Emerging Medications in Anesthesia and Analgesia

Advances in our pharmacology and physiology knowledge have allowed for the creation of medications that have improved safety profiles and enhanced clinical action. One only needs to look at how quickly vaccines and therapeutics for SARS-CoV-2 were produced to realize how our knowledge has advanced. What once took years, if not decades, to make was reduced into an abridged timeline. Medications used in anesthesia and analgesia have also benefited from this enhanced knowledge. Through an increased understanding of drug receptors and mechanisms of action, we have a broad range of medications that can be ideally tailored to unique clinical needs.
Despite the current opioid crisis, the opioid class of medications remains a vital adjunct in managing acute post-surgical pain. The usefulness of opioid-class analgesics has been reduced mainly by their side effect profile. Gastrointestinal side effects of nausea, vomiting and constipation range from inconveniences to use limiting. Opioid-induced respiratory depression can also be use limiting, especially in specific patient populations such as those presenting with obstructive sleep apnea, obesity or advanced age. Tolerance, dependence, and addiction remain extremely concerning of these side effects. While there are several known opioid receptors, activation of the µ-opioid receptor, or MOR, is felt to be the most important for both the desired and undesirable effects of the opioid class of medications used in acute pain management. It is now understood that the MORs belong to a class of what is known as G-protein-coupled receptors (GPCR). Located on the cell membrane, they transduce extracellular signals into key physiological effects.¹ Over 800 human G-protein -coupled receptors have been identified; roughly 350 are deemed “druggable”.² More than 500 FDA-approved drugs are estimated to target G-protein coupled receptors, and approximately 60 of these are currently undergoing clinical therapeutic studies.³ When conventional opioids bind to the MOR, two downstream pathways are activated: G-protein signalling and a ß-arrestin pathway (Fig. 1). Using mice that lack the ß-arrestin pathway (‘knock out’ mice), it has been demonstrated that this second pathway is responsible for many of the opioid-induced adverse effects and limits the efficacy of the opioids.⁴ Oliceridine is a novel intravenous opioid that selectively and preferentially activates the G-protein signalling pathway with the reduced ability to activate the ß-arrestin pathway. As a result of this selectivity, olicerdine has been termed a “biased µ-receptor agonist.” Theoretically, due to the low recruitment of the ß-arrestin pathway, oliceridine would be expected to provide potent analgesia with reduced adverse effects, including opioid induce respiratory depression. In 2020, Trevena Inc. (Chesterbrook, PA) was granted FDA approval for the release of Olinvyk™ (oliceridine) for use in adults in the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Along with the reduced tendency to produce respiratory depression, it is hoped that oliceridine will have fewer GI side effects, tolerance and addiction.⁵

Fig. 1

The effectiveness and safety of oliceridine as an analgesic in managing post-operative pain have been evaluated for hard and soft tissue pain. Bunionectomy surgery was selected as the hard tissue model, while abdominoplasty was used for soft tissue surgery.^6,7 Randomized, controlled studies evaluated the effectiveness of morphine, oliceridine and placebo for acute pain management and the incidence of adverse respiratory events. Both morphine and olicerdine were administered in varying doses as an intravenous fixed loading dose that was followed by demand dosing using a patient-controlled analgesia (PCA) device. If analgesia was inadequate, a clinician-administered, blinded supplemental dose could be provided. In both the hard and soft tissue surgery studies, oliceridine demonstrated significant pain reduction compared to placebo and morphine with no serious adverse events. The most common adverse events were nausea, vomiting, dizziness, headache, constipation, pruritis and hypoxia. In general, the incidence of these events was lower in the oliceridine groups. The gastrointestinal side effects appeared to be dose related in that their incidence increased as the loading dose of oliceridine increased. Concerning the incidence of adverse respiratory events, comparisons are difficult as the definition of an adverse event varies. The PRODIGY (PRediction of Opioid-induced Depression In patients monitored by capnoGraphY) trial sought to better characterize opioid-induced respiratory depression utilizing a validated index that included continuous oximetry and capnography.⁹ When the PRODIGY scoring was used in patients receiving oliceridine, there was a trend towards a lower risk of opioid-induced respiratory depression (ORID) in patients categorized as intermediate or high risk for ORID.¹⁰ While the potential benefits for reducing the adverse respiratory and gastrointestinal side effects appear promising, like other opioids, olicerdine can be subject to abuse, addiction and diversion. Utilizing a rodent model, Zamarripa et al.¹¹ found that the abuse potential of oliceridine was similar to morphine and oxycodone. This suggests that the Holy Grail of opioid analgesics without adverse effects remains elusive. Currently, oliceridine is only approved for managing moderate to severe post-operative pain in adults. As further clinical studies are conducted, other uses may be demonstrated, such as total intravenous anesthesia (TIVA), labour analgesia, and sedation for GI endoscopy and bronchoscopy.

Another trend in developing drugs for use in anesthesia is so-called soft drugs. Such compounds are designed to be vulnerable to rapid biotransformation into inactive metabolites. In practice, a soft drug is metabolically fragile and thus is rapidly eliminated. This allows the ability to titrate the drug up or down as needed. Remifentanil was approved by the FDA in 1996 and has emerged as an extremely useful opioid in general anesthesia and TIVA. Other soft drugs frequently used in anesthesia include the muscle relaxant succinylcholine and the short-acting ß-adrenergic blocker, Esmolol. The commonality with these compounds is the ability to be available for rapid hydrolysis by plasma or tissue esterases. Remimazolam (CNS 7056) is a novel, ultra-short acting benzodiazepine categorized as a soft drug due to its esterase linkage that allows for the rapid hydrolysis to an inactive metabolite by non-specific tissue esterases.¹¹ Byfavo (remimazolam besylate, Acacia Pharma Inc, Indianapolis, IN) was approved by the FDA in 2020 as an intravenous benzodiazepine sedative/anesthetic for the induction and maintenance of procedural sedation lasting less than 30 minutes in adults. Remimazolam is identical to midazolam (Versed®) which is currently frequently selected as an agent in providing intravenous sedation and anesthesia, apart from how the drug is inactivated. They both produce sedation by acting at the γ-aminobutyric acid (GABA) receptors in the CNS. Midazolam is metabolized in the liver via the cytochrome P450 enzymes, whereas remimazolam is degraded by tissue (predominantly liver) esterases. A significant difference between the two drugs is that remimazolam is degraded to a metabolite with minimal activity. Midazolam is converted to an active metabolite contributing to approximately 10% of its activity. The significance of these differences is a faster onset of action and shorter duration of action with a quicker offset for remimazolam. Clinical trials demonstrated an onset time of 3-5 minutes, a duration of action of 8 minutes, and a recovery time between 5.5 and 20 minutes.¹⁵ All these values are significantly less than those of midazolam. Remimazolam has a much shorter context-sensitive half-time when used as a continuous infusion. This characteristic translates into a fast plasma drug clearance when used as a continuous infusion. The drug’s metabolism is not affected by patients with end-stage renal disease, and therefore no dose adjustments are required.¹⁶ Dose adjustments are suggested for patients presenting with severe hepatic dysfunction.¹⁷ Elderly patients may also experience greater degrees of sedation, and therefore careful dose titration is suggested.¹⁸ The most common adverse effects noted following the administration of remimazolam were blood pressure perturbations (hyper- and hypotension), bradycardia, nausea, vomiting, headache and hypoxia (Byfavo package insert). Most of these adverse effects occur at a lower frequency when compared to midazolam. Caution is advised with administering to pregnant or lactating patients and the pediatric population. The suggested dosing for remimazolam when combined with fentanyl 50µg is 5mg with a repeat dose of 2.5mg spaced two or more minutes apart.

Most clinical trials using remimazolam for procedural sedation involved patients undergoing endoscopic or bronchoscopic procedures. Various ‘non-inferior trials’ were conducted to compare remimazolam, alone or in combination. These studies collectively demonstrated that it performs equally well, or better, when compared to other sedatives that are currently used. Few studies in the dental literature evaluate the effectiveness of remimazolam in dental procedures. A review using data from other disciplines has suggested that it may represent an ideal drug for use in dentistry. Still, the authors also point out some of the differing requirements for sedation in dental procedures.¹⁸ The length of some dental procedures requires a duration of sedation that is greater than the duration of the action of remimazolam. The risk in this situation would be the potential for dose stacking that could increase the risk of adverse respiratory events. Using an infusion device for dental procedures may help reduce this risk, but this will add to the cost of care. Given the lack of active metabolites compared to midazolam, the risk of adverse effects due to dose stacking is likely much smaller with remimazolam. Another study in the oral surgery realm compared the advantages of remimazolam as a sedative compared to midazolam in treating patients with dental anxiety who required impacted third molar removal.¹⁹ In this small-scale study, they did report it possesses advantages over midazolam in managing such patients. It is also important to realize that remimazolam offers anxiolysis and amnesia and lacks analgesic action. As such, the concept of a ‘balanced anesthesia’ that offers analgesia, lack of consciousness, amnesia and lack of movement is achieved with multiple drugs. This concept allows the administration of individual medications in lower doses and minimizes the adverse effects native to each drug. However, the combination of drugs increases the risk of synergistic actions that potentially increase the risk of adverse cardiac and respiratory events. In a similar small-scale study, Guo and colleagues²⁰ reported higher degrees of success in patients treated with remimazolam in combination with a fixed dose of fentanyl compared to those treated with midazolam. Adverse effects, including periods of apnea, oxygen saturation levels less than or equal to 92% and hypotension, were statistically similar between groups. The time to safe patient discharge also did not reach a statistically significant difference. When multiple sedative agents are used to provide sedation or anesthesia, the potential for crossing the boundaries between moderate and deep sedation and general anesthesia. With most combinations, the line between moderate to deep anesthesia is fine, and the potential for crossing into a general anesthesia state is high. As such, remimazolam, combined with any other sedative agent, mandates that the user be trained and equipped to recognize and treat cardiac and respiratory changes that will arise. It will take time to demonstrate the safety of remimazolam when combined with other drugs, such as propofol, ketamine and dexmedetomidine which are frequently used to provide sedation and anesthesia in outpatient dentistry and oral surgery.

While oliceridine is currently marketed under the name Olinvyk® by Trevana Pharma, and remimazolam is marketed under the name Byfavo® by Acacia Pharma in the United States, they are not currently available in Canada; however, both medications were listed on the Med Entry Watch of Health Canada in 2020. There are likely regulatory hurdles that need to be met by each manufacturer before they will be available. With increased availability, use, and further clinical studies in a broader range of clinical applications, the actual benefits and possible adverse effects of each of these unique drugs will become more apparent.

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References

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About the Author

Dr. Kevin McCann is in solo practice of Oral and Maxillofacial Surgery in Kitchener-Waterloo, ON. He is a Past President of the Canadian Association of Oral and Maxillofacial Surgeons and the current President of the Canadian Dental Society of Anesthesiology.