied as a potential treatment for BMS. The objective of this systematic review and meta-analysis was to evaluate the effectiveness of ALA compared to that of placebo or other interventions in individuals with BMS. Randomized controlled trials (RCT) using ALA to treat BMS were identified from MEDLINE, Cochrane Library, EMBASE, and Web of Science up to February 3, 2021.The assessment of the risk of bias in the included studies was based on the Cochrane guidelines. The primary outcome evaluated was the visual analog scale (VAS) pain intensity. ALA was compared with placebo, clonazepam, gabapentin, pregabalin, ALA plus gabapentin, capsaicin, Biotène®, and laser therapy. Altogether, 137 records were scanned for inclusion/exclusion, and nine RCTs (two unclear and seven at high risk of bias) were included in the qualitative and quantitative analyses, with a total of 594 patients with BMS included in this review. All studies reported an improvement in VAS pain scores ranging from -0.72 to -2.77. Meta-analysis results showed a non-significant reduction in pain intensity for ALA (P = 0.616) compared to that of placebo on a VAS of 0–10. Patients taking ALA were 1.923 times more likely to show an improvement in self-reported BMS symptoms (P = 0.031) than those in the placebo group. Clonazepam and pregabalin showed a significant VAS pain reduction of 4.08 and 4.68 (P < 0.001), respectively, compared to that with ALA. Although ALA intervention provided a non-significant improvement in the pain score and was more likely to produce a reduction in BMS symptoms, the evidence was of low quality. Further research is needed to establish clear guidelines for the use of ALA for BMS treatment.