Over the recent decades, the interest in intranasal delivery as a non-invasive route for drugs has increased. Since the nasal mucosa offers numerous benefits as a target tissue for drug delivery, a wide variety of therapeutic compounds may be administered intranasally for topic, systemic and central nervous system action.

Acute seizures, status epilepticus, and procedural sedation are all complex medical problems requiring multiple approaches for effective management. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. The clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity.4 Transmucosal delivery of generic benzodiazepines via the nasal mucosa offers an attractive and cost-effective alternative in the out-of-hospital setting.¹

Benzodiazepines enhance the effect of the neurotransmitter, GABA, at the GABAalpha (GABA A) receptor. Their binding causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity. Benzodiazepines do not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential.

This activity results in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties of benzodiazepines making them useful in treating seizures, anxiety, insomnia, agitation and muscle spasms, and as a premedication for medical or dental procedures.⁴,⁵

Benzodiazepines such as midazolam, diazepam and lorazepam are most commonly used in clinical practice. They differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used.⁴

Midazolam is the first short-acting, water-soluble benzodiazepine. It belongs to the class, imidazobenzodiazepines, and was synthesized by Fryer and Walser in 1976. Midazolam has a high affinity for the benzodiazepine receptor in the CNS, almost approximately twice the affinity of diazepam.6 Its unique chemical structure confers a number of physicochemical properties that distinguish it from other benzodiazepines in terms of its pharmacologic and pharmacokinetic characteristics (like rapid absorption and rapid metabolism). At physiological pH, midazolam becomes extremely lipophilic, accounting for its rapid onset of action and penetration into the CNS. Due to its chemical structure, the drug is oxidized by the liver much more rapidly than other benzodiazepines and, consequently, has a short duration of action.⁷,⁸

Midazolam may be administered intravenously, intramuscularly, by the rectal route, or via the nasal mucosa. The intravenous, intramuscular and rectal methods of administration carry some disadvantages in acute situations such as impracticality, variable absorption, and social limitations in rectal administration. Intranasal administration of midazolam has been of interest because of the rapid, reliable onset of action, predictable effects, and avoidance of injection.⁶

Administration of midazolam by the intranasal as an alternative to rectally administered diazepam is becoming increasingly popular for the emergency treatment of seizures in children. Midazolam has a fast recovery time, which makes it useful as a premedication for sedation. The intranasal route provides an easy and painless method of sedation. The anterograde amnesia property of midazolam is useful for premedication before surgery to inhibit unpleasant memories. Several studies have shown that intranasal midazolam is safe and effective in the treatment of seizures both, in and out of the hospital setting, and also as a sedative and anxiolytic pre-anaesthetic medication in children.⁷,⁸

Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Seizures can be associated with mortality and worse neurologic outcome.

Benzodiazepines, such as midazolam, diazepam and lorazepam, are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce the opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection.

Intranasal delivery of benzodiazepines is useful in reducing the time-to-drug administration and cessation of seizures in the pre-hospital setting, when patients with active seizures arrive in the emergency room, and at home where caregivers treat their dependents.¹³

Rectal diazepam has been used for the home and hospital treatment of acute seizures. Its use may be socially embarrassing and undesirable. Moreover, some special arrangement is required to administer it, which is difficult to arrange in homes, schools and daycare centres.

Midazolam, a benzodiazepine, has been described as an alternative rescue medication in the management of acute seizures. Recent studies have demonstrated intranasal midazolam to be effective in the management of acute childhood seizures as it easily crosses the nasal mucosa and the blood-brain barrier, resulting in a rapid rise in both the plasma and the cerebrospinal fluid concentrations.^1,14

Three open-labelled studies prospectively evaluated the time-to-seizure cessation with a dose of nasal midazolam.

Lahat and colleagues assessed intranasal midazolam in the treatment of acute childhood seizures in the emergency department. Children experiencing a generalized seizure lasting longer than 10 minutes were eligible for inclusion in the study. Of the 20 children participating in the study, intranasal midazolam successfully treated all but 1 patient, whose seizure was also refractory to diazepam and required phenytoin for seizure cessation. The mean time to seizure control with midazolam was 3.5 minutes (range, 2.5-5 minutes). There were no repeat seizures within 60 minutes of midazolam use.¹⁵

Kutlu et al. administered midazolam to 9 patients who were seen at an inpatient paediatric clinic or in the emergency department with a seizure lasting more than 10 minutes but less than 30 minutes in the emergency department. Seizures, both focal and generalized, were controlled within a mean time of 139.6 seconds. Only 1 patient required a second dose of midazolam, and all 9 patients experienced cessation.⁹

Fi?gin and colleagues administered intranasal midazolam to 16 children with an acute seizure lasting longer than 10 minutes. In 2 patients, there was a diagnosis of status epilepticus, defined by the authors as a seizure lasting longer than 30 minutes. Most of the patients (68.7%) experienced generalized tonic-clonic seizures, whereas 4 patients had simple partial seizures and 2 had febrile seizures. A single dose of midazolam administered by hospital personnel provided a positive response in 13 patients (81.8%), all of whom stopped seizing in less than 5 minutes and experienced no re-occurrence. Because of the positive response in >80% of patients, the authors concluded that intranasal midazolam is effective for the treatment of acute seizures in the hospital setting.¹⁶

Rectal diazepam is the most common rescue medication given to families for home treatment of seizures. Intranasal midazolam is also an effective rescue medication that can be given safely. A previous study demonstrated that intranasal midazolam controlled seizures better than rectal diazepam in the pre-hospital setting and resulted in fewer respiratory complications and admissions.

The aim of this study was to compare the effectiveness of intranasal midazolam with rectal diazepam for the home treatment of seizures in children by primary caretakers.

It was a prospective, randomized study. Patients' homes and a freestanding children's hospital served as a referral centre for five states. A total of 358 paediatric patients who visited a paediatric neurology clinic from July 2006 through September 2008 and were prescribed a home rescue medication for their next seizure were enrolled. Caretakers were randomized to use either 0.2 mg/kg of intranasal midazolam (maximum, 10 mg) or 0.3 to 0.5 mg/kg of rectal diazepam (maximum, 20 mg) at home for their child's next seizure if it lasted more than 5 minutes.

The primary outcome measure was total seizure time after medication administration. The caretakers' ease of administration and satisfaction with the medication were also assessed.

A total of 92 caretakers gave the study medication during a child's seizure (50, intranasal midazolam; 42, rectal diazepam).

A few studies have compared diazepam and midazolam in the prehospital or ED setting and have shown midazolam to be equally or more effective in treating seizure activity, sometimes with fewer adverse effects. Bhattacharyya and colleagues14 compared intranasal midazolam to rectal diazepam in 46 children who presented to the ED with febrile or afebrile seizures. A mean time to seizure cessation of 2.97