Oliceridine Demonstrates Non-Inferior Analgesia and Superior Safety vs Sufentanil in Post-Cesarean PCIA
核心洞察
Oliceridine was non-inferior to sufentanil for PCIA after cesarean delivery, with a GEE-adjusted mean SPID48 difference of 24.60 (95% CI, 10.83–38.37), exceeding the non-inferiority margin of −20.
The overall adverse event rate was significantly lower with oliceridine (18.8% vs 36.2%, P=0.013), driven primarily by reduced nausea (7.5% vs 20.0%, P=0.022).
Time to first lactation was significantly earlier in the oliceridine group (47.0 vs 52.0 hours, P<0.001), and patient satisfaction scores were higher (7.0 vs 6.0, P<0.001).
Oliceridine, a first-in-class G protein-biased μ-opioid receptor (搜索) agonist, demonstrated non-inferior analgesic efficacy compared with sufentanil when used for patient-controlled intravenous analgesia (PCIA) after cesarean delivery, while offering a significantly improved safety and tolerability profile, according to results from a prospective, randomized, double-blind trial.
The study, conducted at the Affiliated Lianyungang Hospital of Xuzhou Medical University (搜索) between May and November 2025, enrolled 176 patients undergoing elective cesarean delivery under combined spinal-epidural anesthesia. After exclusions, 160 participants were included in the final analysis, with 80 in each group.
Primary Endpoint Met with Superiority Signal
The primary outcome, Sum of Pain Intensity Differences over 48 hours (SPID48), confirmed oliceridine's non-inferiority. Based on generalized estimating equations (GEE) analysis, the adjusted mean SPID48 was 172.50 (95% CI, 163.37–181.63) in the oliceridine group versus 147.90 (95% CI, 137.59–158.21) in the sufentanil group, yielding a mean difference of 24.60 (95% CI, 10.83–38.37). The lower limit of the 95% CI exceeded the pre-specified non-inferiority margin of −20.
Notably, the entire 95% CI for the difference lay above zero, suggesting a possible superiority signal. However, the authors caution that "such an interpretation is hypothesis‑generating only, because the study was not powered for superiority."
The overall treatment effect was significant (Wald χ² = 19.780, df = 1, P < 0.001), as were the time effect (Wald χ² = 1945.929, df = 3, P < 0.001) and the treatment × time interaction effect (Wald χ² = 14.659, df = 3, P = 0.002).
Secondary Pain Outcomes Favor Oliceridine
GEE analysis showed that average resting NRS scores at 12, 24, and 36 hours postoperatively were all significantly lower in the oliceridine group (all P < 0.001). The summed pain intensity differences at 12, 24, and 36 hours were also significantly greater with oliceridine (all P < 0.001).
PCIA usage parameters further supported oliceridine's efficacy. The oliceridine group had significantly fewer median total PCIA demands (34.0 vs 56.0, P < 0.001), fewer valid boluses delivered (32.0 vs 44.5, P < 0.001), and lower total analgesic pump dose (62.5 mL vs 69.0 mL, P = 0.034).
Safety Profile: Reduced Nausea and Overall Adverse Events
The overall incidence of adverse events was 18.8% (15/80) in the oliceridine group, significantly lower than 36.2% (29/80) in the sufentanil group (P = 0.013). The incidence of nausea was notably reduced with oliceridine (7.5% vs 20.0%, P = 0.022), corresponding to an absolute risk reduction of 12.5% (95% CI, 2.0% to 23.0%) and a relative risk of 0.38 (95% CI, 0.15 to 0.91).
No statistically significant differences were found between groups for vomiting, dizziness, constipation, pruritus, chest tightness, or fever (P > 0.05).
Maternal Recovery and Lactation
The median time to first lactation was significantly earlier in the oliceridine group (47.0 hours vs 52.0 hours, P < 0.001). Median overall analgesia satisfaction score at 48 hours was higher with oliceridine (7.0 vs 6.0, P < 0.001). The proportion of patients requiring rescue analgesia was identical in both groups (32.5%), though median time to first rescue request was significantly longer with oliceridine (12.0 vs 10.0 hours, P = 0.010).
Mechanistic Rationale
Oliceridine was specifically engineered to preferentially activate the G protein signaling pathway, which mediates potent analgesia, while minimizing engagement of the β-arrestin-2 pathway believed responsible for many typical opioid-related adverse effects, particularly respiratory depression and gastrointestinal dysfunction. Upon binding to the μ-opioid receptor (搜索), oliceridine exhibits markedly reduced efficacy in recruiting β-arrestin-2—approximately 14% of that of morphine.
The study authors note that the pharmacokinetic profile of oliceridine—with a fast onset of analgesia (1–2 minutes), peak effect within 6–12 minutes, and a short elimination half-life (approximately 1.3–3 hours)—may contribute to its rapid analgesic response and dynamic dose titration capability.
Limitations
The single-center design may affect generalizability. The sample size, while adequate for primary efficacy, was underpowered for rare adverse events. The 48-hour observation period precluded assessment of long-term outcomes such as persistent pain or breastfeeding continuation. The absence of breast milk oliceridine concentration data necessitates future pharmacokinetic studies to fully establish neonatal safety during breastfeeding.
The study was registered with the Chinese Clinical Trials Registry (ChiCTR2500100326) and approved by the Institutional Review Board of the Affiliated Lianyungang Hospital of Xuzhou Medical University (搜索) (Ethic Approval No: KY-20240801002-02).