Comparison of Ciprofol-Nalbuphine and Propofol-Nalbuphine Sedation During Painless Gastrointestinal Endoscopy: A Randomized Controlled Trial

Introduction

Gastrointestinal endoscopy is recognized as a critical modality for the early detection of gastrointestinal tumors and cancer surveillance [1,2]. Sedation during gastrointestinal endoscopy procedures alleviates patient discomfort [2], improves the endoscopist’s procedural experience, and facilitates accurate examinations under stable operative conditions [3,4]. Although intravenous (IV) propofol is currently the widely adopted anesthetic agent for gastrointestinal endoscopy, it presents several well-documented limitations, including a high incidence of injection pain [5], hemodynamic instability manifesting as hypotension, and dose-dependent respiratory depression that can progress to apnea [6,7]. The optimization of procedural sedation protocols to ensure efficacy and patient safety remains a subject of ongoing interdisciplinary debate between the anesthesiology and gastroenterology domains [8].

Ciprofol (HSK3486), a novel 2,6-disubstituted phenolic derivative, is an investigational IV anesthetic sharing structural homology with propofol [8–10]. Building upon the structural framework of propofol, the addition of a cyclopropyl moiety enhances its binding affinity for gamma-aminobutyric acid type A (GABA-A) receptors [11,12], thereby inducing central nervous system inhibition to produce sedative and anesthetic effects [13]. While ciprofol exhibits a pharmacokinetic profile comparable to that of propofol, emerging evidence suggests its superior sedative efficacy with reduced respiratory depression and hemodynamic compromise [2]. These pharmacological advantages position ciprofol as a promising alternative to propofol for procedural sedation during gastrointestinal endoscopy. A meta-analysis of 6 randomized controlled trials (involving 1225 patients) demonstrated that, when used for gastrointestinal endoscopy in adults, ciprofol and propofol provide similar sedative effects. However, ciprofol exhibits a superior safety profile, with a lower incidence of respiratory depression and injection pain and higher patient satisfaction [14].

Similar to propofol, ciprofol lacks intrinsic analgesic properties. When combined with opioids, the opioid can mitigate cardiovascular responses to noxious stimuli, allowing a lower dose of ciprofol to achieve adequate sedation [15]. However, potent opioids carry a risk of dose-dependent respiratory depression. Nalbuphine, a mixed agonist-antagonist opioid, presents a clinically advantageous alternative for gastrointestinal endoscopy. By acting as a μ-receptor antagonist and κ-receptor agonist, nalbuphine provides selective analgesia for visceral pain – a hallmark of gastrointestinal interventions – while it maintains a favorable safety profile [16]. Additional benefits include a reduced incidence of opioid-associated adverse effects, such as postoperative nausea and vomiting, compared with other opioid analgesics [17].

With its distinct pharmacological profile, the synthetic opioid nalbuphine is an attractive option for analgesia in painless gastrointestinal endoscopy [18]. Evidence from several clinical trials and meta-analyses suggests that ciprofol outperforms propofol regarding respiratory depression, hypotension, and injection pain for painless gastrointestinal endoscopy [14,19]. However, it remains unknown whether combining nalbuphine with ciprofol offers a definitive advantage over its combination with propofol in this setting, as relevant studies are lacking.

We hypothesized that the coadministration of ciprofol and nalbuphine can enhance safety margins and accelerate postoperative recovery following painless gastrointestinal endoscopy. While the safety profile of ciprofol monotherapy has been established in gastroscopy and colonoscopy [20], robust clinical evidence supporting the combined use of ciprofol and nalbuphine for procedural sedation remains limited. To address this gap, we conducted a comparative analysis of ciprofol versus propofol for achieving moderate sedation in patients undergoing gastrointestinal endoscopy, specifically evaluating the incidence of cardiopulmonary adverse events and postprocedural recovery metrics.

Material and Methods

DESIGN AND PATIENTS:

This single-center, randomized, controlled clinical trial was conducted at the Endoscopic Center of Wuxi Huishan District People’s Hospital, Jiangsu Province, China. The study protocol was approved by the Institutional Review Board of the hospital (approval No. HYLL20250103001) and was prospectively registered with the Chinese Clinical Trial Registry (rChiCTR2500095492). The trial adhered to the ethical principles outlined in the Declaration of Helsinki (1975 revision). Written informed consent was obtained from all enrolled participants prior to study initiation.

Patients aged 18 to 65 years scheduled for elective painless gastrointestinal endoscopy were eligible for enrollment in this trial. Inclusion criteria were American Society of Anesthesiologists physical status I–II, respiratory rate 12 to 18 breaths per minute, heart rate 50 to 100 beats per minute (bpm), systolic blood pressure (SBP) between 90 and 180 mmHg, diastolic blood pressure between 60 and 100 mmHg, and peripheral oxygen saturation (SpO₂) >95% on room air. Exclusion criteria were history of hypersensitivity to propofol, ciprofol, or nalbuphine; anticipated difficult airway; severe psychiatric disorders or emotional disturbances; impaired cardiopulmonary function, including severe hypertension, myocardial ischemia, heart failure, second-degree atrioventricular block, and severe chronic obstructive pulmonary disease; hepatic or renal dysfunction; and any other conditions deemed clinically inappropriate for participation by the investigators.

ANESTHESIA MANAGEMENT:

Patients were randomly assigned to either the ciprofol or propofol group in a 1: 1 ratio using a computer-generated randomization sequence without stratification. Allocation concealment was achieved through sequentially numbered, sealed opaque envelopes. Following envelope opening, the attending anesthesiologist administered the allocated agent according to a predetermined anesthetic protocol, to ensure patient safety. Participants, endoscopists, and outcome assessors (data collectors) remained blinded to group assignments throughout the trial. All outcome measurements were independently recorded by a blinded, qualified anesthesiologist not involved in patient care or data analysis.

All patients were positioned in the left lateral decubitus position in the endoscopy suite, with standard monitoring in place, including noninvasive blood pressure, electrocardiogram, pulse oximetry (SpO2), and bispectral index. In both groups, supplemental oxygen was administered via a nasal cannula at a flow rate of 3 L/min, starting before the procedure and continuing until the patients regained full consciousness after the procedure. Prior to the procedure, all patients received 0.1 g of lidocaine syrup applied to the throat [2]. All patients received 0.15 mg/kg nalbuphine IV (nalbuphine hydrochloride injection, 10 mg/2 mL; Yangtze River Pharmaceutical Industry Co, Ltd, China) over 15 s prior to the administration of study drugs. Patients were randomized to receive an initial induction dose of either ciprofol (0.4 mg/kg; HaiSiKe, Liaoning, China) or propofol (2.0 mg/kg; HaiSiKe, Liaoning, China) for sedation induction [21]. The anesthesiologist meticulously controlled the IV injection rate, completing the initial dose induction within 30 s. The level of sedation was evaluated using the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale. Gastroscopy was initiated once the patient achieved adequate sedation (MOAA/S ≤3), followed by colonoscopy. During the procedure, the MOAA/S score was recorded every 3 min. Maintenance doses of sedation were administered as bolus top-ups (0.1 mg/kg ciprofol for group ciprofol or 0.5 mg/kg propofol for group propofol) if the patient exhibited body movements or obvious swallowing reflexes [21]. If SpO2 fell below 90% for more than 10 s, airway maneuvers, such as jaw thrust or bag-mask ventilation, were performed. Manual ventilation was initiated in cases of refractory hypoxemia or persistent SpO2 desaturation. Pharmacologic interventions, including atropine, ephedrine, and/or inotropes, were administered if SBP dropped below 90 mmHg or heart rate decreased below 50 bpm.

Upon completion of the colonoscopy, patients were transferred to the Post-Anesthesia Care Unit (PACU) for continuous monitoring of vital signs. The Aldrete score [22,23] was assessed every 2 min after the procedure, and patients were discharged from the PACU to the observation room after achieving 3 consecutive scores of 9 or higher [8]. The Modified Post-Anesthesia Discharge Scoring System score of 10 was used as the discharge criterion [24], encompassing 5 components: vital signs, ambulation, nausea/vomiting, pain, and intraoperative bleeding. Hemodynamic parameters were classified as hypotension or hypertension if there was a 20% or greater decrease or increase, respectively, in mean arterial pressure (MAP) or SBP from baseline values. A heart rate reduction to 50 bpm or lower was defined as bradycardia. Hypoxemia was defined as SpO2 below 90% for more than 10 s.

OUTCOME MEASURES:

The primary endpoint was the incidence of cardiopulmonary adverse events, which included hypotension, bradycardia, and hypoxemia. Hemodynamic parameters demonstrating 20% or greater decrease or increase in MAP or SBP from baseline measurements were respectively classified as hypotension or hypertension. A reduction in heart rate to 50 bpm was considered to indicate bradycardia. The SpO₂ below 90% for more than 10 s was defined as hypoxemia.

The secondary endpoints included the time required for induction, time to awakening, incidence of injection pain, and occurrence of body movements. Injection pain was evaluated 5 s after the administration of the study drug by observing behavioral signs such as facial grimacing or arm withdrawal. Safety outcomes assessed included upper airway obstruction (defined as snoring accompanied by paradoxical breathing), apnea (defined as the absence of respiratory effort for ≥10 s or a flat line on capnography for ≥10 s), and the intraoperative use of atropine, vasopressors, and/or inotropes [25].

CALCULATION OF SAMPLE SIZE:

PASS 15.0.5 (NCSS, LLC, Kaysville, USA) was used for sample size calculation. Based on data from Zhang et al [2], the incidence of cardiopulmonary adverse events was 60.9% with propofol and 34.4% with ciprofol, while the incidence of respiratory adverse events was 38.0% with propofol and 17.2% with ciprofol. A sample size of 55 participants per group was calculated to be sufficient to detect a statistically significant difference (α=0.05, power=90%). Accounting for a 10% attrition rate, a minimum of 64 participants per group were enrolled.

STATISTICAL ANALYSIS:

All data were analyzed using SPSS 22.0 (IBM Corp, Armonk, NY, USA). The Shapiro-Wilk test was employed to assess the distribution of continuous variables. Normally distributed data are expressed as mean±SD and were analyzed using the independent 2-sample t test, while non-normally distributed data are described as median (range) and were analyzed using the Mann-Whitney U test. Repeated measures data, such as blood pressure and heart rate, were analyzed using repeated measures analysis of variance. Categorical variables were analyzed using the chi-square (χ²) test or Fisher exact test and expressed as frequencies and percentages. A P value <0.05 was considered statistically significant.

Results

TRIAL POPULATION AND BASELINE CHARACTERISTICS:

Between January 2025 and May 2025, 150 patients undergoing gastrointestinal endoscopic procedures at Huishan District People’s Hospital, Xinglin College of Nantong University were initially screened for eligibility. Following the application of exclusion criteria, 128 eligible participants were subsequently enrolled in the study and randomized to receive either ciprofol or propofol for sedation (Figure 1). There was no significant difference between the groups in baseline demographic, clinical, and procedural characteristics (P>0.05; Table 1).

ANESTHETIC USE AND SEDATION TIME:

As showed in Table 2, the ciprofol group required significantly lower doses of sedative agents, compared with the propofol group, with a total ciprofol dosage equivalent to one-fourth that of propofol (45.8±7.8 mg vs 125.9±23.5 mg) and an induction dose reduced to one-sixth of propofol’s requirement (26.1±4.4 mg vs 83.42±20.2 mg). Furthermore, ciprofol demonstrated superior induction efficiency, achieving sedation in 48.9±3.6 s, compared with 51.4±4.9 s for propofol (P=0.001).

PRIMARY AND SECONDARY OUTCOMES:

Cardiopulmonary adverse events were reported in 3 patients (4.8%) in the ciprofol group and 10 patients (18.7%) in the propofol group, demonstrating a statistically significant difference (P=0.028). The ciprofol group exhibited a significantly lower incidence of secondary outcomes, including injection pain, cough, and body movement, compared with the propofol group (P=0.011). Similarly, the incidence of safety-related outcomes, such as tachycardia, upper airway obstruction, asphyxia, and the requirement for vasoactive drug administration, was significantly lower in the ciprofol group than in the propofol group (P=0.022; Table 3).

HEMODYNAMICS:

Hemodynamic parameters, including blood pressure and heart rate, were continuously monitored throughout all phases of the procedure. Both groups exhibited significant alterations in blood pressure and heart rate at the time of induction (P<0.005). At the T2 time point (at the time of gastroscopy reaching the throat), SBP, diastolic blood pressure, and MAP were notably lower in the propofol group than in the ciprofol group, suggesting that the ciprofol group maintained more stable arterial pressure during the induction phase. However, no statistically significant differences in blood pressure were observed between the 2 groups during the endoscopic procedure or the recovery period. No statistically significant differences in heart rate variations were observed between the 2 groups at the 5 designated time points (P>0.05; Table 4).

SATISFACTION AND POSTPROCEDURAL ASSESSMENTS:

From the perspectives of endoscopists, anesthesiologists, and independent observers, ciprofol demonstrated superior sedation satisfaction, compared with propofol, as assessed by visual analog scale scores (P<0.005). Additionally, the ciprofol group exhibited greater patient cooperation, as evaluated by the observers. Although the propofol group reported slightly prolonged abdominal pain or distension after awakening, the difference did not reach statistical significance (P>0.05; Table 5).

Discussion

This study was the first to evaluate the combination of ciprofol and nalbuphine for gastrointestinal endoscopy sedation. The results are highly encouraging and support the study hypothesis, showing that the regimen effectively achieved adequate sedation, reduced respiratory adverse events, and improved hemodynamic stability.

Despite the extended induction duration in the propofol group, our results demonstrated a markedly reduced induction time relative to the 1.1-min benchmark established by Zhang et al [2] for 0.3 mg/kg ciprofol. We speculate that this phenomenon may be attributed to the IV administration of nalbuphine (0.15 mg/kg) 3 min prior to anesthesia induction. Based on the pharmacokinetic profile of nalbuphine, which exhibits an onset of analgesic action within 2 to 3 min following IV administration [26], gastroscopy was intentionally initiated 2 to 3 min after injection, to align with the drug’s therapeutic efficacy window. The induction dose indicated that ciprofol demonstrated 4- to 5-fold greater potency relative to propofol, a finding that aligns with that of a prior study conducted by Hu et al [27]. In a randomized, double-blind phase IIb clinical trial evaluating procedural sedation during colonoscopy, ciprofol administered at 0.4 to 0.5 mg/kg demonstrated comparable sedative/anesthetic efficacy to propofol 2.0 mg/kg, with statistically equivalent safety outcomes, as evidenced by similar incidence of adverse events across treatment arms [28]. The preclinical investigations demonstrated that ciprofol exhibits 5-fold greater GABA receptor potentiation efficacy, compared with propofol. Mechanistically, this enhanced receptor activation correlates with the superior therapeutic margin of ciprofol, as shown by the toxicological assessment of the therapeutic index (TI=LD50/ED50), which demonstrates a 2.5-fold enhancement over propofol [29,30]. Dose-response analysis revealed that, in the context of procedural sedation for painless gastroscopy, the nalbuphine-propofol coadministration regimen exhibited a median effective dose (ED50) of 0.078 mg/kg and a 95% effective dose (ED95) of 0.162 mg/kg, as quantified by pharmacodynamic modeling under standardized anesthetic protocols [16]. Therefore, the present study established an IV nalbuphine administration regimen at 0.15 mg/kg.

This investigation demonstrated that ciprofol was more effective than propofol in reducing treatment-related respiratory adverse events and the need for clinical interventions, a finding that is consistent with prior studies using varied pharmacological regimens [28,31]. Notably, the findings further corroborated ciprofol’s favorable respiratory safety profile, demonstrating stable respiratory parameters and a low incidence of respiratory depression in geriatric and non-geriatric patient cohorts, thereby highlighting its potential advantages in perioperative respiratory management [32].

The present study demonstrated that ciprofol caused less cardiovascular depression than propofol, particularly during anesthetic induction phases. The observed prevalence of hypotensive episodes and sinus bradycardia associated with anesthetic administration may be mechanistically linked to propofol’s GABA-ergic modulation within brainstem autonomic nuclei, which exerts inhibitory effects both on chronotropic regulation and vasomotor tone maintenance [29,33]. Emerging evidence has demonstrated that hemodynamic instability during gastrointestinal endoscopy procedures, particularly hypotension, may correlate with the other studies revealing that fluid depletion occurring after intestinal preparation procedures might trigger hypotension [34].

Although Li et al reported a higher frequency of injection pain [20], the propofol group in the present study exhibited an incidence of only 14.1%, a statistically significant reduction possibly resulting from systematic nalbuphine premedication. According to a recent study, the concentration of ciprofol in the aqueous phase of a 1% lipid emulsion is markedly lower than that of propofol, and ciprofol’s increased hydrophobic properties may result in less injection pain [35]. The lower incidence of injection pain with ciprofol administration was theorized to correlate with heightened patient satisfaction scores.

A key strength of our treatment protocol lies in its shortened onset and recovery periods, which facilitated prompt patient discharge from endoscopy departments. The prolonged sedation onset time (63.4 s) reported in the 0.4 mg/kg ciprofol group by Gao et al [36], compared with our findings, may be attributed to the concomitant administration of nalbuphine in our study design. Bian et al [11] demonstrated the superior anesthetic profile of ciprofol, with minimal residual effects, noting patient recovery typically occurring within 5 to 14 min; however, our study recorded a mean recovery time of 7.1 min with ciprofol-nalbuphine. Although previous studies on painless gastrointestinal endoscopy have shown that the recovery time with ciprofol is shorter than that with propofol, interestingly, the present study showed no statistically significant difference in recovery time between the ciprofol and propofol groups. We hypothesize that the preoperative administration of nalbuphine reduced the required doses of both agents. The satisfaction of the endoscopist is predominantly determined by optimal patient cooperation (eg, absence of involuntary movements) and efficient workflow in the gastroenterology suite, which is closely linked to recovery time. The low occurrence of postoperative nausea and vomiting observed in both groups in the present study may be due to the established safety profile of nalbuphine, as shown previously [17].

The limitations of this study included the following. 1) The relatively young patient population and exclusion of individuals with obesity potentially reduced the incidence of upper airway obstruction. 2) Routine blood glucose monitoring was not performed during gastrointestinal endoscopy, as hypoglycemia can contribute to hypotensive symptoms. 3) The single-center design with a small sample size limits generalizability. 4) The adverse effects of sedative medications after patient discharge were not systematically evaluated. Given these limitations, it is imperative to conduct multicenter, large-scale trials assessing IV ciprofol combined with nalbuphine for endoscopic polypectomy in diverse patient populations.

Conclusions

This study demonstrates that the combination of ciprofol and nalbuphine is a promising sedation regimen for gastrointestinal endoscopy. This protocol achieves rapid anesthetic onset within less than 1 min and recovery within approximately 7 min, while maintaining a low incidence of cardiopulmonary adverse events. Based on this study’s findings, ciprofol may emerge as a pivotal agent in future endoscopic sedation protocols, offering an effective and safe pharmacological profile for procedural sedation.