A critical review of oliceridine injection as an IV opioid analgesic for the management of severe acute pain

ABSTRACT

Introduction

Oliceridine is a G protein-selective (biased) agonist at the μ-opioid receptor, with less recruitment of β-arrestin-2, a signaling pathway associated with opioid-related adverse events. Nonclinical evidence showed that oliceridine elicits a rapid systemic analgesic effect while attenuating opioid-related adverse events.

Areas covered

Three pivotal studies in patients with moderate-to-severe acute pain, including two randomized, double-blind, placebo- and morphine-controlled efficacy studies following either orthopedic surgery-bunionectomy or plastic surgery-abdominoplasty; and an open-label safety study following a surgical procedure or due to a medical condition.

Expert opinion

Poorly controlled acute postoperative pain is associated with poorer recovery, longer hospitalization, increased complications, and worse healthcare outcomes. Recently, oliceridine intravenous injection was approved for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Introduction of this new IV opioid provides a valuable option to manage postoperative pain.

KEYWORDS:

• Oliceridine
• opioid analgesics
• μ-opioid receptor agonists
• opioid-related adverse events
• postoperative pain

1. Introduction

Postoperative pain, one of the most common forms of acute pain, is experienced in more than 80% of all surgical patients, with the pain being reported as moderate to severe in intensity in at least 75% of these patients [1]. Lack of adequate management of postoperative pain can have a significant impact in clinical and economic outcomes, including functional and quality-of-life impairment, delayed recovery time, extended hospitalization, and higher health-care costs [2,3]. Although opioids remain an important pharmacotherapy for the management of moderate-to-severe acute postoperative pain, they are associated with dose-related adverse events (AEs), resulting in worst patient outcomes, including increased inpatient mortality, prolonged length of hospital stay, and increased overall cost of hospitalization [4–6]. Over the last decade, with the growing utilization of Enhanced Recovery After Surgery (ERAS) protocols and the use of multimodal non-opioid analgesia for optimal postoperative pain management, the focus has shifted to a reduction in the use of opioids or to the use of opioid-sparing measures with a view to reducing opioid-related side effects [5,7]. Opioid overdose has become a leading cause of unintentional death in the United States, and use of multimodal analgesia and enhanced recovery pathways are key tools utilized by anesthesiologists and surgeons toward achieving effective analgesia without undesirable sequelae [8].

In recent years, a growing understanding of the molecular mechanisms by which opioids elicit their analgesic effect, including findings from β-arrestin-2 knockout mice demonstrating improved analgesia with significantly reduced AEs [9], has led to an expansion in the field of biased agonism, especially that of G-protein coupled receptor (GPCR) drug discovery [10]. The development of oliceridine, a µ-opioid receptor agonist that is structurally distinct from natural opiates (e.g. morphine) and from its semi-synthetic derivatives (e.g. hydromorphone), was based on the G-protein biased ligand technology [10]. Indeed, oliceridine is considered a partial agonist in both G-protein signaling and β-arrestin-2 recruitment, as well as a biased agonist for G-protein signaling [11]. Nonclinical studies have shown that oliceridine provides potent analgesia with an improved respiratory and gastroinestinal (GI) safety profile [12]. However, the translation of these findings in humans has not been fully established.

In a Phase 2 clinical study using fixed-dose oliceridine in a hard tissue surgical model (buninectomy,192 patients), oliceridine provided a rapid onset of action – median time of 1 to 3 minutes after administration of the first dose [13]. Oliceridine is metabolized by cytochrome P450 hepatic enzymes, primarily by CYP3A4 and CYP2D6, and none of the metabolites have any appreciable activity at the µ-opioid receptor [14]. No dose adjustment of oliceridine is needed in patients with renal impairment or in patients with mild-to-moderate hepatic dysfunction [15]. There is no significant difference in oliceridine clearance in elderly (≥65 years) patients compared to younger adults [14]

Oliceridine received approval on 7 August 2020 in the United States of America (US) for use in adults in the management of acute pain severe enough to require an intravenous (IV) opioid and for whom alternative treatments are inadequate [16,17]. It is indicated for short-term IV use in hospitals or other controlled clinical settings (during inpatient and outpatient procedures), under medical supervision, and is not for use in a take-home prescription [17]. The US Food and Drug Administration (FDA) approval of oliceridine was based on results from the Phase 3 development program that evaluated oliceridine in over 1,500 patients with moderate-to-severe acute pain, including two randomized placebo- and active-controlled trials [18,19] and an open-label safety study [20] .

Both pivotal controlled clinical trials (APOLLO-1, NCT02815709 and APOLLO-2, NCT02820324) included an active reference comparator (morphine). Morphine is considered the archetypal opioid analgesic and the agent to which all other opioids are compared [21]. In the oliceridine clinical development program, use of morphine as a comparator allowed to confirm assay sensitivity of the trial as designed, and also to place the overall safety and efficacy results in clinical context, since morphine’s dose–effect relationship is among the best understood of any parenteral opioid in common use.

The open-label, ‘real world’ safety study (ATHENA, NCT02656875), evaluated the safety and tolerability of oliceridine in a broad range of surgical procedures or medical conditions, in a clinically challenging patient population, including the elderly, obese, and among patients with comorbid conditions such as hypertension, diabetes, chronic obstructive pulmonary disease (COPD), and sleep apnea [20].

This review will discuss the efficacy and safety endpoints utilized in the oliceridine pivotal Phase 3 controlled studies, and critically review study findings in light of the US FDA regulatory approval.

2. Efficacy endpoints in the Phase 3 randomized placebo- and morphine-controlled studies

The two randomized, double-blind, placebo- and morphine-controlled studies in patients with moderate-to-severe acute pain following either orthopedic surgery-bunionectomy (APOLLO-1; N = 389) or plastic surgery-abdominoplasty (APOLLO-2; N = 401), evaluated the efficacy of oliceridine [18,19]. Patients with a numeric (pain) rating scale (NRS; 0 to 10) score ≥4 in the bunionectomy trial, and an NRS score ≥5 in the abdominoplasty study were randomized to receive one of five demand-dose regimens: oliceridine 0.1 mg, 0.35 mg or 0.5 mg; a morphine-control of 1 mg; or a volume-matched placebo dose. Patients were treated for up to 48 hours in the orthopedic surgery–bunionectomy study, and for up to 24 hours in the plastic surgery-abdominoplasty study. The loading dose for all oliceridine treatment regimens was 1.5 mg; demand doses were 0.1, 0.35, or 0.5 mg, according to assigned treatment group; supplemental doses of 0.75 mg were permitted, beginning 1 hour after the loading dose, and hourly thereafter, as needed. The loading dose for the morphine treatment regimen was 4 mg; the demand dose was 1 mg; and supplemental doses of 2 mg were permitted, beginning 1 hour after the loading dose, and hourly thereafter, as needed. A lockout interval of 6 minutes was used for all patient-controlled analgesia (PCA) regimens. Patients could receive rescue pain medication (pre-defined in the protocols as etodolac 200 mg every 6 hours, as needed) if they requested rescue pain medication and reported an NRS score ≥4. Oliceridine was not administered as part of multimodal analgesia in these studies [18,19].

The primary efficacy endpoint in both studies was the proportion of patients that were treatment responders (oliceridine vs placebo). A patient was considered a responder if they met all four of the following prespecified response criteria: 1) at least a 30% improvement in final time-weighted SPID from baseline at 48 hours (SPID-48; bunionectomy) [18] or at 24 hours (SPID-24; abdominoplasty) [19]; 2) without use of rescue pain medication during the randomized treatment period; 3) without early discontinuation of study medication for any reason; and 4) without reaching the study medication volume-based dosing limit. In both studies, patients in each of the oliceridine regimens showed a statistically superior responder outcome compared to those receiving placebo (Figure 1). Exploratory analyses indicated that the oliceridine 0.35 mg and 0.5 mg demand-dose regimens were noninferior to morphine (both P < 0.01) [18,19].

Figure 1. Analgesic efficacy: responder rates in the pivotal randomized controlled trials [18,19].

The primary endpoint analysis compared the percentage of treatment responders in each oliceridine regimen with the percentage of responders in the placebo regimen at 48 hours for the bunionectomy study and 24 hours for the abdominoplasty study. Responders were those who reached a ≥ 30% improvement in time-weighted sum of pain intensity differences (SPID) (at 48 hours for the bunionectomy study/24 hours for abdominoplasty study) from baseline while not receiving rescue pain medication, discontinuing study medication early, or reaching dosing limits. Figure Reproduced from Drugs of Today 2020, 56(4): 269. Copyright © 2020 Clarivate or its licensors. All rights reserved. DOI:10.1358/dot.2020.56.4.3107707

The secondary endpoint in both studies was the sum of pain intensity differences (SPID) over the entire randomized period (48 hours in the bunionectomy study; and 24 hours in the abdominoplasty study). This endpoint was utilized by the US FDA as the basis of approval for oliceridine. In the orthopedic surgery–bunionectomy study, average SPID-48 scores for the oliceridine 0.1, 0.35, and 0.5 mg demand-dose regimens were 132, 138, and 163, respectively, compared with 85 for placebo (Table 1). The difference from placebo was statistically significant for all demand doses of oliceridine (all P < 0.01) [22]. In the plastic surgery-abdominoplasty study, the average SPID-24 scores for the oliceridine 0.1, 0.35, and 0.5 mg demand-dose regimens were 77, 90, and 94, respectively, compared with 75 for placebo (Table 1). The difference from placebo was statistically significant for only the demand doses of oliceridine 0.35 and 0.5 mg (P = 0.75 for 0.1 mg; P < 0.01 for 0.35 or 0.5 mg vs. placebo) [22]. Since analgesic efficacy using this measure was not significantly better in the oliceridine 0.1 mg demand-dose regimen compared to placebo in the abdominoplasty study, the initial recommended demand dose is 0.35 mg for patient-controlled analgesia [16].

Table 1. Sum of pain intensity differences (SPID) from Phase 3 randomized placebo and morphine controlled studies: pre rescue scores carried forward 6 hours. Adapted from [18,19].

Orthopedic Surgery-Bunionectomy
SPID 48 Hours	Placebo N = 79	Oliceridine Demand Dose			Morphine
		0.1 mg N = 76	0.35 mg N = 76	0.5 mg N = 76	1 mg N = 76
Average	85	132	138	164	193
P-value vs placebo		<0.01	<0.01	<0.01	<0.01
Superiority vs placebo		Yes	Yes	Yes
Plastic Surgery-Abdominoplasty
		Oliceridine Demand Dose			Morphine
SPID 24 Hours	Placebo N = 79	0.1 mg N = 76	0.35 mg N = 76	0.5 mg N = 76	1 mg N = 76
Average	75	77	90	94	103
P-value vs placebo	-	0.75	0.017	<0.01	<0.01
Superiority vs placebo	-	No	Yes	Yes

2.1. Responder analysis vs. SPID

Pain is a subjective sensation. When rating pain, patients consider not only changes in their pain intensity but also any improvements in other domains such as physical functioning or sleep [23]. An analysis of the responder rate as utilized in the oliceridine pivotal trials is a more comprehensive assessment that combines indices of efficacy, tolerability, and rescue medication use, as opposed to an exclusive focus on pain intensity as measured by SPID. In the case of the latter, a patient simply rates his or her pain intensity ‘at the current moment’ [23]. Indeed, studies in acute pain research have reported that utilization of total pain relief (TOTPAR) score to assess efficacy may be a more sensitive measure than SPID, which focuses only on pain intensity [23]. Furthermore, patients can show large differences in SPID scores, with some reporting virtually no pain relief and others rating high pain relief, resulting in highly skewed distributions [24].

To obtain regulatory approval, pharmacological treatments must show a therapeutic effect over and above a placebo response [25]. Although the magnitude of placebo analgesic effects is highly variable in randomized clinical trials, many studies measuring pain have reported a high placebo response [25]. Several neurotransmitter studies evaluating mechanisms of action have hypothesized that the analgesic effects of placebos may be mediated by the release of endogenous opioids [25]. A patients’ perception of the intervention and their expectations and emotions toward treatment efficacy can further influence the outcome [22].

In the oliceridine randomized controlled clinical trials, utilizing SPID alone as a measure for analgesic efficacy can perhaps be influenced by the placebo effect, patient perception, emotions, and expectations contributing to the underestimation of the drug effect, highlighting the challenges of evaluating analgesic efficacy in clinical trials. Moreover, for SPID analyses in these studies, rescue medication use was imputed using last observation carried forward (LOCF) for the duration of the labeled dosing interval. Furthermore, discontinuation of study medication for any reason, which is an important indicator of patient comfort, is not accounted for; discontinuation for lack of efficacy is also handled with LOCF imputation; and discontinuation for an AE is handled using baseline observation carried forward (BOCF) imputation.

In contrast to SPID, the responder analysis may be more sensitive, as in addition to the 30% improvement in SPID, the endpoint also takes into account the use of rescue pain medication as well as tolerability (early discontinuation of study medication). The clinically significant events that could detract from efficacy include inadequate analgesia (lack of efficacy) or drug not well tolerated. In the responder analysis, patients who met any one of these criteria (defined above) were considered as ‘non-responders.’ Lastly, in the case of responder analysis, no imputation is required since those patients who used rescue analgesia or discontinued study medication were categorically assigned as ‘non-responders.’ Thus, this endpoint does not favor efficacy at the expense of tolerability. Indeed, in studies measuring pain associated with conditions such as osteoarthritis, a dichotomous responder analysis has been reported to provide a more informative interpretation of drug efficacy [26].

3. Adverse events in the Phase 3 studies

3.1. Overall adverse events (AEs)

The most common AEs (≥10%) in the two randomized placebo- and morphine-controlled controlled trials were nausea, vomiting, dizziness, headache, constipation, pruritus, and hypoxia [18,19]. In general, the incidence of AEs with oliceridine, including vomiting, were numerically lower with oliceridine than with morphine in both studies [16,18,19]. The types of AEs observed in the open-label safety study were similar to those observed in the controlled clinical trials [16,20]. The approved label mentions that the data are not an adequate basis for comparison of AE rates between the oliceridine treatment group and the morphine treatment group as the dosing regimens studied are not considered equipotent [16]. Based on the data collected in Phase I studies, an initial 1 mg dose of oliceridine is approximately equipotent to morphine 5 mg [18]. It should be noted that individual patients may differ in their response to opioid drugs. Further, unlike morphine, which has an active metabolite, the metabolite of oliceridine is inactive. Thus, the dose equivalency of oliceridine to morphine after cumulative dosing is difficult to establish.

3.2. Adverse events of specific interest: Postoperative nausea and vomiting (PONV)

PONV are among the most common complications in the postoperative period, with a reported 30% incidence among all post-surgical patients and up to 80% among high-risk patients, with use of conventional opioids known to further increase this risk [27]. The Fourth Consensus Guidelines for the Management of PONV recommend the use of two prophylactic antiemetics in patients with one to two risk factors; and use of three to four prophylactic agents in patients with >2 risk factors. In the oliceridine randomized controlled clinical trials, prophylactic antiemetics were not permitted perioperatively or during the randomized treatment period [18,19]. In both trials, enrolled patients were at increased risk of PONV, as indicated by Apfel scores at baseline of ≥3 (~60% to 80% risk of PONV [27]) in 77% of the patients in the orthopedic surgery–bunionectomy study [18] and 95% of patients in the plastic surgery-abdominoplasty study [19]. In the pooled data across both studies, the incidence of nausea was 60% with the oliceridine 0.35 mg dosing regimen, 69% with the oliceridine 0.5 mg dosing regimen, and 70% with the morphine 1 mg regimen. Likewise, the incidence of vomiting was 30%, 42% and 52% for the oliceridine 0.35 mg regimen, oliceridine 0.5 mg regimen, and morphine 1 mg regimen, respectively [14]. To further characterize the GI tolerability, a recently conducted exploratory post-hoc analysis evaluated the endpoint of complete GI response defined as ‘no vomiting and no use of rescue antiemetics,’ in each of the Phase 3 controlled studies and in the pooled data, using a logistic regression model. In this analysis, a higher proportion of oliceridine-treated patients achieved a complete GI response than morphine-treated patients in each study [28].

3.3. Adverse events of specific interest: opioid-induced respiratory depression (OIRD)

OIRD is indeed one of the most serious complications associated with the use of opioids [29]. There are no standardized definitions to characterize OIRD and incidence rates reported in the literature vary from 0.3% (0.1%–1.3%) using requirement for naloxone to 17% (10.2%–26.9%) using SpO₂ < 90% as an indicator [30]. Furthermore, in the recenty conducted ‘PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY)’ prospective, observational trial using continuous monitoring, respiratory depression episodes as high as 46% were reported [31].

In a Phase 1 proof-of-concept single-dose study in healthy volunteers, a single injection of oliceridine 1.5, 3, or 4.5 mg showed rapid analgesia, with the 1.5 mg dose being equianalgesic to morphine 10 mg injection using the cold pressor test; and significantly less OIRD than morphine using ventilatory response to hypercapnia (respiratory drive reduction of 7.3, −7.6, and 9.4 h*L/min, respectively, vs. 15.9 for morphine; each P < 0.05) [32]. A retrospective clinical utility analysis using the Phase 1 data showed that over clinically relevant concentration ranges, the probability of analgesia exceeded the probability of OIRD for oliceridine, while the probability of OIRD exceeded the probability of analgesia for morphine [33]. In a randomized, double-blind, Phase IIb study that investigated the efficacy, safety, and tolerability of oliceridine (administered as PCA), morphine, and placebo in patients with moderate-to-severe pain following abdominoplasty (NCT02335294), rates of respiratory events were 15% with 0.1 mg oliceridine demand-dose regimen, 31% with 0.35 mg demand-dose regimen and 53% with morphine 1 mg demand-dose regimen) [34].

In the Phase 3 randomized controlled clinical trials, a key secondary endpoint was respiratory safety burden (RSB) calculated as the mathematical product of the incidence of a defined set of observed respiratory safety events (RSE) multiplied by the mean expected cumulative duration of these events (in hours) [18,19]. Observations included as a respiratory safety event were clinically relevant changes in respiratory rate, oxygen saturation, and sedation (measured using the Moline-Roberts Pharmacologic Sedation Scale). In each study, the RSB and RSE measures were numerically lower for each olicerdine dose regimen compared with the morphine regimen; however, they did not reach the threshold for statistical significance (Figure 2, Table 2). In an exploratory analysis evaluating the rate of dosing interruptions due to an RSE and average cumulative duration of interruptions in each study, the proportion of patients with dosing interruptions was higher with morphine 1 mg (17.1% in orthopedic surgery and 25.6% in plastic surgery) compared to oliceridine 0.35 mg (7.6% in orthopedic surgery, 20.3% in plastic surgery) and 0.5 mg (11.4% in orthopedic surgery, 18.8% in plastic surgery) demand dose [35]. The average cumulative duration of interruptions was also lower for all oliceridine demand doses in both Phase 3 controlled clinical trials compared to morphine [35]. 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 [35].

Figure 2. Respiratory safety burden in pivotal Phase 3 studies of oliceridine [18,19]. RSB calculated as the mathematical product of the incidence of respiratory safety events and the mean duration of such events in affected patients. No statistically significant differences for any of the oliceridine treatment groups vs. morphine. Figure Reproduced from Drugs of Today 2020, 56(4): 269. Copyright © 2020 Clarivate or its licensors. All rights reserved. DOI:10.1358/dot.2020.56.4.3107707.

Table 2. Respiratory safety event measures in the pivotal Phase 3 studies. Adapted from [18,19].

Orthopedic Surgery (Bunionectomy) Study	Placebo (N = 79)	Oliceridine Regimens			Morphine 1 mg Regimen (N = 76)
		0.1 mg (N = 76)	0.35 mg (N = 79)	0.5 mg (N = 79)
Respiratory safety event measures
Oxygen saturation < 90%, n (%)	1 (1.3)	3 (3.9)	8 (10.1)	11 (13.9)	15 (19.7)
P value vs morphine	0.005	0.006	0.100	0.352	–
P value vs placebo	–	0.32	0.042	0.016	0.005
Respiratory rate ≤ 8 breaths/min, n (%)	0	0	1 (1.3)	1 (1.3)	4 (5.3)
P value vs morphine	0.956	0.956	0.188	0.185	–
P value vs placebo	–	1.0	0.961	0.961	0.956
Sedation (Moline-Roberts scale ≥3), n (%)	10 (2.7)	14 (18.4)	16 (20.3)	13 (16.5)	15 (19.7)
P value vs morphine	0.242	0.838	0.926	0.610	–
P value vs placebo	–	0.331	0.205	0.501	0.242
Plastic Surgery (Abdominoplasty) Study	Placebo (N = 83)	Oliceridine Regimens			Morphine 1 mg Regimen (N = 82)
		0.1 mg (N = 77)	0.35 mg (N = 79)	0.5 mg (N = 80)
Respiratory safety event measures
Oxygen saturation < 90%, n (%)	7 (8.4)	6 (7.8)	15 (19.0)	16 (20.0)	20 (24.4)
P value vs morphine	0.02	0.01	0.57	0.76	–
P value vs placebo	–	0.86	0.06	0.04	0.02
Respiratory rate ≤ 8 breaths/min, n (%)	1 (1.2)	0	4 (5.1)	6 (7.5)	8 (9.8)
P value vs morphine	0.054	0.95	0.38	0.84	–
P value vs placebo	–	0.96	0.18	0.07	0.054
Sedation (Moline-Roberts scale ≥3), n (%)	15 (18.1)	8 (10.4)	19 (24.1)	18 (22.5)	21 (25.6)
P value vs morphine	0.25	0.02	0.83	0.65	–
P value vs placebo	–	0.17	0.35	0.49	0.25

In both the controlled clinical trials, detection of each RSE required professional judgment by a trained clinician, introducing an element of personal bias. Further, 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 presence of medical co-morbidities and the need to provide clinical relief by the administration of supplemental O₂ [35]. Of note, in both of the randomized controlled trials, patients with a diagnosis of sleep apnea or body mass index (BMI) >35 kg/m² were excluded from participation. Moreover, none of the enrolled patients had COPD, and patients with medical comorbidites such as hypertension, diabetes, or any other cardiovascular disease comprised <15% of the study population (Data on file). Additionally, the rate of RSEs in the Phase 3 controlled trials was lower than expected overall (approximately 50% lower than that observed in the Phase 2b trial) in all active and placebo groups. This may have resulted in a reduced statistical power to detect a significant effect. Thus, the absence of a statistically significant result on the protocol-specified key secondary outcome using the composite index of RSB underscores the methodologic challenges of differentiating respiratory safety outcomes in controlled therapeutic trials across treatment conditions. Nevertheless, differences in the RSEs and the interventions, e.g. drug interruption (lower incidences of drug interruption) do suggest a trend or signal of improved safety that needs further evaluation.

Furthermore, in an exploaratory analysis of a subset of 724 surgical patients from the ATHENA study, OIRD defined as either SpO₂ < 90% or respiratory rate <10 bpm was observed among 13.7% of that population (including SpO₂ < 90% in 5.2% and respiratory rate <10 bpm in 9.3%) [36]. In this subset, 241 patients (33.3%) were ≥65 years of age and 335 (46.3%) were obese (BMI ≥30 kg/m2). OIRD in the elderly patients (vs. young adults) was 10.8% vs. 15.1%: odds ratio 0.68, 95%CI [0.42, 1.1], P = 0.11; and in the obese patients (vs. non-obese) was 14% vs. 13.4%: odds ratio 1.06, 95%CI [0.69, 1.62], P = 0.80. Among 120 patients (16.6%) who were both elderly and obese, the incidence of OIRD was 10.8%. These findings suggest that postoperative oliceridine use in patients with advanced age, increased BMI, or in the elderly with increased BMI was not associated with increased risk of OIRD.

Future trials to further evaluate the respiratory safety of oliceridine should include more detailed prospective indices of respiratory compromise, including the use of continuous respiratory monitoring tools in the postoperative setting; and real-world evidence trials.

3.4. Adverse events of specific interest: cardiac safety

During the clinical development process and review meetings with health authorities regarding the safety database, the US FDA asked the sponsor to clarify the highest dose that had at least 350 patients exposed for 24 hours. This dose was 27 mg of oliceridine; thus, it was agreed with the FDA that 27 mg would be established as the maximum recommended daily dose [22]. Cardiac safety assessments are commonly employed in the clinical development program and mandated by regulatory authorities. The effect of oliceridine on cardiac physiology was evaluated in single- and multiple-dose thorough QT studies using healthy volunteers [16]. The multiple-dose study was conducted with a maximum daily cumulative dose of 27 mg [16]. In both studies, there was mild QTc interval prolongation. In the multiple-dose study, the maximum mean ΔΔQTcI was 11.7 ms (two-sided 90% UCI 14.7 ms) at 9 hours. Thereafter, the QTc effect did not progressively increase with repeat dosing and, despite continued dosing, began to diminish after 12 hours [16].

In the two pivotal controlled Phase 3 studies, no deaths were reported and there were no clinically meaningful differences between active treatment regimens in electrocardiogram findings (including the length of the QT interval) in either study (Data on File). In the Phase 3 open-label safety study, 3% of patients (22/768) met predefined criteria for QT prolongation. Half of these patients had at least one potential confounding factor, and none had an AE or ECG assessment abnormality suggestive of ventricular extrasystoles, premature ventricular contractions, or ventricular tachycardia. One patient who met predefined QTcF criteria of both QTcF >500 msec post-baseline and a change from baseline in QTcF>60 msec was discontinued early in the study; however, the investigator considered this as nonserious, moderate, and unlikely related to oliceridine.

The underlying mechanism and clinical significance of the transient mild QT changes seen in the single-dose and multiple-dose studies in healthy volunteers are unknown and the approved prescribing information does recommend careful consideration when oliceridine is administered in clinical settings where prolongation of the QT interval has been observed either due to the use of concomitant medications known to cause QT prolongation or to underlying medical conditions associated with QT interval prolongation [16].

4. Summary and conclusions

The sum of findings from Phase 3 studies, including findings from exploratory analyses and observational studies, suggest a potentially improved safety profile associated with oliceridine. However, these findings need to be confirmed in future studies and in settings including critical care/intensive care units, emergency departments, and operating rooms. Furthermore, comparative studies are needed using other opioids such as hydromorphone or fentanyl as comparators.

5. Expert opinion

Over the last decade, with the implementation of surgery-specific ERAS protocols, the goal has been to standardize and integrate a range of interventions throughout the perioperative, intraoperative, and postoperative periods in an attempt to achieve early patient recovery with optimized physiologic/organ function [7,37].

With opioid overdoses at epidemic levels in the USA, the rational use of opioids in the perioperative period has been much debated, and implementation of ERAS protocols that promote opioid-free and multimodal analgesia has been proposed [7,38]. However, the term ‘opioid-free’ representing ‘no use of opioid’ is not well defined and subject to interpretation [39,40]. True multimodal analgesia is defined as two or more non-opioid analgesics around the clock with opioids employed as rescue agents. Studies evaluating ‘opioid-free’ anesthesia techniques have reported opioid consumption within 6 h after extubation and a significant increase in the discharge time from recovery [38]. Likewise, a metanalysis of 23 trials that compared ‘opioid-free anesthesia’ with intraoperative opioid use reported that in at least 15 of these trials, parenteral opioids were used in the postoperative period [40]. These findings corroborate that in many surgical situations, opioids are efficacious analgesics and that nonopioid multimodal analgesic components alone are not sufficiently effective [41]. Note that this is not incompatible with the definition of multimodal analgesia. Opioid use disorder is not a ‘silo’ event and the majority of individuals with a substance use disorder are polysubstance users [42]. However, in surgical patients, withholding the use of opioids for acute postoperative surgical pain may result in insufficient pain control and uncontrolled pain is a risk factor for chronic postoperative pain [43], further increasing the risk of opioid misuse post-discharge [44].

Thus, in an era when opioid crisis is increasing, management of surgical patients should focus on ‘opioid minimization’ and defining the ‘optimal’ postoperative multimodal analgesia. At the time of writing this expert opinion, the data from post-approval use of oliceridine is limited. Nonetheless, the findings from all clinical evidence gathered thus far, including the findings from exploratory analyses, suggest a lower incidence of opioid-related adverse events associated with oliceridine. Future studies investigating the use of oliceridine or other opioids with different pharmacological profiles in a perioperative setting and focusing on patient outcomes in minimally invasive surgeries, will further help in moving the field forward.

Article highlights

• Oliceridine IV was recently approved in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate.

• The sum of pain intensity differences (SPID) over the entire randomized period in the pivotal trials of oliceridine vs. placebo was the basis of approval for oliceridine. This was a secondary endpoint in the pivotal controlled studies.

• The primary efficacy endpoint in the pivotal controlled studies was the proportion of patients that were treatment responders (oliceridine IV vs. placebo), defined as patients 1) with at least a 30% improvement in final time-weighted SPID from baseline; 2) without use of rescue pain medication during the randomized treatment period; 3) without early discontinuation of study medication for any reason; and 4) without reaching the study medication volume-based dosing limit. This measure was a more comprehensive assessment that combined indices of efficacy, tolerability, and rescue medication use, as opposed to an exclusive focus on pain intensity as measured by SPID.

• Findings from the clinical studies, including exploratory analyses, suggest that oliceridine may have improved gastrointestinal and respiratory tolerability, although, doses studied were not chosen to be equianalgesic and statistical significance was not reached.

• Further clinical studies are needed in high-risk patients in clinical settings including in critical/intensive care, operating rooms, or emergency departments, and in comparison with other opioid analgesics.

• In the management of postoperative pain, precision medicine with ‘no patient left behind’ will be the direction in the near future. This approach will require utilization of ‘optimal analgesia’ with the rational use of opioids in the perioperative period focusing on ‘opioid minimization.’ A better understanding of the selective pharmacology of opioids including oliceridine, in a perioperative setting will allow the consideration of a tailored approach and implementation of personalized care.

Declaration of interests

E Viscusi was previously a consultant for Trevena and was involved in the design, conduct of the randomized controlled clinical trials, interpretation of the data findings and the preparation of the manuscripts, now published. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The author would like to thank Kanaka Sridharan, MS, employee at Trevena, Inc. for providing editorial assistance and development of the figures.

Additional information

Funding

This paper was not funded.