Patients treated with 5-mg midazolam nasal spray were more likely than those given placebo to remain seizure free for 6 hours after treatment or have their seizure terminated within 10 minutes, with no recurrence seen from 10 minutes to 6 hours after the treatment.
Approved by the FDA in 2019 as the first nasally administered spray for treating seizure clusters, MDZ-NS is considered a rescue therapy in patients 12 years and older. Prior clinical trials have suggested the potential of the nasally administered spray as an effective alternative to standardized routes (intravenous/rectal), but the present researchers noted that there remains a paucity of evidence-based studies to support this hypothesis.
“It is proposed that MDZ-NS suppresses all types of epileptic seizures by increasing the gamma-aminobutyric acid (GABA) levels in the brain and can be absorbed consistently, rapidly, and extensively, which is crucial for seizure termination in seizure clusters to avoid the progression of status epilepticus,” they explained.
“It is widely known that many seizure-related emergencies occur outside of the health care settings, such as at home or in public places, so a convenient route of administration is essential, which has a rapid onset of action, is cost-effective, and is user friendly to caregivers or non–health professionals. So, in such cases, the intranasal route is beneficial because it is painless, noninvasive, and easy to access.”
The study authors conducted a systematic review and meta-analysis on published studies of the pharmacokinetic and pharmacodynamic profiles of MDZ-NS to further assess its efficacy and safety, as well as better understand the potential benefits of this newer medication in clinical use among patients with seizure clusters.
Studies accounting for outcomes of MDZ-NS among patients with epilepsy, published in the PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane, Embase, Google Scholar, ScienceDirect, and Ovid databases until October 31, 2022, were eligible for inclusion.
The primary outcomes assessed were potential benefits of the use of MDZ-NS and duration of benefits, such as either the patients remained free of seizures for 6 hours or more or the seizure was terminated within 10 minutes and had no recurrence between 10 minutes and 6 hours after drug administration. Secondary outcomes were the adverse event profile due to the use of MDZ-NS and long- and short-term safety profiles.
Three full-text articles were considered for the systematic review, of which 2 were included in the meta-analysis.
Compared with placebo, findings indicated that patients treated with 5-mg MDZ-NS were more likely to achieve the primary outcome of remaining seizure-free for 6 hours or more or having the seizure terminated within 10 minutes, wtih no recurrence observed between 10 minutes and 6 hours (risk ratio [RR], 1.54; 95% CI, 1.25-1.91).
The result was statistically significant, as a higher success rate was shown with the use of 5-mg spray compared with placebo (P < .0001). MDZ-NS was also found to be as safe as placebo (RR, 1.01 (95% CI, 0.67-1.53). No heterogeneity was detected in the results of the included studies (I2, 0%).
Pharmacokinetic and pharmacodynamic data suggested that up to 20 mg of MDZ-NS is safe and well tolerated in humans, but not more than 10 mg is advised to treat a single episode if the recommended dosage of 5 mg provides no response.
The small sample size for one of the included analyses in the meta-analysis was cited as a limitation of the study findings. There are also few studies comparing MDZ-NS with other antiseizure drugs, with the authors noting that blinded comparative trials between them would be complicated.
The researchers also intended to perform subgroup analysis depending on the dose and the duration of the studies, but could not due to a lack of data.
“It is expected that MDZ-NS is an effective alternative to currently established drugs as a rescue medication for seizure clusters, which may fulfill the unmet need of the current clinical epileptic regimen,” they concluded.
Niraj N, Mahajan S, Prakash A, Sarma P, Medhi B. The evaluation of the efficacy and safety of midazolam nasal spray in patients with seizure clusters: a systematic review and meta-analysis. Cureus. Published online January 22, 2023. doi:10.7759/cureus.34064