Remimazolam, a novel drug, for safe and effective endoscopic sedation
Article information
Abstract
Remimazolam is a novel benzodiazepine with unique pharmacokinetic and pharmacodynamic properties, making it an ideal candidate for sedation during endoscopic procedures. Distinguished by its rapid onset and short duration of action, remimazolam offers a safer and more efficient alternative to traditional sedatives, such as midazolam and propofol, with fewer side effects, such as hypotension, bradycardia, and respiratory depression. This article reviews the characteristics of remimazolam and its practical advantages, including ease of use, quick recovery time, and minimal residual sedation, emphasizing its potential to improve patient safety and procedural efficiency in clinical endoscopy settings.
INTRODUCTION
Sedative medications are administered to patients during procedures to enable the effective performance of tests or treatments that may be painful or uncomfortable.1 According to the American Society of Anesthesiologists (ASA), sedation depth can be categorized into four levels: minimal sedation, moderate sedation (or conscious sedation), deep sedation, and general anesthesia. Moderate sedation is recommended to ensure the safety and efficiency of endoscopic procedures. During moderate sedation, patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No intervention is required to maintain a patent airway, and adequate spontaneous ventilation persists.2
The degree of sedation is continuous and nongradual, and the extent to which each patient is sedated varies significantly from person to person. Additionally, the possibility of unexpected drug responses highlights the importance of effective sedation during endoscopy. The characteristics of ideal sedatives include ease of use, rapid onset of action, rapid postadministration recovery, and minimal residual sedation.3 Rapid onset and recovery times contribute to the efficient operation of the endoscopy and recovery rooms, whereas minimal residual sedation increases patient safety upon leaving these areas. Midazolam, a benzodiazepine, is preferred because of its short onset of sedation, low risk of thrombophlebitis, and amnesic effects.4 However, the active metabolites of midazolam may prolong sedation time, especially with cumulative administration.5 Propofol, also known as 2,6-diisopropylphenol, is an intravenous (IV) anesthetic used for the induction and maintenance of general anesthesia.6 It is a preferred sedative for gastrointestinal endoscopy because of its faster recovery time than midazolam. However, side effects include anaphylaxis, bronchospasm, angioedema, temporary airway obstruction leading to apnea, and unstable blood pressure.
Remimazolam besylate, also known simply as remimazolam and marketed as Byfavo (Hana Pharm) in Korea, BYFAVO (Acacia Pharma) in the United States of America (USA), Anerem (Mundipharma) in Japan, Byfavo (PAION AG) in the European Union and Ruima (Yichang Humanwell) in China in China, is a benzodiazepine sedative. It is characterized by rapidly hydrolyzed ester linkages.7 Unlike midazolam, remimazolam produces inactive metabolites and has been developed as a soft drug that offers rapid action and a predictable recovery time.8,9 In the USA, remimazolam is approved for sedation induction and maintenance in adults for procedures lasting less than 30 minutes.10 It has recently been approved in the European Union as a sedative for adults11 and is authorized in Korea for use in short-term procedures, including anesthesia and endoscopy. In this article, we summarized the characteristics of remimazolam and investigated its efficacy as a sedative in endoscopic procedures.
PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES
Remimazolam exerts its sedative effect by binding to the benzodiazepine binding site on γ-aminobutyric acid (GABA) receptors in the brain within the central nervous system.12 Unlike other benzodiazepines, remimazolam does not selectively affect specific GABA receptor subtypes. It is characterized by a high clearance rate, small steady-state volume of distribution (Vss), short elimination half-life, and first-order linear pharmacokinetics. A key study comparing remimazolam to midazolam found that the mean Vss of remimazolam was significantly smaller (34.8 L vs. 81.8 L for midazolam), and its elimination rate was about three times faster.10 The terminal half-life of remimazolam is notably shorter (0.75 hours) than that of midazolam (4.29 hours). Remimazolam undergoes rapid and extensive metabolism, predominantly by tissue esterases (chiefly liver carboxylesterase), into an inactive metabolite (CNS 7054) with a substantially lower affinity than its parent compound.
The drug is primarily excreted in urine, with over 80% detected as a metabolite and less than 1% remaining unchanged within 24 hours.13 During the elimination phase, over 90% of remimazolam binds to plasma proteins, mainly serum albumin, with a terminal half-life of 37 to 53 minutes independent of body weight. The context-sensitive half-life of remimazolam is shorter than that of midazolam but similar to that of propofol. In addition, it is relatively independent of infusion duration. The pharmacokinetic properties of remimazolam appear to be unaffected by chronic kidney disease, age, sex, race, or weight.14 However, patients with severe hepatic impairment (Child-Pugh class C) exhibited a higher area under the concentration-time curve and lower clearance than those with normal hepatic function.14 The pharmacokinetic properties were not significantly different between patients with normal hepatic function and those with mild/moderate hepatic dysfunction (Child-Pugh classes A and B).
Remimazolam, when administered intravenously, activates GABA-A receptors featuring γ-subunits. This activation leads to an influx of chloride ions, causing neuronal membranes to hyperpolarize, thereby diminishing neuronal activity.15 Its influence on GABA-A receptors spans multiple subtypes (α1, α2, α3, α5) and mirrors the action of midazolam, albeit without specific subtype selectivity. Clinical evaluation of the sedative properties of remimazolam, assessed using tools such as the electroencephalogram beta ratio and modified observer’s alertness/sedation (MOAA/S) scores, consistently show a swift onset and resolution of sedation, which vary in intensity and duration based on the administered dosage.16,17 Comparative studies have highlighted that remimazolam induces a more immediate and profound state of sedation than does midazolam, along with a more rapid return to alertness.16 The MOAA/S score rapidly decreased from 5 to less than 2, indicating a transition from complete alertness to a state approaching unconsciousness within five minutes of starting a 35-minute infusion of remimazolam. Complete alertness was regained within 19 min of infusion discontinuation.
RECENT STUDIES ON THE SEDATIVE EFFECTS OF REMIMAZOLAM
Table 1 presents the results of two comparative studies on the effects of midazolam and remimazolam.18,19 A randomized double-blind study compared remimazolam with a placebo and open-label midazolam for sedation for outpatient colonoscopy in 461 patients, focusing on safety and efficacy.18 Remimazolam exhibited higher procedural success rates than placebo, necessitating fewer rescue medications and top-up doses, with a statistically significant difference in success rates. The time to achieve optimal sedation was shorter with remimazolam, and the patients experienced deeper sedation levels during the procedure. Recovery times were consistently shorter for remimazolam and patient recall of the procedure was similar across all groups, indicating effective sedation without significant effects on memory. The incidence of adverse events, particularly hypotension, was lower with remimazolam than with midazolam, with no significant differences in laboratory safety parameters between the treatment groups. In another multicenter, double-blind study, the safety and efficacy of remimazolam were compared with those of placebo and midazolam in the procedural sedation of patients classified as high-risk ASA III/IV undergoing colonoscopy.20 Remimazolam demonstrated superior efficacy in terms of procedural success (87.1%) compared with placebo (0%) and midazolam (13.3%), with a quicker onset of appropriate sedation and faster recovery to full alertness after colonoscopy. Patients treated with remimazolam required lower cumulative doses of fentanyl for pain control during the procedure and fewer rescue medications than patients in the other groups. The study concluded that remimazolam was safe and effective for procedural sedation in patients with high-risk ASA classifications undergoing colonoscopy, with a safety profile comparable to that of patients classified as low-risk.
Clinical trials of remimazolam for procedural sedation in patients undergoing colonoscopy
RECENT STUDIES OF REMIMAZOLAM COMPARED WITH PROPOFOL
Propofol is one of the most used agents for procedural sedation,21 and comparative studies have been conducted on the efficacy of propofol and remimazolam in endoscopy. Table 2 presents the results of comparative studies on the effects of propofol and remimazolam in older patients undergoing gastroscopy.22,23 In a recent meta-analysis that included seven randomized controlled trials, propofol demonstrated superior efficacy compared to remimazolam, whereas remimazolam showed superior safety.24 Propofol, acknowledged for its merits, including rapid onset, context-sensitive half-life, and predictable duration, is considered as useful as midazolam. Generally, it is well tolerated and favored owing to its quick recovery profile.4,25 However, because of its vasodilatory effects, propofol can induce severe hypotension, especially in older patients and those with cardiovascular diseases.26 In addition, the absence of a propofol antagonist requires caution in patients with respiratory depression.27 In contrast, remimazolam is less likely to cause severe respiratory depression.
Remimazolam versus propofol for procedural sedation in elderly patients undergoing gastroscopy
A multicenter randomized controlled trial involving older patients (65–85 years) undergoing upper gastrointestinal endoscopy compared remimazolam, tosilate, and propofol administered in conjunction with fentanyl.28 The primary focus was on the sedation levels and incidence of hypotension, bradycardia, and respiratory depression. The study found that remimazolam had significantly lower rates of hypotension (36.5% vs. 69.6%), bradycardia (1.5% vs. 8.5%), and respiratory depression (4.5% vs. 10.0%) and caused less pain at the injection site than propofol. These findings suggest that remimazolam is safer for older patients undergoing deep sedation.
In another trial, a 95% effective dose (ED95) for the induction of sedation in older patients undergoing outpatient gastroscopy was determined using remimazolam and propofol in combination with remifentanil.29 The ED95 for remimazolam was significantly lower than that for propofol, and the incidence of adverse events was considerably lower in the remimazolam group than in the propofol group (40.6% vs. 83.1%). However, the remimazolam group had a higher incidence of hiccups and a marginally shorter median time to awakening than did the propofol group. Propofol and remimazolam have distinct advantages that merit consideration when selecting procedural sedatives during endoscopy. According to a recent meta-analysis, propofol showed a considerably shorter time to loss of consciousness and a higher success rate of sedation after the initial dose. Conversely, remimazolam significantly reduced the incidences of bradycardia, hypoxemia, and pain at the injection site.30 Remimazolam may be a safer and more suitable alternative to propofol for sedation during endoscopy, particularly in older patients.
REMIMAZOLAM FOR SEDATION DURING ENDOSCOPY
The dose of remimazolam for inducing and maintaining sedation in adults is personalized and adjusted to attain the desired effect. The recommended dose for the induction of procedural sedation was 5 mg administered over 1 minute. If necessary, additional IV doses of remimazolam (2.5 mg) were administered over 15 seconds with a minimum interval of 2 minutes between each dose.8 For patients with an ASA-physical status (ASA-PS) score of III/IV, the induction dose would be reduced from 5 to 2.5 mg of remimazolam. Depending on the patient's condition, supplemental doses of 1.25 to 2.5 mg may be added as directed by the physician. In the European Union, when remimazolam is co-administered with opioids in adults under 65 years of age, the recommended dose is 5 mg for induction and 2.5 mg for maintenance,11 aligning with the recommendations in the USA. A starting remimazolam dose of 7 mg is recommended in the absence of concurrent opioid use. For patients with an ASA-PS score of III/IV, aged 65 years or older, or weighing less than 50 kg, an induction dose of 2.5 to 5 mg is recommended regardless of concomitant opioid medication, with subsequent doses of 1.25 to 2.5 mg.
The safety profile of remimazolam remains undefined as it is a newly introduced medication. Prescription guidelines for remimazolam caution against potential side effects during sedation, including hypoxia, bradycardia, and hypotension. Recent studies have reported anaphylaxis associated with remimazolam.24 It is possible that anaphylaxis could be caused by the excipient dextran-40 or remimazolam. Therefore, remimazolam should only be administered to individuals undergoing procedural sedation. Given the higher risk of anaphylaxis with rapid administration, careful consideration of both the dose and rate of administration is necessary. It is also important to continuously monitor the patient's vital signs not only during the sedation process but also throughout the entire period of recovery. The sedative effects of remimazolam can be counteracted by treatment with a benzodiazepine antagonist.31 The recommended initial dose of flumazenil is 0.2 mg to counteract benzodiazepine-induced sedation. This dose should be injected over 15 seconds to minimize side effects such as hypertension and anxiety. If the patient does not fully recover within 60 seconds, additional doses (0.2 mg) up to a maximum of 1 mg can be administered. The dosage is tailored based on the patient's response, with a maximum dose of 3 mg administered within an hour.32 Routine use of flumazenil to reverse remimazolam sedation is not recommended because of remimazolam’s potential for rebound sedation.33
Remimazolam is effective for inducing and maintaining procedural sedation, particularly during endoscopic procedures. It has emerged as a safe and efficacious alternative, showing substantial promise in replacing existing sedatives (Table 3). Midazolam and propofol are the preferred sedatives for procedural sedation during endoscopy were midazolam and propofol.34,35 However, research on the effectiveness of remimazolam across all areas of endoscopy, including therapeutic procedures, is ongoing, and results are fully expected.36,37 With the introduction of remimazolam, there is potential for the development of updated guidelines that reflect the outcomes of current and forthcoming studies on remimazolam in endoscopy.
Characteristics of propofol, midazolam, and remimazolam
CONCLUSIONS
Remimazolam, a novel short-acting sedative that has emerged from ‘soft drug’ development, is highly effective in inducing and maintaining procedural sedation. Its benefits such as rapid action, predictable duration, stable hemodynamics, and independence from organ function make it promising for various clinical applications. It has shown high success and tolerability in endoscopic procedures, significantly improving onset and recovery times compared to other methods. Based on a thorough review of recent guidelines and multiple studies, remimazolam may be particularly beneficial in patients with cardiovascular instabilities, including unstable blood pressure or arrhythmias caused by other sedatives. Its rapid onset and predictable pharmacokinetics allow for a smoother induction and recovery period, making it a preferable option for effectively managing procedural stress and discomfort. These advantages suggest that remimazolam can be used to improve endoscopy room operations and sedation practices. Understanding the full benefits, including cost-effectiveness, requires a thorough pharmacoeconomic analysis. We believe that remimazolam holds great promise as a standard sedative. However, its efficacy and safety across different settings require validation through comprehensive studies.
Notes
Conflicts of Interest
Jae Min Lee is currently serving as a KSGE Publication Committee member; however, he was not involved in the peer reviewer selection, evaluation, or decision-making processes for this article.
Funding
None.
Author Contributions
Conceptualization: KHL, JKL; Data curation: YP, DWA; Formal analysis: JML; Investigation: JML; Methodology: JKL; Project administration: KHL; Resources: JKL; Software: JML; Supervision: KHL; Validation: YP, DWA; Visualization: JML; Writing–original draft: JML; Writing–review & editing: YP, DWA, JKL, KHL.