The neurotransmitter gamma aminobutyric acid (GABA) reduces the excitation of neurons, and an entire class of anesthetic agents functions by interacting with GABA receptors; they are GABA receptor “agonists.” The anesthetic propofol, for example, decreases the rate of GABA dissociation from its receptor, thus prolonging the inhibition of neuron excitation.¹ Propofol has a few drawbacks, including pain on injection and its association with bradycardia (abnormally slow heart action) and respiratory depression.² Two other medications that are GABA receptor agonists are midazolam and remimazolam. 

Midazolam is another GABA receptor agonist that bypasses some of propofol’s shortcomings, though it has shortcomings of its own. Used for a variety of medical conditions including seizures, end of life care, and anesthesia before a surgical operation, midazolam does not typically cause more pain at the injection site than other anesthetic agents in its class. It can, however, cause impaired memory, especially in the elderly, and, in some patients, can paradoxically cause anxiety and involuntary movements.³ 

Remimazolam, a newer anesthetic, might resolve some of these complications. Remimazolam is structurally similar to midazolam, but preliminary trials have shown that there are minimal residual effects in patients, even for prolonged infusions.² This is on account of the drug’s first order kinetics, which means that a constant proportion of the drug is eliminated per unit time. In other words, more remimazolam is eliminated in higher doses, thus precluding the possibility of prolonged effects.⁴ 

  A recent paper analyzed the data from clinical trials for remimazolam, in which patients undergoing colonoscopy and bronchoscopy were separated into groups and received either remimazolam, midazolam, or a placebo.⁵ The trials took a number of factors into consideration, such as onset time, recovery time, total sedation time, and cognitive function. 

In their paper, Dao et al. marshal the results of these trials to argue that remimazolam offers significant advantages over midazolam. Onset and recovery time were significantly lower in patients treated with remimazolam compared to those who were administered midazolam. These data points largely remained true whether the dose of midazolam administered was the “on-label” dose, the dose prescribed by the FDA, or the higher “real-world” dose, the dose typically used in medical practice. While total sedation time was not significantly different, patients with remimazolam experienced significantly less post-treatment cognitive decline, as determined by their scores on the Hopkins Verbal Learning Test – Revised (which measures verbal learning and memory and provides scores for multiple categories such as recall and retention)⁶.  

The authors acknowledge that their study has several limitations. The study was a post hoc analysis: the data was generated from an earlier clinical trial, from which the authors conducted analyses that were not necessarily the intention of the trial. While this does not render the authors’ conclusions invalid, the comparison of remimazolam against midazolam could have been probed more precisely if the authors had designed the trials themselves. Furthermore, treatment failures in all groups were removed from statistical analysis, which may have introduced bias in the results. Regardless, the paper, excitingly, suggests that remimazolam is a safe and effective anesthetic, and further research will determine if it will supersede midazolam as an anesthetic of choice. 

References 

1. Trapani, G., Altomare, C., Liso, G., Sanna, E. & Biggio, G. Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery. Curr. Med. Chem. 7, 249–271 (2000), DOI: 10.2174/0929867003375335
2. Kilpatrick, G. J. Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent. Front. Pharmacol. 12, (2021), DOI: 10.3389/fphar.2021.690875
3. Shafer, A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit. Care Med. 26, 947–956 (1998), DOI: 10.1097/00003246-199805000-00034
4. Wiltshire, H. R., Kilpatrick, G. J., Tilbrook, G. S. & Borkett, K. M. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation. Anesth. Analg. 115, 284–296 (2012), DOI: 10.1213/ANE.0b013e318241f68a
5. Dao, V.-A., Schippers, F. & Stöhr, T. Efficacy of remimazolam versus midazolam for procedural sedation: post hoc integrated analyses of three phase 3 clinical trials. Endosc. Int. Open 10, E378–E385 (2022), DOI: 10.1055/a-1743-1936
6. Hopkins Verbal Learning Test–Revised | HVLT-R. https://www.parinc.com/Products/Pkey/130.