Use of progressively higher doses of conventional opioids such as morphine can result in an increased risk for the development of respiratory depression when used to manage postoperative pain . These respiratory events can also have a prolonged course due to the delayed appearance and persistence of active metabolites, an event that can be further aggravated in patients with organ system failure. For example, the delayed appearance of the active metabolite of morphine, morphine-6-glucuronide, in patients with hepatic dysfunction is known to contribute to the accumulating analgesic effect of morphine and to unnecessarily prolonged episodes of respiratory depression . Moreover, certain patient populations, including the elderly, morbidly obese, patients with sleep apnea, the very young, or patients with renal disease or neurologic disease are considered to be at higher risk for these respiratory complications [13, 15].
Although there is an increased awareness of the need to minimize the risk of OIRD, there are challenges associated with the clinical assessment of this postoperative complication . Most significantly, there is no standardized definition of OIRD, and many studies reporting prevalence of this outcome have utilized definitions ranging from the requirement of naloxone to reverse OIRD to observations of changes in breathing frequency and/or oxygen saturation < 90% [3, 13, 16]. This variability in the definition of OIRD and the assessment methodology used clearly influences the reported incidence, with an incidence rate of 0.3 (0.1–1.3) % using requirement for naloxone and 17 (10.2–26.9) % using oxygen saturation < 90% as an indicator . Clinically concerning symptoms of bradypnea or hypoxemia are typically used to characterize earlier grades of respiratory compromise . In one study, early hypoxemia (defined as oxygen saturation < 90%) was common and reported among 20% of postoperative patients, with prolonged episodes extending for 1 h or longer reported in 37% of patients, and with most of these episodes largely undetected during routine nursing care . Undetected hypoxemia is a serious safety concern. The Anesthesia Patient Safety Foundation (APSF) recommends continuous monitoring with routine pulse oximetry and capnography in all patients prescribed opioids . Indeed, in the recently completed PRODIGY trial, which attempted to detect OIRD using continuous cardiorespiratory monitoring (heart rate [HR], oxygen saturation [SpO2], end-tidal carbon dioxide [etCO2] and respiratory rate [RR]) , rates of OIRD as high as 46% were reported .
The heterogeneity in the reported incidence of OIRD clearly indicates that these are multifactorial events, and defining them based on a single criterion may not be adequate [16, 22]. RSB as an endpoint, introduced for the first time in the oliceridine pivotal trials, required application of trained clinician judgment to detect each RSE. On the other hand, the metrics used to measure RSE, including respiratory rate or oxygen saturation, are single-measure readings that can be confounded by patient factors such as medical co-morbidities and the need to provide clinical relief by the administration of supplemental O2 . Thus, despite the unique mechanism of action of oliceridine, any difference that potentially exists in reducing respiratory events compared with morphine and observed in earlier clinical trials [10, 23] may not have been fully delineated in the phase III studies using these measures alone. Of note, neither studies enrolled patients with medical illness co-morbidities based on protocol exclusion criteria. Furthermore, although the use of supplemental oxygen was allowed, the proportion of patients requiring such use was lower in the oliceridine treatment groups compared to the morphine group [11, 12].
In routine clinical treatment settings, dose reduction, interruption, or discontinuation are among the most immediate and unambiguous measures employed to address adverse events. Therefore, the use of DI as a surrogate measure to evaluate the “respiratory safety profile” of oliceridine can be thought of as a pragmatic, verifiable indicator compared to the subjective assessment endpoints used in the RSB construct. In this post hoc analysis of the two phase III placebo- and active-controlled studies, the proportion of patients with a DI due to an RSE was lower for the equianalgesic doses of oliceridine 0.35 mg and 0.5 mg demand doses in both studies compared to morphine; 7.6% and 11.4%, respectively, versus 17.1% for morphine in the bunionectomy study; 20.3% and 18.8%, respectively, versus 25.6% for morphine in the abdominoplasty study. Likewise, the proportion of patients with any DI was numerically lower for all doses of oliceridine, and for the comparably analgesic demand doses of 0.35 mg and 0.5 mg ranged from 15% to 18%, compared with 25% for morphine-treated patients. Similarly, the CDDI was also lower for the comparably analgesic doses of oliceridine 0.35 mg and 0.5 mg compared to morphine.
This analysis had several limitations. Of note, this was a post hoc analysis based on post-randomization events. The analysis was restricted to dose interruptions alone and dose reductions were not captured. In addition, the decision to interrupt a dose was based on the clinical judgment, and lacked standardization of a measure for when to interrupt the dosing of pain medication.