Pharmacodynamics of Nasal and Buccal Midazolam Using EEG

Study Overview
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Brief Summary
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Approximately 3 million individuals suffer from epilepsy in America alone and about 200,000 new cases of epilepsy in America are diagnosed each year (Epilepsy Foundation, 2005). Epilepsy can be defined as a condition in which a person has recurrent, unprovoked seizures. Prolonged or back-to-back repetitive seizures, known as acute repetitive seizures (ARS), are medical emergencies. ARS can occur unexpectedly, a circumstance for which quick and efficient antiepileptic drugs are needed for household and prehospital use. Currently, benzodiazepines are the antiepileptic drug of choice when dealing with ARS because they are proven to be efficient and take little time to work. Benzodiazepines can be administered by mouth, by vein via a needle (intravenously; IV), rectally, between the cheek and gum (buccally), or in the nose (intranasally; IN). The nasal formulation is not yet FDA-approved. The rectal treatment route has been commonly used for acute seizure treatment in past years, but recent studies propose that the nasal route for benzodiazepines may be better overall for home treatment and easier to administer (see Wermeling, 2009). For many out of hospital situations, nasal benzodiazepines can be more convenient and more comfortable than rectal treatment. In addition to the above benefits, nasal benzodiazepines are rapidly absorbed by the blood vessels in the nose and the time of drug administration and cessation of seizures may thus be reduced using nasal routes. This study sets out to characterize how fast buccal and nasal treatments begin to work on the brain by monitoring brain waves during administration of the drug, and to determine whether nasal or buccal administration is best.

Detailed Description
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Past out-of-hospital treatments for acute epileptic seizures have met with limited effectiveness, convenience, speed, and safety. The only FDA-approved treatment for acute repetitive seizures must be given rectally, but nasal or buccal midazolam have been shown to be at least as effective. The purpose of this study is to characterize the time to effect on brain activity of intranasal (or nasal) midazolam and compare it with buccal midazolam. This research will recruit patients with epilepsy who are undergoing EEG recordings for clinical purposes, including those with intracranial EEG. EEG will be evaluated during administration of buccal or nasal midazolam for augmentation of beta waves signifying action of midazolam on the brain, and the time to effect will be compared between buccal and nasal formulations. Subjects will be given a brief survey after the administration to evaluate sedation, discomfort and other adverse effects of the medication. This study will help characterize the action of nasal and buccal benzodiazepines and to determine the most effective method of administration.

Official Title
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Comparing the Pharmacodynamics of Nasal and Buccal Midazolam Using EEG

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: nasal Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adults undergoing extracranial EEG in an Epilepsy Monitoring Unit adults undergoing intracranial EEG in an Epilepsy Monitoring Unit adults with chronically implanted intracranial neurostimulators with the capacity for continuous intracranial EEG monitoring Exclusion Criteria: any patient on additional sedative medications (narcotics, other central nervous system depressants) any patient with documented sensitivity or adverse reaction to any benzodiazepine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nasal Midazolam<br>3 mg of the standard IV solution of midazolam (5 mg/mL) was given via a metered-dose nasal sprayer (6 sprays × 0.1 ml/spray, or 6 × 0.5 mg/spray) divided between the two nostrils within 1-2 min. During the EEG, vital signs (blood oxygen saturation, blood pressure, pulse and respiratory rate) were monitored and a nurse and a physician were available at all times. Subjects were monitored for 2 hours after administration of midazolam to ensure adequate recovery from sedation. | Drug: nasal Midazolam<br>* Intranasal and buccal administration of the standard IV formulation of midazolam (5mg/mL), administered via a metered dose sprayer at 0.1mL/spray (i.e. 0.5mg/spray). Administration will be via three sprays in each nostril (for nasal) or three sprays between the cheek and the gum per side (for buccal).<br>* Other names: Versed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 25% increase in total beta power for at least 1 minute at 10-30Hz | Quantitative and qualitative visual EEG analysis for benzodiazepine-induced beta activity, total power of  10-30 Hz activity | for 30 mins after administration of drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| beta activity at 10-12 Hz | Qualitative visual and quantitative EEG analysis for benzodiazepine-induced beta activity at bands of 10-12 Hz | for 30 minutes after drug administration | 
| beta activity at 30-40Hz | Qualitative visual and quantitative EEG analysis for benzodiazepine-induced beta activity at bands of 30-40Hz. | for 30 minutes after drug administration | 
| sedation | Subject perception of sedation will be evaluated using yes or no type questions, evaluation questions using a visual analogue scale (from 1 to 10) and open response questions. | for 30 minues after drug administration | 
| pain/discomfort | Subject perception of discomfort will be evaluated using yes or no type questions, evaluation questions on a visual analogue scale (from 1 to 10), and open-response questions. | for 30 minutes after drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Electroencephalography, Benzodiazepines, Midazolam