The Satisfactory Analgesia and Minimal Emesis of Elderly Patients After Thoracoscopic Lung Surgery: Oliceridine versus Sufentanil in a Randomized Controlled Trial

Introduction

Video-assisted thoracoscopic surgery (VATS) is a widely adopted minimally invasive procedure characterized by reduced trauma and faster recovery.^1–3 Nevertheless, postoperative pain remains a significant concern following VATS, with over half of patients experiencing moderate to severe acute pain,⁴ and approximately 25–50% developing chronic post-surgical pain.⁵

Patient-controlled intravenous analgesia (PCIA) is recommended by the American Pain Society as a primary approach for postoperative analgesia,⁶ and it can be combined with intercostal nerve blocks to form an effective multimodal analgesia regimen in VATS.^7,8 Opioids serve as the core therapeutic agents in PCIA due to their potent analgesic effects. Among these, sufentanil has gained increasing utilization for postoperative analgesia owing to its rapid onset and manageable safety profile.^7,9 Nevertheless, it still carries a significant risk of opioid-related adverse events, especially postoperative nausea and vomiting (PONV), which occurs in over 30% of patients even with prophylactic measures.¹⁰

Elderly patients exhibit unique physiological vulnerabilities following VATS. Age-related reductions in respiratory muscle strength and impaired cough clearance predispose elderly patients to sputum retention, atelectasis, and pulmonary infection.¹¹ Postoperative cough-associated pain further suppresses effective expectoration, exacerbating these risks. Although opioids provide potent analgesia, opioid-induced nausea and vomiting (OINV) often lead to premature dose reduction or discontinuation, resulting in inadequate pain control.¹² Consequently, patients avoid coughing due to pain, which impairs sputum clearance and increases the risk of pulmonary complications. Additionally, elderly patients often exhibit declined swallowing function and airway protective reflexes, rendering them more susceptible to aspiration pneumonia secondary to OINV,¹³ while age-related declines in hepatic, renal, and respiratory function further predispose them to opioid-related respiratory depression.¹⁴ Thus, an analgesic that effectively controls cough-related pain while minimizing opioid-related adverse events is essential for optimizing outcomes in this population.

Mechanistically, conventional opioids exert analgesia via μ-opioid receptor activation, engaging both the analgesic G protein pathway and the β-arrestin pathway linked to adverse events,^15,16 such as respiratory depression, nausea and vomiting, and gastrointestinal dysfunction. In contrast, oliceridine, a novel US FDA-approved (August 2020) G protein-biased μ-opioid receptor agonist for moderate to severe acute pain, exhibits biased agonism that markedly reduces β-arrestin recruitment,^17,18 theoretically, offering a safer profile for vulnerable patients. However, the therapeutic potential of oliceridine for elderly VATS patients remains unexplored.

The satisfactory analgesia with minimal emesis (SAME) is a clinically meaningful composite endpoint that has been previously applied in VATS patients,^19,20 which can balance the benefits of G protein pathway mediated analgesia and β-arrestin-mediated adverse events. Therefore, we conducted this randomized controlled trial to compare the efficacy of PCIA with oliceridine versus sufentanil using the composite endpoint of SAME in elderly VATS patients.

Materials and Methods

Ethical Statements

This study (2024-SR-793) was approved by the Ethics Committee of The First Affiliated Hospital with Nanjing Medical University in accordance with the Declaration of Helsinki. Informed consents were obtained from all enrolled patients. The trial was registered with the Chinese Clinical Trial Registry (www.chictr.org.cn, ChiCTR2500102213).

Criteria for the Subjects

Patients aged 65–80 years with ASA physical status II or III, BMI 18–30 kg/m², scheduled for elective video-assisted thoracoscopic lobectomy or segmentectomy were included in this study. Exclusion criteria included hepatitis, renal dysfunction, severe cardiovascular or cerebrovascular disease, chronic pain, mental illness, hypersensitivity to study medications, regular use of sedatives or analgesics, inability to read, write or comprehend, intraoperative blood loss ≥ 800 mL, conversion to thoracotomy, and postoperative admission to ICU.

Randomization and Blinding

An independent statistician generated the randomization sequence using SAS version 9.3 (SAS Institute Inc., Cary, NC, USA) with permuted blocks of 4, to achieve 1:1 allocation to the oliceridine or sufentanil group. Allocation was sealed in sequentially numbered opaque envelopes controlled by investigators who were not involved in data acquisition or study implementation. After surgery began, the coordinator opened the envelopes and prepared the PCIA pump with the assigned study drug (oliceridine or sufentanil). All pumps were labeled only as “trial drug” to ensure visual uniformity and were delivered to the anesthesiologists before the end of surgery. All patients, healthcare team members, and outcome assessors were therefore blinded to treatment allocation.

Anesthesia and Interventions

Before surgery, patients adhered to a standard preoperative fast of 6 h for solids and 2 h for clear fluids and received instructions on the PCIA pump and the Numerical Rating Scale (NRS) for pain assessment.

In the operating room, standard monitoring was applied, including electrocardiography, pulse oximetry (SpO₂), invasive arterial blood pressure, end-tidal CO₂, and nasopharyngeal temperature. Bispectral index was used to monitor depth of anesthesia. General anesthesia was induced with i.v. midazolam 0.04 mg/kg, ciprofol 0.3 mg/kg, sufentanil 0.4 μg/kg and cisatracurium 0.2 mg/kg. Double-lumen endotracheal intubation was performed for mechanical ventilation (Dräger Fabius^® Plus, Germany). Ventilator parameters were set as tidal volume 5–8 mL/kg, PEEP 5 cmH₂O, and were adjusted to maintain SpO₂ ≥ 95% and an end-tidal CO₂ 35–45 mmHg. Anesthesia was maintained with a continuous intravenous infusion of propofol 2–5 mg/kg/h, remifentanil 0.1–0.3 μg/kg/min, and sevoflurane 1–3% titrated to maintain BIS between 40–60. Cisatracurium was administered intermittently based on surgical requirements. Intraoperative blood pressure fluctuation was maintained within 20% of baseline values, and nasopharyngeal temperature was kept above 36 °C. Moreover, dexamethasone 5 mg and ondansetron 8 mg were routinely administered during anesthesia to prevent PONV. Prior to wound closure, the intercostal nerve block under direct thoracoscopic vision was performed by the same designated surgeon with 20 mL of 0.66% liposomal bupivacaine at T4 to T7 intercostal space. A independent nurse then connected them to the PCIA pump according to their group assignment after the patient had fully emerged from anesthesia. Moreover, flurbiprofen axetil 50 mg was administered intravenously twice daily for the first 3 postoperative days (PODs). The patients were randomized to one of the following PCIA program: The oliceridine group received 20 mg oliceridine diluted in 100 mL 0.9% saline, while the sufentanil group received 100 μg sufentanil prepared similarly in 100 mL 0.9% saline. The pump parameters were standardized across both groups, comprising 2 mL bolus (oliceridine 0.4 mg or sufentanil 2.0 μg), 10-minute lockout time, and background infusion of 1 mL/h (oliceridine 0.2 mg/h or sufentanil 1.0 μg/h). Earlier studies indicate that the analgesic potency of oliceridine is approximately 5 times that of morphine,²¹ whereas sufentanil is 1000 times stronger.²² Consequently, the dose ratio of sufentanil to oliceridine was calculated to be 1:200.²³

Postoperative pain was assessed using the NRS (11-point scale: 0 [no pain], 0 < NRS < 4 [mild pain], 4 ≤ NRS < 7 [moderate pain], 7 ≤ NRS < 10 [severe pain], 10 [worst pain imaginable]). Rescue analgesia with dezocine 5 mg iv. was administered if the patient had a NRS score ≥ 4 or complained of pain even after a PCIA bolus. The PONV score was defined as follows: 0 = no nausea, 1 = mild nausea (no treatment needed), 2 = moderate nausea or retching (may need treatment), 3 = frequent vomiting (controlled with antiemetics), and 4 = severe vomiting (uncontrolled with antiemetics). Rescue antiemetic therapy with additional ondansetron 8 mg i.v. was administered to patients who had a PONV score ≥ 2.

Study Outcomes

The primary outcome was the proportion of patients achieving SAME within the first 3 PODs, defined as a daily average NRS score during coughing (assessed at 8-h intervals) < 4 and daily highest PONV score < 2.¹⁹ Secondary outcomes included the NRS scores during coughing, 15-item Quality of Recovery (QoR-15) scale scores (ranging from 0 to 150, with higher score indicating better postoperative recovery) on POD1–3, the incidence of nausea and vomiting, number of PCIA bolus, and incidence of rescue analgesics within the first 3 PODs, time to ambulation, postoperative length of stay, patient satisfaction score (ranging from 0 [worst] to 5 [best]) for postoperative PCIA, and safety outcomes (including constipation, dizziness, pruritus, urinary retention, severe sedation, and severe respiratory depression) within the first 3 PODs.

Sample Size Calculation

In our pilot study involving 30 patients (15 per group), the observed SAME rates were 60% in the oliceridine group (9/15) and 40% in the sufentanil group (6/15). Based on these preliminary data, a sample size of 99 participants per group was calculated using PASS (version 15.0.5; NCSS, LLC, Kaysville, Utah, USA) for a two-group comparison, providing 80% statistical power at a two-tailed significance level of α = 0.05. To account for potential 20% dropout rate, the final sample size was set to 248 patients, with 124 in each group.

Statistical Methods

The Per-protocol set (PPS) analysis was used to compare the SAME endpoint between oliceridine and sufentanil under standardized conditions, minimizing confounding from protocol deviations and non-adherence. For continuous variables, data are presented as mean ± standard deviation (SD) or median (Quartile 1, Quartile 3) according to the normality of distribution; for categorical variables, data are presented as number (%).

Group differences between the oliceridine and sufentanil groups were examined using independent samples t tests for normally distributed continuous variables and Mann–Whitney U-tests for non-normally distributed continuous variables. Categorical variables were analyzed using Pearson’s chi-squared test or Fisher’s exact test. For longitudinal outcomes, distributional assumptions for repeated-measures ANOVA were assessed. Normality was assessed using the Shapiro–Wilk test, and sphericity was examined using Mauchly’s test. Two-way repeated-measures ANOVA was applied for data satisfying both normality and sphericity assumptions (NRS scores), whereas generalized estimating equations (GEE) were used for variables violating these assumptions (QoR-15 scores). Simple effects with Bonferroni correction were performed for between-group comparisons at each time point. Statistical significance was defined as a two-sided P < 0.05.

The Hodges–Lehmann estimator was used to calculate the median difference with its 95% confidence interval (CI). All statistical analyses were performed using SPSS (version 26.0; IBM SPSS, Chicago, IL, USA) and R software (version 3.5.3; R Foundation for Statistical Computing, Vienna, Austria).

Results

Study Population

From May 2025 to October 2025, a total of 313 patients were assessed for eligibility. Of these, 65 patients were excluded, and 248 patients were randomly (1:1) assigned to either the oliceridine or the sufentanil group. One patient in the oliceridine group was lost to follow-up, per-protocol analysis ultimately included 123 patients in the oliceridine group and 124 in the sufentanil group, as shown in the CONSORT-adherent flowchart (Figure 1). Baseline characteristics and perioperative data were comparable between groups (Table 1).

Table 1 Baseline and Perioperative Characteristics

Figure 1 Study flow diagram.

Primary Outcome

Within the first 3 PODs, a higher proportion of patients achieved SAME in the oliceridine group than in the sufentanil group (46.3% vs 32.3%; absolute difference = 14.1%, 95% CI: 2.0 to 26.1; relative increase 44%; P = 0.023; NNT = 7). On POD1 and POD2, the oliceridine group also demonstrated higher SAME rates, with absolute differences of 14.9% (95% CI: 2.8 to 27.1; P = 0.017) and 14.2% (95% CI: 2.0 to 26.4; P = 0.024), respectively (Table 2).

Table 2 Achievement of SAME and Related Outcomes Within the First 3 Postoperative days

Secondary Outcomes

The oliceridine group displayed significantly lower NRS scores on POD1 (3.6 ± 1.9 vs 4.4 ± 2.1; mean difference, –0.7; 95% CI, –1.3 to –0.1; P = 0.018) and POD2 (3.2 ± 1.2 vs 3.7 ± 1.3; mean difference, –0.4; 95% CI, –0.7 to –0.1; P = 0.039). On POD3, no significant difference was observed between the two groups (2.3 ± 0.8 vs 2.5 ± 0.9; mean difference, –0.2; 95% CI, –0.5 to 0.1; P > 0.05) (Table 3 and Figure 2a).

Table 3 Postoperative NRS Scores, PCIA Utilization and Patient Satisfaction Scores on PCIA

Figure 2 The numerical rating scale (NRS) scores and incidence of nausea and vomiting within the first 3 postoperative days (PODs). (a) NRS scores, Data are presented as mean ± SD; (b) incidence of nausea and vomiting, Data are presented as n (%).

Within the first 3 PODs, the oliceridine group required fewer PCIA boluses (9 [8, 12] vs 11 [8, 13]; P = 0.030) and had a lower incidence of rescue analgesia (4.1% vs 12.1%; P = 0.021) compared to the sufentanil group (Table 3). The incidence of nausea was lower in the oliceridine group than in the sufentanil group (12.2% [15/123] vs 24.2% [30/124]; P = 0.015). A lower incidence of vomiting was also observed in the oliceridine group, but with no statistical difference between groups (5.7% [7/123] vs 10.5% [13/124]; P = 0.167) (Figure 2b).

The oliceridine group exhibited significantly higher QoR-15 scores on POD1 (125 [123, 128] vs 118 [116, 121]; median difference = 7; 95% CI: 4 to 9; P < 0.001) and POD2 (133 [129, 137] vs 128 [125, 131]; median difference = 5; 95% CI: 1 to 8; P = 0.010). In addition, time to ambulation was significantly shorter in the oliceridine group (19 h [16, 22] vs 22 h [18, 25]; median difference = –3 h; 95% CI: –4 to –2; P < 0.001). No significant differences were observed between the two groups in time to chest tube removal, postoperative length of stay, or patient satisfaction scores (Tables 3 and 4).

Table 4 Postoperative Recovery

Safety Outcomes

The incidences of constipation (24 [19.5%] and 21 [16.9%]), dizziness (16 [13.0%] vs 18 [14.5%]), pruritus (6 [4.9%] vs 4 [3.2%]), and urinary retention (3 [2.4%] vs 1 [0.8%]) were similar between the oliceridine and sufentanil groups, with no statistically significant differences. Additionally, one case (0.8%) of severe sedation was reported in the oliceridine group, and one case (0.8%) of severe respiratory depression occurred in the sufentanil group (Table 5).

Table 5 Safety Outcomes

Discussion

In this randomized clinical study, we firstly showed oliceridine provided a 44% relative increase over sufentanil in the proportion of elderly patients achieving SAME within 3 PODs following thoracoscopic lung surgery, underscoring its superior benefits in balance analgesia and side effects.

Post-VATS pain is notably exacerbated by chest wall-stretching movements like coughing, primarily due to intercostal nerve injury or chest tube irritation, which can lead to pulmonary complications and delayed recovery.² While traditional opioids like sufentanil are effective, their utility is limited by a high incidence of PONV.^24,25 Considering the unique challenges of post-thoracotomy pain and the adverse event profile of opioids, our study focused on the proportion of SAME. The proportion of patients achieving SAME within the first 3 PODs was 32.3% in the sufentanil group, which is consistent with prior report,²⁰ whereas the oliceridine group showed a significant increase, with a SAME proportion of 46.3% primarily attributed to its superior analgesic efficacy. Notably, oliceridine reduced moderate-to-severe cough-related pain and rescue analgesia requirements. This finding contrasts with some evidence suggesting oliceridine is not superior^26,27 or is even inferior²⁸ to sufentanil. This discrepancy may be attributed to our specific focus on cough-related pain, which reflects visceral and stretch-sensitive nociception. This interpretation is supported by Meng et al,²⁹ who reported that oliceridine effectively reduced NRS scores during coughing after thoracoscopic surgery, despite no difference in resting pain. The shorter context-sensitive half-time and linear pharmacokinetics of oliceridine likely contribute to more stable plasma concentrations,³⁰ reducing the risk of pain exacerbations. Nonetheless, large-scale, multicenter trials are needed to confirm whether oliceridine provides superior efficacy specifically against visceral pain.

Our findings confirm the superior gastrointestinal tolerability of oliceridine, with the incidence of PONV halved compared to the sufentanil group, a trend similarly observed in a recent study.^23,28 This effect can be explained by the reduced recruitment of β-arrestin in enteric neurons by oliceridine.¹⁵ Notably, the PONV incidence was higher in their study than in our cohort. Additionally, no significant difference was observed in the incidence of moderate-to-severe nausea and vomiting (PONV score ≥2) between oliceridine and sufentanil in our study. These differences may be attributed to the fact that most of patients were not at high risk for PONV, perioperative prophylactic antiemetics, and application of multimodal analgesia.

Previous studies have reported that oliceridine could improve QoR-15 scores at 24 h postoperatively²⁹ and shorten the time to first flatus in patients undergoing laparoscopic hysterectomy.²⁶ Consistent with these findings, our study demonstrated higher QoR-15 scores in the oliceridine group on POD1 and POD2, with median differences of 7 and 5, respectively. As the minimal clinically important difference for QoR-15 is 6.0,³¹ the improvement in quality of recovery was clinically meaningful on POD1. This benefit may be attributable to better analgesia, fewer opioid‑related adverse events, and earlier ambulation. Despite earlier ambulation and higher QoR-15 were observed in Oliceridine group, the postoperative length of stay shown no different, which may be attributed to the consistent duration of chest tube placement and the standardized hospital discharge protocol.

The incidence of safety outcomes was comparable between groups in this study. Among these, opioid-induced respiratory depression is the primary concerned in clinical practice. It was reported that 23% of patients receiving oliceridine-based PCIA experienced respiratory compromise events,²¹ and compared with sufentanil, oliceridine reduced the incidence of respiratory depression in gastrointestinal endoscopy.²³ However, recent studies suggested that oliceridine did not reduce the risk of opioid-induced respiratory depression compared to conventional opioids.^26,27 In our study, no severe respiratory events occurred in the oliceridine group. These inconsistence between studies may due to the differences in the patients enrolled and evaluation indicators.

The findings of this study provide valuable insights for the development of drugs targeting biased μ-opioid receptor signaling pathways. In elderly patients undergoing VATS, oliceridine achieves effective analgesia while producing minimal opioid-related emesis, supporting its potential to dissociate analgesic effects from adverse side effects. Future research can focus on developing agonists with higher selectivity and evaluating their benefits in vulnerable patients at high risk of nausea, vomiting, respiratory depression and oversedation,³² as well as integrating biased agonists into multimodal analgesic regimens to optimize pain management and reduce opioid-related complications.

This study has several limitations. The observed treatment effect (14.1% absolute difference) in our study might be smaller than the anticipated 20% absolute difference from our pilot study, and consequently, further studies are needed to confirm the clinical effectiveness of this analgesic strategy. Second, the study only evaluated NRS scores during coughing, as defined by the SAME endpoint, and did not assess NRS scores at rest. Third, chronic pain after VATS also requires attention; however, we only evaluated the efficacy of oliceridine in acute pain treatment and did not address its impact on chronic pain. Finally, the single-center design may limit the generalizability of our findings.

Conclusion

In elderly patients undergoing thoracoscopic lung resection, oliceridine was associated with a higher proportion of achieving SAME within the first 3 PODs and improved early recovery outcomes as evidenced by higher QoR-15 scores, earlier ambulation, and reduced rescue analgesia needs, with no compromise to safety. These findings support oliceridine as a valuable and well-tolerated opioid option within multimodal analgesic strategies for this population, offering effective pain control while meaningful reducing PONV.