Rectal Diastat (dye-ah-stat) is the best known treatment for acute repetitive seizures (bout or cluster of seizures with retention of consciousness in between seizures). Yet, there are other “off-label” medications under discussion and being researched for the treatment of acute repetitive seizures. One of those off-label medications is intranasal midazolam.
What is a Seizure Emergency?
A seizure emergency is a prolonged seizure or continuous state of seizure or frequently occurring seizures. One common type of seizure emergency is called status epilepticus (SE). SE is defined as a prolonged seizure lasting longer than 30 minutes, though many experts now say a seizure lasting longer than 10 minutes constitutes SE. SE is also diagnosed when there is a series of repeated seizures without the return of consciousness in between seizures. SE is a medical emergency, carrying high morbidity and mortality (1,2). Because the duration of SE greatly impacts outcome, early intervention can decrease morbidity and mortality. Alldredge et al. found that pre-hospital treatment of status epilepticus by emergency medical technicians (EMTs) not only reduced seizure duration, but also reduced the incidence of respiratory complications (3).
Another type of seizure emergency is acute repetitive seizures, which is a bout or cluster of seizures over a short period of time in which the patient regains consciousness between seizures. Diastat is the only FDA-approved drug for acute repetitive seizures.
What is Diastat?"
The active ingredient in Diastat is diazepam (dye-az-eh-pam), which is a widely used drug for the acute management of all types of seizures in both adults and children. Diazepam was first used in the United States in 1968. It subsequently was widely used intravenously in hospitals to treat prolonged seizures or status epilepticus. In the mid 1990s a rectal form of diazepam, Diastat, was tested for treatment of acute repetitive seizures outside the hospital. “Diastat was approved by the FDA for the treatment of acute repetitive seizures, but has been used by clinicians to treat febrile seizure and status epilepticus”, said William R. Garnett, Pharm D., Professor of Pharmacy & Neurology, Virginia Commonwealth University, Medical College of Virginia.
Diazepam has a short duration of action when given intravenously but an intermediate duration of action when administered rectally. Injections by auto-injectors into the thigh have been shown to have rapid absorption and are under development at the present time. The pill form (best known by the brand name Valium, but also available in many generic forms) is too slowly absorbed when taken by mouth to be used to stop an ongoing seizure, and is only moderately effective against preventing seizures from occurring. Further, when diazepam pills are used daily, they become less effective, and dependence also becomes a potential problem. The liquid form of diazepam can be useful in treating acute repetitive seizures, but the patient must be sufficiently alert to ensure that the dose is swallowed and that none of the liquid goes into the lungs.
Diastat is a gel that is inserted into the patient's rectum to stop a cluster of repeated seizures. Similar products are available in the UK and elsewhere. Emergency personnel sometimes give diazepam by injection to stop prolonged or repeated seizures. Diastat was approved by the United States Food and Drug Administration (FDA) in 1997 for acute repetitive seizures.
What is Midazolam?
Midazolam is a water-soluble benzodiazepine and was initially used as an anesthetic agent in patients undergoing various diagnostic and minor surgical procedures. When administered intranasally, midazolam is rapidly, but variably, absorbed through the lining of the nose into the bloodstream. From there it travels directly to the brain where it acts on the GABA mechanism to inhibit the seizure activity.
Margaret Kyrkou and colleagues in South Australia recently studied pre-hospital (in the community) treatment of prolonged seizures with intranasal midazolam (INM) (4). Kyrkou et al. developed a training package to be used by educational staff as well as by parents, and caregivers. The training package included four components, (1) an overview of epilepsy including definition and types of seizures, (2) training on how to give INM, (3) a folder containing a medical order stating the dose and time, when an ambulance should be called, pictures of INM administration and a detailed description of the individual’s seizure disorder, and (4) a survey.
The focus of the survey was to determine how caregivers and parents perceived using both rectal diazepam and INM to treat a prolonged seizure (note that neither Diastat nor INM are FDA-approved at present to treat a prolonged seizure, and emergency medical treatment should be sought in the event of a prolonged seizure). For the purposes of the study, Kyrkou and colleagues selected parents and caregivers who had administered both rectal diazepam and INM. “33 of the 47 participants in the study preferred INM, 7 preferred RD, 5 were happy with either and 2 preferred neither,” said Kyrkou. According to Kyrkou “the reasons for preferring INM were that it was less intrusive, gave greater privacy, was easier to administer, particularly to a person in a wheelchair, control of the seizure was faster, and effects wore off faster. “None of the parents thought INM took over 10 minutes to start to have an effect, compared with 47% of rectal diazepam taking over 10 minutes.” She believes the fast acting nature of intranasal midazolam provides parents a sense of comfort, “Knowing they have a safe and reliable means of controlling a prolonged seizure in the community has given parents and care givers a sense of comfort that they did not previously experience when rectal administration of emergency anticonvulsants [such as diazepam] was required.”
In another study, Lahat et al. (5) compared midazolam given intranasally with diazepam given intravenously for the treatment of febrile seizures. Intranasal midazolam was given for 26 episodes of febrile seizures in 21 children and intravenous diazepam for 26 episodes in 23 children. Results showed that both INM and intravenous diazepam were equally effective at stopping seizures. However, they found a significant difference between the time of treatment and control of seizures. Time from arrival at hospital to treatment was faster in the midazolam group, which intuitively makes sense because it takes less time to administer midazolam intranasally than it does to establish an IV line. But the time it took to stop the seizures was in fact faster with intravenous diazepam.
The Drawbacks of Intranasal Midazolam
While there may be benefits to administering intranasal midazolam over rectal diazepam, there are drawbacks too. James C. Cloyd, Pharm D., Weaver Endowed Chair-Orphan Drug development, Director, Epilepsy Research & Education Program, College of Pharmacy, University of Minnesota said, “Intranasal midazolam has some short-comings. The commercial formulation of midazolam is acidic and there have been complaints of mild nasal irritation because of the acidity. Also, intranasal midazolam is not very concentrated (5 mg/ml). In fact, the capacity of the nose to handle a liquid is ½ (about 0.250 ml per nostril) ml-- no more. Therefore, a lot of the fluid will end up being swallowed. Because of variable absorption from the intestine, it may be difficult to determine the optimal dose for a patient. In addition, midazolam has a short half-life which means the body will eliminate it fairly quickly and a second dose may be required.” He believes INM and diazepam given intranasally need to be investigated more carefully in a blinded control study to determine the real efficacy and safety in treating prolonged or repetitive seizures outside the hospital.
Garnett agreed with Cloyd in terms of potential shortcomings of intranasal midazolam stating, “The problem is, how do you give it to someone who is seizing?” As for diazepam he believes the future route of administration may lie in the autoinjection delivery system. Similar to the EpiPen, the autoinjector injects diazepam intramuscularly in the outer thigh region. It is currently commercially available for military use, but is not FDA approved. The autoinjector delivery system is undergoing clinical trials.
Take Home Message
While preliminary, uncontrolled studies using intranasal midazaolam as a pre-hospital treatment for a seizure emergency show promising results, it is important to remember that these results need confirmation in larger controlled trials. Use of intranasal midazolam may be warranted in treating seizure emergencies by medical professionals when other approaches are not practical or possible. Patients, caregivers, and their physicians should be aware that there is limited information about intranasal midazolam and that careful monitoring of therapy by a health care provider is warranted.
The availability of therapy to treat seizure emergencies such as acute repetitive seizures at their onset outside of the hospital has been an important advance in epilepsy. Rectal diazepam is the only drug currently approved for this use. However, while some caregivers and patients object to this mode of therapy, Cloyd cautions that “Controlled clinical trials are needed that demonstrate the effectiveness and safety of other drugs and alternate routes of administration, such as intranasal midazolam, before these therapies can be recommended.”
DeLorenzo RJ, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46(4):1029-35.
Reviewed and revised March 2005 by Steven C. Schachter, M.D., William R. Garnett, Pharm D., James C. Cloyd, Pharm D., epilepsy.com Editorial Board.
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