Intranasal Delivery of Medications for the Treatment of Neurologic Conditions: A Pharmacology Update.

ABSTRACT: INTRODUCTION: Nurses have a central role in educating patients and families about treatment options and how to integrate them into action plans for neurologic conditions. In recent years, a growing number of intranasal formulations have become available as rescue therapy for neurologic conditions or symptoms including migraine, opioid overdose, and seizures. Rescue therapies do not replace maintenance medications or emergency care but are designed to enable rapid treatment of urgent or disabling conditions in community settings. Yet, discussion of rescue therapies for neurologic conditions remains limited in nursing literature. CONTENT: Intranasal formulations are specifically formulated for delivery and absorption in the nose and have several characteristics that are well suited as rescue therapies for neurologic conditions. Intranasal formulations include triptans for migraine, naloxone and nalmefene for opioid overdose, and benzodiazepines for seizure clusters in patients with epilepsy. Therapeutic attributes discussed here include ease of use in community settings by nonmedical professionals, relatively rapid onset of action, and favorable safety profile and patient experience. This information is critical for nurses to make informed decisions about rescue therapy options, incorporate these into plans of care, and educate patients, care partners, and other healthcare providers. CONCLUSION: Rescue therapies are increasingly important in the care of people with neurologic conditions. Various formulations are available and continue to evolve, offering easy and quick ways for nurses, patients, and nonmedical care partners to administer critical rescue medications. For nurses overseeing medication management, the attributes of intranasal rescue therapies should be considered in the context of providing patients with the right care at the right time.

Development of a novel dosing paradigm to model diazepam rescue therapy in preclinical seizure and epilepsy models.

Diazepam is a cornerstone immediate-use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose-dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain-to-plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long-acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology in rodent models of epilepsy. PLAIN LANGUAGE SUMMARY: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters.

Taking a Newer, Faster, Intranasal Route: A Narrative Review of Transitioning to a Less-Invasive Rescue Treatment for Seizure Clusters.

In the US, 3 rescue treatment options are approved for patients with seizure clusters (ie, acute repetitive seizures), which are intermittent increases of seizure activity. This narrative PubMed review of these 3 treatments examines newer intranasal options that are well suited for adolescent and adult patients who may desire a transition from rectal treatment. Diazepam rectal gel is indicated for patients ≥2 years, diazepam nasal spray for those ≥6 years, and midazolam nasal spray for those ≥12 years. Approvals for diazepam rectal gel and midazolam nasal spray were based on safety and efficacy comparisons with placebo. Approval for diazepam nasal spray was based on results from long-term safety and tolerability studies in addition to its comparable bioavailability to diazepam rectal gel, while also showing less interpatient variability. The safety profiles of diazepam rectal gel and nasal spray are similar, and the medications share safety, warning, and precaution labeling. Thus, patients ≥6 years could be introduced to intranasal diazepam, allowing for continuity of familiar treatment while improving access and comfort. Intranasal midazolam also has a well-characterized safety profile. A proxy for effectiveness is the number of seizure clusters that were treated with a single dose, and these differed in separate, noncomparative studies. The safety and effectiveness of diazepam nasal spray have been examined in multiple subpopulations, whereas patient/caregiver experiences with both approved intranasal formulations have been characterized. Users may prefer nasal administration because it is noninvasive and effective, and provides social advantages, comfort, ease of use, and less variability compared with rectal gel. Nasal sprays are portable and convenient for use in the community (school, work, travel), and self-administration was reported in one study, with patients as young as 11 years old self-administering diazepam nasal spray. These newer, intranasal rescue treatments for seizure clusters provide an alternative to the rectal route.

Alternative Approaches for Addressing Acute Agitation in Schizophrenia and Bipolar Disorder.

Importance: The prompt effective treatment of acute agitation among patients with schizophrenia or bipolar disorder can alleviate distressing symptoms for the patient and decrease the risk of escalation to aggression and the potential for serious harm to the patient, health care providers, and others.Observations: A commonly used approach for the management of acute agitation has been the intramuscular administration of antipsychotic medications and/or benzodiazepines. However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film. Two formulations of intranasal olanzapine for acute agitation are in development.Conclusions and Relevance: Intranasal formulations offer the potential for favorable pharmacokinetics and onset of action combined with ease of delivery obviating the need for injections and are thus consistent with patient-centered factors such as preference and self-administration. In this review, alternative methods of medication delivery are discussed, with an emphasis on the potential for intranasal administration to treat acute agitation in adult patients with schizophrenia or bipolar disorder.Prim Care Companion CNS Disord 2024;26(1):23nr03596. Author affiliations are listed at the end of this article.

Rapid Rescue Treatment with Diazepam Nasal Spray Leads to Faster Seizure Cluster Termination in Epilepsy: An Exploratory Post Hoc Cohort Analysis.

INTRODUCTION: Although prompt treatment of status epilepticus is standard of care, the effect of timing of rescue therapy administration for seizure clusters in epilepsy remains unknown. Seizure clusters are a rare but clinically important condition, and benzodiazepines are the cornerstone rescue therapy for seizure clusters in epilepsy. We characterized temporal patterns from a large dataset of treated seizure clusters in the safety study of diazepam nasal spray. METHODS: This post hoc analysis used timing data of treated seizure clusters recorded by care partners and patients in seizure diaries during a 1-year safety study. Data analysis used time from seizure start to administration of diazepam. RESULTS: From 4466 observations, 3225 had data meeting criteria for analysis. Overall, median times from seizure start to dose administration, dose administration to seizure termination, and total seizure duration were 2, 3, and 7 min, respectively. In seizure clusters treated in < 5 min (median 1.0 min), median time from dose to seizure termination was 2.0 min, and median total seizure duration was 4.0 min. Among seizure clusters treated in ≥ 5 min (median 10.0 min), median time to seizure termination was 10.0 min, and median total seizure duration was 23.0 min. Previously published safety results reported that over a mean participation of 1.5 years, 82.2% of patients had ≥ 1 treatment-emergent adverse events (TEAEs) irrespective of relationship to treatment, including 30.7% with serious TEAEs; 18.4% had TEAEs deemed at least possibly related to the study drug, none of which were serious. There were no events of cardiorespiratory depression. CONCLUSION: Echoing the importance of early use of benzodiazepines in status epilepticus, the findings from this exploratory analysis of patients with refractory epilepsy and frequent seizure clusters identify a potential benefit of early diazepam nasal spray treatment leading to faster seizure resolution within the seizure cluster. Trial Registration Information: ClinicalTrials.gov identifier NCT02721069 ( https://clinicaltrials.gov/ct2/show/NCT02721069 ).

Some people with epilepsy who take daily antiseizure drugs might still have seizures. Some of these seizures may be emergencies that can be treated with rescue medicine. For status epilepticus, rescue treatment should be given as soon as this seizure emergency is recognized. Seizure clusters are rare and might also become emergencies, but until now it had not been clear if earlier treatment would be better. Diazepam nasal spray is a rescue medicine approved to treat seizure clusters. The report used data from a study of the safety of diazepam nasal spray in people needing treatment ≥ 6 times a year. We looked at the time the seizure in a seizure cluster started to the time rescue treatment was given. We also looked at the time from taking rescue treatment to the time when that specific seizure stopped. For some seizure clusters, rescue medicine was given in < 5 min after the seizure started; on average, these seizures stopped within 2 min after rescue treatment. The total time from the start of the seizure in the seizure cluster to when it stopped was 4 min. In contrast, for seizure clusters treated after 5 min, the seizures stopped in an average of 10 min after treatment. Overall, these seizures lasted 23 min. In conclusion, this analysis found that seizures in a seizure cluster ended more quickly when diazepam nasal spray was given sooner. These findings are suggestive that select patients and caregivers should not wait to treat a seizure cluster once it has been identified.

Analyses of patients who self-administered diazepam nasal spray for acute treatment of seizure clusters.

For acute treatment of seizure clusters in patients with epilepsy, intranasal administration of acute seizure therapies has been shown to provide accessibility and ease of use to care partners as well as the potential for self-administration by patients. Diazepam nasal spray (Valtoco®) was approved by the US Food and Drug Administration for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Self-administration consistent with the prescribing information is feasible and was reported by a subgroup of patients (n = 27 of 163) in a long-term phase 3 safety study. Data regarding self-administration among these patients with seizure clusters are examined here to explore the safety profiles and measures of effectiveness, as well as the quality of life of those who self-treated. In addition, this focused look at patients who self-administered diazepam nasal spray may offer some insights into the characteristics of patients who may be appropriate for self-administration.

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study.

Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).

Use of intranasal rescue therapy for seizure clusters in students with epilepsy: Nurses' knowledge, perceptions, and practice.

School nurses play a crucial role in the prompt, appropriate response to epilepsy-related seizure emergencies among students in the school setting. Two intranasal benzodiazepine rescue therapies are now approved and offer potential benefits of being easy to use and socially acceptable. In July 2021, a survey was sent to 49,314 US school nurses to assess knowledge, perceptions, and practice with seizure rescue therapy. Responses were received from 866 (1.8% response rate). Of respondents, 45.7% had used rectal diazepam gel; 9.3%, midazolam nasal spray; and 6.0%, diazepam nasal spray. The majority (58.7%) had not delegated authority to administer rescue therapy, with state/local regulations and lack of willingness of school personnel being the most common barriers to delegation (37.7% and 20.1%, respectively). Additional training of nurses and school staff and progress on delegation policies may help optimize appropriate use of intranasal rescue therapy for seizures and enhance care of students with epilepsy in schools.

Acute seizure therapies in people with epilepsy: Fact or fiction? A U.S. Perspective.

Patients with epilepsy (PWE) may experience seizure emergencies including acute repetitive seizures despite chronic treatment with daily antiseizure medications. Seizures may adversely impact routine daily activities and/or healthcare utilization and may impair the quality of life of patients with epilepsy and their caregivers. Seizures often occur at home, school, or work in a community setting. Appropriate treatment that is readily accessible for patients with seizure urgencies and emergencies is essential outside the hospital setting. When determining the best acute antiseizure therapy for PWE, clinicians need to consider all of the available rescue medications and their routes of administration including the safety and efficacy profiles. Benzodiazepines are a standard of care as a rescue therapy, yet there are several misconceptions about their use and safety. Reevaluating potential misconceptions and formulating best practices are necessary to maximize usage for each available option of acute therapy. We examine common beliefs associated with traditional use of acute seizure therapies to refute or support them based on the current level of evidence in the published literature.

Acute Abortive Therapies for Seizure Clusters in Long-Term Care.

OBJECTIVES: To describe acute seizure treatment for the long-term care setting, emphasizing rescue (acute abortive) medications for on-site management of acute unexpected seizures and seizure clusters. DESIGN: Narrative review. SETTING AND PARTICIPANTS: People with seizures in long-term care, including group residences. METHODS: PubMed was searched using keywords that pertained to rescue medications, seizure emergencies/epilepsy, seizure action plans, and long-term care. RESULTS: Seizure disorder, including epilepsy, is prevalent in long-term care residences, and rescue medications can be used for on-site treatment. Diazepam rectal gel, intranasal midazolam, and diazepam nasal spray are US Food and Drug Administration (FDA)-approved seizure-cluster rescue medications, and intravenous diazepam and lorazepam are approved for status epilepticus. Benzodiazepines differ by formulation, route of administration, absorption, and metabolism. Intranasal formulations are easy and ideal for public use and when rectal treatment is challenging (eg, wheelchair). Intranasal, intrabuccal, and rectal formulations do not require specialized training to administer and are easier for staff at all levels of training compared with intravenous treatment. Off-label rescue medications may have anecdotal support; however, potential disadvantages include variable absorption and onset of action as well as potential risks to patients and caregivers or care partners. Delivery of intravenous-administered rescue medications is delayed by the time needed to set up and deliver the medication and is subject to dosing errors. Seizure action plans that include management of acute seizures can optimize the quality and timing of treatment, which may reduce emergency service needs and prevent progression to status epilepticus. CONCLUSIONS AND IMPLICATIONS: Seizure disorder is prevalent across all ages but is increased in older adults and in those with intellectual and developmental disabilities. Prompt intervention may reduce negative outcomes associated with acute unexpected seizures and seizure clusters. Seizure action plans that include acute seizures can improve the treatment response by detailing the necessary information for staff to provide immediate treatment.