Is Remimazolam the hoped for Perfect Sedation Drug?

By Dr Wicus Nienaber  

A question posed by Dr Mari v Rensburg in our discussion group prompted me to look again at this  wonder drug. Given that it is in use for 4 years in other countries with millions of sedations done the tragicomedy of South Africa’s SAHPRA government regulatory office and its inability to get new and well tested drugs through its cumbersome processes is par for course. 

History

The search for the ideal sedative medication has continued for decades in sedation and critical care. An optimal agent would combine rapid onset, predictable duration tailored to the procedure length, minimal side effects, and rapid elimination from the body without accumulation after prolonged infusions. No currently available sedatives possess all these properties; thus the quest has persisted. Now a new medication, remimazolam, is demonstrating tremendous promise to fulfil these criteria and transform sedation practices.

Approved initially in 2019 in China for gastrointestinal endoscopy procedures, remimazolam has rapidly gained additional clearances globally for both procedural sedation and ICU sedation. Its use as an anesthesia induction agent although well studied and proven to be an excellent if not superior choice to propofol has not yet found favor amongst anaesthetists. Early clinical experiences showcase advantages over existing options like midazolam and propofol including faster onset and recovery, improved safety, higher success rates for completing planned procedures, and lower drug doses needed for adjunct opioids. Remimazolam appears poised to assume a prominent place in the sedation medication armamentarium owing to its ultra-short duration reflecting rapid metabolism to an inactive compound, lack of accumulation, and favorable side effect profile.

Remimazolam represents the culmination of decades of work by medicinal chemists seeking to create the perfect sedative. The conceptual inspiration blended key components of two commonly used medications—midazolam and remifentanil.

Midazolam, a benzodiazepine, offers quick onset of action, anxiolysis, anterograde amnesia, and muscle relaxation making it one of the most widely used agents for sedation and anesthesia induction. However its longer duration of action extending beyond typical procedure times leads to slower recovery. It also accumulates in the body with prolonged infusions requiring dose reductions giving it a poor comparison against remimazolam when comparing context sensitive half-lives.

Introduced in the 1990s, the opioid remifentanil revolutionized anesthesia due to its ultra-short action from rapid breakdown by blood and tissue esterases. This allows administration to be varied based precisely on the procedural requirements and enables quick emergence since effects dissipate minutes after stopping an infusion. However offsetting mu-receptor mediated side effects like respiratory depression remain a challenge in sedation. Hence the guidelines recommending not using it outside of hospital theatre.

By structurally incorporating the ester linkages of remifentanil into midazolam’s core ring structure, scientists aimed to retain its potent, reliable sedative-hypnotic effects mediated through the GABA-A receptor while adding remifentanil’s signature characteristic—organ-independent metabolism by tissue esterase enzymes in blood and tissues throughout the body. The resulting new chemical entity was dubbed “remimazolam.”

Development research

 An initial key study published in Anesthesiology in 2004 analyzed remimazolam’s effects compared to midazolam on chloride currents via  GABA-A receptors expressed in frog oocytes. While remimazolam displayed slightly lower intrinsic its potency based on half maximal effective concentration (EC50) equalled midazolam. This confirmed robust sedative-hypnotic activity mediated through the classic benzodiazepine binding site. 

Importantly, the study also examined binding affinity after metabolism of both drugs by human liver esterases added to the assay solution. While midazolam retained high affinity after incubation with the enzymes as expected from its hepatic clearance pathway, remimazolam lost practically all binding capability reflecting addition of the carboxylate that inactivates the molecule. This rapid abolition of activity by ester hydrolysis pointed to the potential for much shorter duration than midazolam after systemic administration.

An initial Phase 1 trial published in 2008 administered ascending intravenous doses of remimazolam versus an active comparator, midazolam, to healthy volunteers. Doses spanned 0.01 to 0.3 mg/kg in the typical procedural sedation range. Remimazolam demonstrated faster onset reaching peak sedative effect within 3 minutes across doses. At higher doses from 0.075 to 0.2 mg/kg, time for patients to become fully alert again averaged just 5.5-20 minutes for remimazolam depending on dose compared to 40 minutes for midazolam. 

Several pharmacokinetic parameters quantified remimazolam’s ultra-short duration including higher systemic clearance, smaller volume of distribution steady-state and shorter terminal half-life (0.75 hours) than midazolam (2.89 hours). Of particular note, the context-sensitive half-time defining duration was far shorter such that remimazolam plasma levels dropped 50% in just 7-8 minutes after stopping longer 2 hour infusions whereas midazolam required 90-180 minutes. 

With Phase 1 results demonstrating pharmacological activity like midazolam but markedly shorter duration, the next wave of studies aimed to prove remimazolam’s efficacy and safety for procedural sedation across a spectrum of surgeries and interventions requiring conscious sedation. Gastrointestinal endoscopy represented an initial prominent focus given the huge patient numbers undergoing procedures like colonoscopy and upper endoscopy worldwide.

Among the first formal efficacy trials, a 2015 Phase 2 study compared single intravenous doses of three remimazolam levels (0.1, 0.15 and 0.2 mg/kg) against the standard midazolam (0.075 mg/kg) for sedation during upper endoscopy. All remimazolam arms showed faster onset reaching targeted sedation levels within 1.5-2.5 minutes versus 5 minutes for midazolam. Similarly mean time to fully alert status again was shorter at 7-10 minutes depending on dose compared to 11.5 minutes for midazolam suggesting much briefer clinical effects. While procedural success rates approached 60% for remimazolam groups, the study design utilized no supplemental opioids like fentanyl that are routine to improve completion rates. Adverse events proved similar between groups, demonstrating early safety.

Sedation

Multiple later phase 3 studies strengthened the evidence base confirming remimazolam’s effectiveness for endoscopy sedation against both midazolam and propofol as reference comparators. In colonoscopy trials, adding fentanyl then comparing fixed 5 mg remimazolam doses to traditional midazolam dosing (initial 1.75 plus additional titration) significantly boosted procedure completion rates to over 90% exceeding both midazolam and placebo groups. Faster onset and recovery persisted with superiority in times to reach and emerge from targeted sedation depths. Safety again equalled comparators while using lower total opioid amounts. By establishing non-inferiority across metrics versus standard agents, data supported remimazolam’s regulatory approval specifically for gastrointestinal procedural sedation in China, South Korea, the United States and European Union by 2020.

ICU

A pivotal study in 2019 sedated 50 Japanese ICU patients requiring sustained ventilation with remimazolam infusions titrated based on sedation depth assessments. Forty-seven of the fifty patients were successfully sedated for periods between 9 and 503 hours without major adverse events suggesting efficacy. By protocol, seven patients received continuous infusions exceeding 24 hours reaching one to three days. These patients exhibited higher than predicted blood remimazolam levels based on initial clearance rates and pharmacokinetic modelling. Yet rather than excessive sedation from accumulation, investigators discovered clearance declined by about 25% over the first day then remained stable. This time-dependent change indicates some enzyme tolerance develops but reaches a plateau enabling sustainable long-term use. 

During critical remdesivir shortages early in the COVID-19 pandemic, remimazolam gained emergency approval for compassionate ICU use in Belgium beginning in August 2020. An observational study followed 68 patients administered remimazolam infusions for sedation for up to 14 days duration. Median infusion length measured 2.1 days with 10 patients exceeding 7 days. No adverse safety signals emerged with heart rate/rhythm and respiratory parameters remaining stable. These early reports hint at the potential for sustained ICU sedation with remimazolam for periods up to several days without accumulation concerns that limit benzodiazepines like midazolam. Further trials are launching to rigorously evaluate this attractive application.  

Pediatrics 

While investigational efforts clearly concentrated early on adult procedural and perioperative sedation, remimazolam’s properties suggest great promise for pediatric sedation. The ability to carefully titrate doses based on the desired depth and duration of sedation then rapidly emerge patients could reduce emotional trauma, delirium and separation anxiety. However pharmaceutical companies excluded children from initial registration trials; thus experience in pediatric settings remains extremely limited. 

Scattered publications include case reports of using remimazolam for general anesthesia in children between ages 4 and 12 years undergoing procedures like tumor resection and cardiac implantation. Combining with low-dose adjunct propofol, remimazolam preserved cardiovascular stability and enabled rapid recovery within minutes. Younger ages and specific conditions like congenital heart disease still await future controlled evaluation. New planned trials on the horizon aim to define appropriate weight-tiered dosing strategies and formally determine efficacy.

Interestingly I could not find reference to paradoxical reactions like what we see in pediatric midazolam use, with remimazolam, but given the similarity of the molecule it is highly likely. But because it is not yet available in oral form and because of the extreme short action I do not foresee that as a problem soon.

Current use 

Within five short years of first market approval in 2019, remimazolam witnessed rapidly expanding adoption for procedural sedation and anesthesia crossing Europe, Asia and North America. While initial dosing recommendations originated from registration trials for gastrointestinal endoscopy and short surgery, the true range of potential clinical applications surely exceeds colonoscopies and endoscopies. Intensive care sedation, radiology, OB anesthesia, neurocritical care, cardiovascular procedures, pediatrics, palliative ventilator weaning represent just some arenas where a rapidly reversible, organ independent sedative without accumulation could shine.

Yet optimizing precise dosing strategies will take time requiring careful titration and outcome measurement across diverse patient groups and procedures of varying stimulation levels and desirable depths/durations of sedation. Will fixed standard doses suffice or should formulas based on age, weight, organ dysfunction guide individualized care? Can ICU sedation be sustained for days without accumulation concerns that plague benzodiazepines? We lack data on stopping long infusions abruptly—is rebound agitation or hypotension a risk? Combining adjunct agents like propofol and opioids will further vary dosing targets. Addressing these real-world practice questions through expansive clinical research in coming years promises to unlock remimazolam’s full disruptive potential.

While I failed to find TCI  Algorithms on current infusion pumps, there is a remimazolam algorithm on the  iTIVA App, but be careful the pre coded settings are very high and careful setting up is mandatory. 

While early in its life cycle, remimazolam appears positioned to follow in remifentanil’s footsteps revolutionizing sedation care by facilitating precise titration  and rapid recovery. In an era embracing efficiency with pressures throughout healthcare, a sedative like remimazolam perfectly matched to procedure times with less cardiopulmonary effects facilitates turnover, throughput and cost savings. Expect exponential growth in utilization, ongoing optimization of protocols expanding use cases as clinicians realize the promise of precision sedation. 

To answer the question posed at the beginning of this article: Is this the perfect sedation drug ?  Maybe  a serious yes for ultra short sedation procedures and strangely enough maybe a yes for ultra long ICU sedations. I am certainly exited to try to use it for my endoscopy lists and will for now be wary with pediatric cases. Whether it will be seen as safe in out of hospital cases, I will rely on the wisdom of our mentors in sedation like Prof James Roelofse and ICAPS and their final decisions when it is included in the new sedation guidelines. 

For prospective users in South Africa,  we are currently trying several pathways to bring product to Sedationists. Clinigen International has the rights to distribute locally and has apparently requested regulatory clearance for remimazolam from SAPHRA a few years ago already, with no positive outcome in sight. Requests for Section 21 imports can be done on individual patient requests but is obviously cumbersome, but other possibilities are investigated.  Watch this space!

This article data  information was sourced from the National Library of Medicine and published in accordance with their fair use rules.

Published: January 15, 2024 3.37pm SAST

A new drug called kush is wreaking havoc in west Africa, particularly in Sierra Leone where it is estimated to kill around a dozen people each week and hospitalise thousands. 

The drug, taken mostly by men aged 18 to 25, causes people to fall asleep while walking, to fall over, to bang their heads against hard surfaces and to walk into moving traffic.

Kush should not be confused with the drug of the same name found in the US, which is a mixture of “an ever-changing host of chemicals” sprayed on plant matter and smoked. Kush in Sierra Leone is quite different; it is a mixture of cannabis, fentanyl, tramadol, formaldehyde and – according to some – ground down humans bones.

It is mixed by local criminal gangs, but the constituent drugs have international sources, facilitated no doubt by the internet and digital communications. 

While cannabis is widely grown in Sierra Leone, the fentanyl is thought to originate in clandestine laboratories in China where the drug is manufactured illegally and shipped to west Africa. Tramadol has a similar source, namely illegal laboratories across Asia. Formaldehyde, which can cause hallucinations, is also reported in this mixture. 

As for ground human bones, there is no definitive answer about whether or not they occur in the drug, where such bones would come from, or why they might be incorporated into the drug. Some people say that grave robbers provide the bones, but there is no direct evidence of this. 

But why would bones be incorporated into the drug? Some suggest that the sulphur content of the bones causes a high. Another reason might be the drug content of the bones themselves, if the deceased was a fentanyl or tramadol user. 

However, both are unlikely. Sulphur levels in bones are not high. Smoking sulphur would result in highly toxic sulphur dioxide being produced and inhaled. Any drug content in bones is orders of magnitude less than that required to cause a physiological effect.

Where is the drug found?

The drug is reported in both Guinea and Liberia, which share porous land borders with Sierra Leone, making drug trafficking easy. 

Kush costs around five leones (20 UK pence) per joint, which may be used by two or three people, with up to 40 joints being consumed in a day. This represents a massive spend on drugs and illustrates the addictive nature of the mixture, in a country where the annual income per capita is around £500.

The effects of the drug vary and depend on the user and the drug content. Cannabis causes a wide variety of effects, which include euphoria, relaxation and an altered state of consciousness. 

Fentanyl, an extremely potent opioid, produces euphoria and confusion and causes sleepiness among a wide range of other side-effects. Similarly, tramadol, which is also an opioid but less potent than fentanyl (100mg tramadol has the same effect as 10mg morphine) results in users becoming sleepy and “spaced out” – disconnected from things happening around them. 

The danger of the drug is twofold: the risk of self-injury to the drug taker and the highly addictive nature of the drug itself. A further problem is the need to finance the next dose, often achieved through prostitution or criminal activity.

Joining the ranks of existing polydrugs

Kush is another example of polydrug mixtures of which forensic scientists are becoming increasingly aware. Another tobacco and cannabis-based drug, nyaope, otherwise known as whoonga, is found in South Africa. This time the tobacco and cannabis are mixed with heroin and antiretroviral drugs used to treat Aids, some of which are hallucinogenic. 

A further polydrug, “white pipe”, a mixture of methaqualone (Mandrax), cannabis and tobacco, is smoked in southern Africa. These drugs are inexpensive and provide an escape from unemployment, the drudgery of poverty, sexual and physical abuse, and the effect, in some cases, especially in west Africa, from having been a child soldier. So what can be done about these drugs? 

The effectiveness of legislation alone is questionable, and many of those who attend the very limited rehabilitation centres return to drug use. Perhaps what is required is an integrated forensic healthcare system where legislative control is backed up by properly resourced rehabilitation centres coupled with a public health and employment programme. What changes are made in response to this epidemic remains to be seen.