Chronotherapeutic considerations of benzodiazepine administration for agitation management in the emergency department.

Objective: Agitation in the emergency department (ED) affects up to 2.6% of encounters, posing significant risks to patients and caregivers. This review investigates the impact of circadian rhythms on benzodiazepine (BZD) pharmacokinetics and pharmacodynamics, focusing on how dosing time influences outcomes in managing acute agitation.

Methods: A comprehensive literature search was performed using PubMed and Google Scholar (updated April 2024) to identify studies on BZD use in adult ED patients for acute agitation. Search terms included "antipsychotic agents," "lorazepam," "midazolam," "diazepam," and "emergency service." Studies focusing solely on substance intoxication were excluded. Priority was given to double-blind clinical trials, while open-label studies were included if no double-blind data were available. Referenced citations from identified publications were also reviewed.

Results: Twenty-nine studies met the inclusion criteria: 16 randomised, double-blinded placebo-controlled trials, 5 prospective open-label studies and 8 retrospective reviews. Of these, 22 studies either did not report the time of day of patient recruitment or recruited patients over a year-long time frame. Four studies that specified the time of day of patient recruitment suggested a possible circadian variation in BZD sedation efficacy. Additionally, three studies that reported recruitment months revealed potential seasonal patterns in sedation requirements and efficacy.

Conclusions: Circadian rhythms appear to influence BZD metabolism and therapeutic effects, which could have implications for optimising treatment strategies. Aligning BZD dosing schemes with biological timing may enhance treatment outcomes and minimise adverse effects. Further research is needed to validate these findings and develop personalised chronopharmacotherapy strategies for acute agitation in the ED.