Gastroscopy is the gold standard for diagnosing upper gastrointestinal diseases and can effectively detect conditions such as gastritis, gastric polyps, and gastric or esophageal tumors. Relevant epidemiological studies indicate that gastroscopy is recommended for the general population aged ≥45 years, and individuals with normal findings are advised to undergo repeat gastroscopy every 3–5 years, while patients diagnosed with chronic atrophic gastritis or higher-grade lesions should receive annual endoscopic surveillance (Li et al., 2024). Nevertheless, the clinical utility of conventional gastroscopy is compromised by procedure-induced viscerosensory reactions (including emesis, laryngospasm, and autonomic instability), which contribute to suboptimal adherence. Among patients undergoing gastroscopy, 41%–61% exhibited clinically significant procedural discomfort and anxiety (Abraham et al., 2002). With advancements in medical technology and heightened health awareness, painless gastroscopy has gained increasing clinical adoption. Sedated gastroscopy maintains patients in a sleep state throughout the procedure, effectively eliminating anxiety and pain during procedure. This approach not only enhances endoscopic visualization quality but also facilitates the detection of subtle early-stage lesions and improves diagnostic accuracy. The current pharmacological mainstay predominantly utilizes propofol combined with opioids. Propofol demonstrates favorable sedative properties, including rapid onset, short duration of action, and predictable recovery profiles. However, its limited analgesic efficacy and inability to suppress stress responses necessitate dose escalation, which may induce dose-dependent hypotension and respiratory complications (e.g., shallow breathing, bradypnea, or transient apnea) (Martorano et al., 2008). Consequently, adjunct administration with opioid analgesics remains standard practice. Nevertheless, the concomitant use of traditional opioids such as fentanyl elevates risks of opioid-related adverse events, particularly nausea/vomiting and respiratory depression (Tsai et al., 2021). It was demonstrated that the incidence of opioid-related adverse events (ORAE) has been reported to reach 10.6%, which is associated with prolonged hospital stays, increased in-hospital mortality, elevated healthcare expenditures, and higher 30-day readmission rates (Shafi et al., 2018).

Oliceridine is a novel opioid analgesic that functions as a G protein-biased μ-opioid receptor agonist. It provides effective analgesia while demonstrating a reduced incidence of adverse effects such as respiratory depression and gastrointestinal dysfunction compared to conventional opioids (Simons et al., 2023). Based on oliceridines’ pharmacokinetic profile, intravenous bolus administration achieves rapid onset of action within 1–2 min, peaks at 6–12 min, and maintains therapeutic effects for approximately 1–3 h (Kaye et al., 2021). The drug is primarily metabolized by cytochrome P450 (CYP) hepatic enzymes, with inactive metabolites exhibiting negligible pharmacological activity. Pharmacokinetic studies reveal comparable clearance between patients with hepatic or renal impairment and those with normal organ function, supporting its safety in these populations (Nafziger et al., 2020). However, dose reduction may be required for moderate-to-severe hepatic impairment during prolonged administration (Gan and Wase, 2020). These characteristics make oliceridine not only suitable for acute pain management but also advantageous for short-duration procedures such as gynecological interventions and gastrointestinal endoscopy.

Oliceridine demonstrates potent analgesic efficacy with a favorable adverse effect profile characterized by reduced incidence of respiratory depression and gastrointestinal dysfunction. This pharmacological advantage suggests that its combination with propofol may establish a safer and more effective paradigm for painless diagnostic or therapeutic procedures. However, current evidence on oliceridine utilization in non-operating room anesthesia (NORA) contexts remains limited. The safety and efficacy profiles have not been fully characterized owing to a paucity of data regarding clinically validated dosing regimens, and no studies to date have systematically investigated potential sex-specific variations in therapeutic outcomes. This study therefore quantified the median effective dose (ED₅₀) and 95% effective dose (ED₉₅) of oliceridine-propofol coadministration stratified by biological sex during procedural sedation. The established dose-response profiles provide pharmacodynamic references to optimize gender-tailored oliceridine administration in clinical practice.

The study cohort comprised 24 female patients and 19 male patients. One participant in the male group was lost to follow-up after endoscopic procedure (Figure 1). The baseline characteristics of the patients are summarized in Table 1. No statistically significant differences in baseline characteristics were observed between positive and negative subgroups within either sex-stratified cohort (P > 0.05). In the male cohort, patients in the negative group required higher doses of oliceridine compared to the positive group (P < 0.05). In the female cohort, the total propofol dose was lower in the negative group than in the positive group (P < 0.05), while oliceridine doses was higher in the negative group (P < 0.05) (Table 1).

1. Our study was conducted until data for seven crossover points were collected (Figure 2). The ED₅₀ and ED₉₅ values of oliceridine fumarate combined with propofol in painless gastroscopy were 10.38 μg·kg⁻¹ (95% CI: 9.02–11.96) and 13.19 μg·kg^-1 (95% CI: 11.62–28.23) in the female group, and 12.63 μg·kg⁻¹ (95% CI: 11.43–13.79) and 14.46 μg·kg⁻¹ (95% CI: 13.41–20.33) in the male group, respectively (Figure 3).

No significant intraoperative complications, including hypotension, bradycardia, or respiratory depression, were observed in any patient during the procedure. Male patients exhibited vomiting (1/18, 5.56%) and one male participant was lost to follow-up during the study period. Among female, postoperative adverse events included dizziness (3/24, 12.50%), nausea (1/24, 4.17%), and fatigue (1/24, 4.17%) (Table 3).

Our study established the effective dose of oliceridine combined with propofol for gastroscopic procedures. Probit regression analysis determined the ED₅₀ and ED₉₅ of oliceridine to suppress endoscope insertion responses as 10.38 and 13.19 μg·kg⁻¹ in females, 12.63 and 14.46 μg·kg⁻¹ in males. All patients safely and effectively completed the examination without serious complications. Jia et al. (2024) demonstrated that the ED₅₀ of oliceridine combined with propofol for suppressing gastroscope insertion responses was 15 μg·kg⁻¹ in patients aged 18–65 years, compared with 12 μg·kg⁻¹ in those aged >65 years. These findings are similar with our observations. The study by Tang et al. (Tang et al., 2025) reported ED₉₀ and ED₉₉ values of 22.5 and 23.8 μg·kg⁻¹ for oliceridine. The observed discrepancies in our findings may be attributed to methodological variations, particularly their use of the biased coin design (BCD), which potentially enhances the precision of ED₉₀ determination compared to our approach.

Previous studies have demonstrated sex-related differences in the analgesic efficacy of various opioid analgesics. Our findings revealed that both ED₅₀ and ED₉₅ values were significantly lower in the female cohort compared to the male cohort. The mechanisms underlying these sex-based disparities in opioid efficacy are multifactorial. Key contributors include differential pain sensitivity, sex-specific nociceptive signal processing, and variations in drug concentration requirements, receptor sensitivity, and gonadal hormone modulation (Bradbury, 2003; Chaudhary et al., 2017). Notably, neuroimaging evidence indicates that females exhibit stronger μ-opioid receptor binding capacity in cortical and subcortical regions, enabling enhanced analgesic responses to equivalent opioid doses (Bodnar and Kest, 2010). Furthermore, heightened opioid sensitivity in females may stem from gonadal hormone-mediated regulation of opioid receptors (Joe et al., 2016). These hormonal interactions potentiate the inhibitory effects of opioids on stress responses in female patients, underscoring the necessity for sex-specific considerations in clinical analgesic regimens. In clinical practice, individualized dose adjustments of oliceridine should be implemented based on patients’ sex, body weight, pain intensity, and previous medication responses, with particular attention to the potential requirement for lower initial doses in female populations. Close monitoring of therapeutic responses, especially in female patients, remains imperative. These tailored therapeutic strategies and vigilant surveillance constitute the cornerstone for ensuring optimal drug safety and efficacy.

Oliceridine dosage requirements exhibit significant variation across different clinical procedures. Zhang et al. (2024) reported that the ED₅₀ of oliceridine combined with 2 mg·kg⁻¹ propofol for analgesia during induced abortion was 19 μg·kg⁻¹ (95% CI: 15–23 μg·kg⁻¹) in patients with a history of vaginal delivery, compared to 26 μg·kg⁻¹ (95% CI: 21–31 μg·kg⁻¹) in those without such history. Compared to gastroscopy, induced abortion procedures induce more intense nociceptive stimulation, thus necessitating higher oliceridine doses to achieve adequate pain control.

Oliceridine demonstrates approximately 5-fold greater analgesic potency than morphine, effectively suppressing gag reflex, cough, and cardiovascular adverse responses triggered by gastroscope passage through the oropharynx. When combined with propofol, it reduces propofol requirements while mitigating the risk of severe respiratory depression. No procedure-related adverse events (respiratory depression, hypotension, or bradycardia) were observed in the study cohort. This safety profile may be attributed to two key factors: (1) oliceridine’s minimal respiratory depressive effects, as evidenced by prior studies showing comparable respiratory depression rates between oliceridine and placebo even in high-risk populations (BMI ≥30 kg/m²) (Brzezinski et al., 2021); (2) All patients in this study were administered oxygen via dedicated endoscopic masks, which potentially contributed to the reduced incidence of hypoxemia.

Oliceridine has gained significant interest for demonstrating a reduced risk of adverse events (e.g., respiratory depression and gastrointestinal complications) relative to conventional opioids, thereby positioning itself as a potential therapeutic breakthrough to mitigate the clinical challenges associated with existing opioid regimens (Wang et al., 2024). A systematic review and meta-analysis of randomized controlled trials has shown that oliceridine exhibits robust therapeutic efficacy and a favorable safety profile as an intravenous analgesic for postoperative pain management, delivering prompt pain relief with superior tolerability and a significantly lower risk of adverse events relative to morphine and hydromorphone (Biskupiak et al., 2024; Niu et al., 2023). In our study, nausea and vomiting were reported in both male and female cohorts, with a higher incidence observed among female participants. This disparity may be associated with sex-specific physiological characteristics in females, potentially linked to differential pharmacokinetic responses or estrogen-mediated visceral sensitivity modulation.

Postoperative adverse events were infrequent: dizziness (3/24, 12.5%), nausea (1/24, 4.2%), and fatigue (1/24, 4.2%) in females; vomiting (1/19, 5.3%) and one loss to follow-up in males. These findings align with oliceridine’s biased μ-opioid receptor agonism-preferentially activating G protein-coupled signaling pathways while minimizing β-arrestin recruitment-thereby reducing classic opioid-related adverse effects without compromising analgesia (Bergese et al., 2019; Sun et al., 2023).

This study has the following limitations. Firstly, the research was constrained by the modified sequential method and its single-center design, leading to a relatively limited final sample size. Adopting multicenter studies with larger sample sizes would enhance the accuracy of the findings. Secondly, patients with comorbid chronic conditions were not included in this investigation. The anesthetic efficacy and safety of propofol combined with oliceridine in populations with underlying chronic diseases require further exploration. Thirdly, this study did not employ end-tidal carbon dioxide (PetCO₂) monitoring. Future research incorporating PetCO₂ monitoring could more sensitively and precisely reveal the dynamic changes in respiratory depression during sedation and its independent association with adverse reactions such as hemodynamic changes. Fourthly, additional randomized controlled trials are warranted to investigate the clinical applications of oliceridine in anesthesia practice.

The combination of oliceridine and propofol effectively suppresses the response to gastroscope insertion during painless gastroscopy, with high safety and minimal complications. In the female group, the ED₅₀ of oliceridine was 10.38 μg·kg⁻¹, and the ED₉₅ was 13.19 μg·kg⁻¹. In the male group, the ED₅₀ of oliceridine was 12.63 μg·kg⁻¹, and the ED₉5 was 14.46 μg·kg⁻¹.