Emergency: Lack of Seizure Rescue Preparedness

Abstract

Evolution in the Prescription and Cost of Non-Intravenous Rescue Benzodiazepines for the Treatment of Seizure Emergencies

Sánchez Fernández I, Amengual-Gual M, Barcia Aguilar C, Khan TF, Gaínza-Lein M, Torres A, Rinat J, Douglass L. Epilepsia. 2025;66(3):648–661. doi:10.1111/epi.18232. Epub 2025 Feb 1.

Objective: The proportion of patients with epilepsy who have a non-intravenous rescue benzodiazepine (non-IV-rBZD) available for seizure emergencies is unknown. This study aims to describe prescription patterns from 2006 to 2022, factors associated with prescription, and the impact of recently introduced intranasal benzodiazepines on prescription and cost. Methods: Retrospective analysis of the MarketScan Database, a claims database of privately insured patients in the United States. Results: Among 213,384 patients (53% female, median (p25–p75) age: 33 (17–50) years) with epilepsy taking long-term anti-seizure medications with follow-up of 2.62 (1.54–4.73) years, only 30,371 patients (14.2%) had at least one non-IV-rBZD prescription. The proportion of patients with at least one non-IV-rBZD prescription was higher among: (1) younger patients (61.4% in the 0–5 year age group, 44.2% in the 6–12 year age group, 23.9% in the 13–21 year age group, 4.8% in the 22–35 year age group, 1.8% in the 36–50 year age group, 1.3% in the 51–60 year age group, and 1.0% in the older than 60 years age group); (2) patients with refractory epilepsy (24.3% vs 10.9% in non-refractory epilepsy); and (3) patients with more emergency department visits or hospital admissions for epilepsy (7.1% among patients with 0, 19.2% among patients with 1–3, and 31.1% among patients with more than 3). Multivariate analysis confirmed young age, refractory epilepsy, and emergency department visits or hospitalizations for epilepsy as strong independent predictors of having at least one non-IV-rBZD prescription. Prescriptions for intranasal midazolam and intranasal diazepam have increased rapidly; they had moderately increased the overall proportion of patients with a non-IV-rBZD prescription, whereas the inflation-adjusted cost of non-IV-rBZDs has markedly increased. Significance: The vast majority of patients with epilepsy have not filled a prescription for non-IV-rBZDs. Seizure emergency readiness can be markedly improved, especially among adults. The cost of non-IV-rBZDs has increased with intranasal rescue medications.

Commentary

Emergency preparedness is critical for a condition such as epilepsy—seizures are unpredictable. Seizure clusters have many potential adverse consequences on quality of life, Sudden Unexpected Death in Epilepsy, and emergency utilization. ¹ Fortunately, numerous benzodiazepine rescue options exist for seizure clusters or status epilepticus in the home setting. For example, rectal diazepam was approved by the Food and Drug Administration in the US in 1997 for patients aged 2 and up, then intranasal midazolam (age 12 and up) and diazepam (age 6 and up) followed suit in 2019–2020, each with at least 60% efficacy in terms of aborting seizure clusters. ²

However, limited data have captured whether and how rescue benzodiazepines are being implemented. Prior studies have documented that even in Emergency Medical Services settings, benzodiazepines tend to be underdosed. ³ But upstream in the outpatient setting—how often do patients even have a prescription?

Sanchez-Fernandez et al ⁴ recently studied this and related questions. They identified 200,000 patients in a large private insurance claims database (MarketScan) with administrative codes for epilepsy plus antiseizure medication fills between 2006 and 2022. Only about 14% of patients had any prescription for any nonintravenous rescue benzodiazepine at any point. They concluded that it seems less than ideal. This was reinforced by the fact that they used one of the most specific administrative claims definitions of epilepsy, requiring multiple diagnostic codes and multiple sustained antiseizure medication prescriptions for inclusion. Certain demographics had greater prescription rates, notably younger patients (eg, 30% to 40% of patients <5 years old vs. <1% to 2% of patients >60 years old), but also those with refractory epilepsy, emergency department visits, full-time employment, or chronic respiratory failure.

They next asked—how are benzodiazepine prescriptions changing over time? A major trend was the uptake of intranasal prescriptions, since midazolam and diazepam were approved in 2019–2020. Although follow-up in this database was more plentiful before the introduction of intranasal formulations, there was a noticeable uptick in prescriptions around then, with a fairly stable 6% to 7% of patients receiving a benzodiazepine prescription each year from 2006 to 2019, followed by an abrupt rise to about 13% by 2022. This corresponded to a rapid decline in rectal diazepam prescriptions starting around 2019 as intranasal formulations increased.

Finally, they described cost trends. Both average wholesale costs and out-of-pocket costs increased after the introduction of brand-name intranasal formulations.

So, who should receive rescue benzodiazepines, do these data suggest an implementation gap, and what can we do? Although definitions vary, typical definitions for seizure clusters and thus indications for rescue medications include back-to-back convulsions without return to normal in between or else at least 2 to 3 seizures within some time period (eg, 24 h), in addition to available definitions of status epilepticus such as convulsions exceeding 5 min. ⁵

However, determining the degree to which patients with a potential indication go without rescue prescriptions is a more difficult judgment, not directly answered by these data. Insurance claims data poorly capture whether patients have had convulsions or clusters, thus key covariates remain unmeasured. And while only about 20% of patients with refractory epilepsy codes (who might be expected to have stronger indications for rescue prescriptions) had a rescue benzodiazepine prescription in 2022, it does not appear that the data were analyzed according to a history of status epilepticus. Thus, while the data suggest that rescue prescriptions are uncommon overall, and likely a treatment gap exists, they do not exactly identify what percentage of patients with past seizure clusters or status epilepticus are dangerously going without rescue prescriptions. One older report, for example, found that about 30% of adults with epilepsy in a general neurology clinic who had at least 1 seizure in the past year reported at least 3 seizures in a 24-h period. ⁶ However, other data increase concern that most patients with seizure clusters do not receive rescue medications. ⁷ The challenge here is that definitions of seizure clustering vary, and given the difficulty in measuring the desired constructs of interest, it is difficult to get a clear denominator regarding what percentage of patients who clearly should have a rescue medication on hand do have one.

Another way of looking at the data is – should all patients with epilepsy have a rescue prescription to be safe rather than sorry? Or is it permissible for certain types of patients to forego rescue prescriptions, such as those without past seizure clusters or status epilepticus, or those with only nonmotor seizures? Prescriptions represent controlled substances, and even if out-of-pocket costs are typically low (average $26/prescription in 2022), the average wholesale cost in 2022 was a sizeable $720 per prescription.

Let's say there was a clear implementation gap, as is likely the case—what can we do? The question of how often patients have a rescue benzodiazepine prescription is intimately tied to how often patients have a Seizure Action Plan. Much like rescue benzodiazepines are likely underprescribed, Seizure Action Plans are also rare for children and adults alike. ⁸ While Seizure Action Plans and rescue treatments are not included in existing outpatient epilepsy quality of care guidelines, ⁹ it is still worth having an explicit conversation with all patients regarding their personalized risk of seizure clusters and what steps they should take under what parameters. Even if all the right patients had a rescue medication ready to go in their hands, simply having a prescription is still no guarantee of timely or proper use, which cannot be measured in administrative data like these; thus, the problem could go even deeper than described here.

One more caveat of this study is that generally, the analyses were conducted without considering buccal clonazepam. The rationale was that insurance claims do not inform whether as-needed clonazepam is prescribed for seizures versus anxiety. However, sensitivity analyses including buccal clonazepam did not change the overall story much. The major finding that stuck out to me was that whereas the average wholesale cost per prescription for intranasal prescriptions was on the order of $700, the average wholesale cost for buccal midazolam prescriptions was…$2 (!). Now, intranasal administration does have advantages by virtue of not having to administer anything into the oral (or rectal) cavity. But still, the enormous cost difference is something worth keeping in mind, as healthcare costs spiral upwards, given brand-name medications are known to be up to an order of magnitude more expensive than generic medications. ¹⁰

While conversations regarding which patients should receive rescue benzodiazepine and which type must be individualized, and it is encouraging that rescue benzodiazepines have increased since the introduction of intranasal formulations, these data likely highlight an important area for improvement.