Oxycodone reduces postoperative pulmonary complications compared to sufentanil in high-risk patients with pulmonary dysfunction: a randomized clinical trial

Abstract

Purpose

To compare the effects of oxycodone versus sufentanil on postoperative pulmonary complications (PPCs) in patients with preoperative pulmonary dysfunction undergoing laparoscopic gastrointestinal surgery.

Methods

This single-center, double-blind, randomized, parallel controlled trial was conducted at the First Affiliated Hospital of Ningbo University in Ningbo, China. A total of 142 patients with preoperative pulmonary dysfunction who were scheduled to receive elective laparoscopic gastrointestinal surgery (including Da Vinci robot-assisted surgery) were enrolled between June 6, 2024, to June 30, 2025. Patients were randomized to receive intraoperative oxycodone (0.2 mg/kg) or sufentanil (0.4 µg/kg) during anesthesia induction, and oxycodone 0.1 mg/kg/sufentanil 0.2 µg /kg thirty minutes prior to the end of surgery, followed by PCIA with oxycodone (0.5 mg/kg diluted to 100 mL) or sufentanil (1 µg/kg diluted to 100 mL), with a background infusion of 2 mL/h, bolus 2 mL, and lockout 15 min. The primary outcome was the incidence of PPCs within 30 days after surgery.

Results

Among 142 patients enrolled, 71 were randomized to receive intraoperative oxycodone, and 71 were randomized to receive sufentanil. In total, 7 patients were excluded and 135 patients were included in the ITT analysis. The incidence rate of PPCs was significantly lower in the oxycodone group compared to the sufentanil group (38.2% [26 of 68] vs. 56.7% [38 of 67]; relative risk = 0.67 [95% CI, 0.47 to 0.97]; P < 0.05). The incidence of PONV was also lower in the oxycodone group (16.2% vs 32.8%; relative risk = 0.49 [95% CI, 0.26 to 0.94]; P < 0.05). Pain scores at each time point and Opioid consumption within 48 h postoperatively were comparable between the oxycodone group and the sufentanil group. No statistically significant differences were observed between the two groups regarding postoperative rehabilitation metrics, including time to first flatus and length of hospital stay.

Conclusions

Compared with sufentanil, oxycodone significantly reduced PPCs incidence in high-risk patients with pulmonary dysfunction without compromising analgesia or recovery, suggesting its utility in perioperative lung-protective strategies.

Trial registration

Registration number: ChiCTR2500099262. Registration date: March 20, 2025(Retrospectively registered).

Supplementary Information

The online version contains supplementary material available at 10.1186/s12871-025-03540-x.

Introduction

Postoperative pulmonary complications (PPCs) are characterized by a spectrum of respiratory adverse events occurring within 30 days following surgery. Common PPCs include pneumonia, atelectasis requiring clinical intervention, respiratory failure necessitating prolonged mechanical ventilation or reintubation, bronchospasm, and exacerbation of preexisting chronic lung disease [1]. These complications are typically diagnosed through a combination of clinical assessment, imaging findings, and laboratory criteria. According to previous studies, the incidence of PPCs ranges from 6%−80% [2–5]. PPCs are associated with increased morbidity, prolonged hospitalization, and higher healthcare costs, particularly in high-risk populations such as elderly patients or those with preexisting pulmonary dysfunction [6, 7].

Opioids, while effective for pain management, can suppress respiratory drive and impair mucociliary clearance, exacerbating pulmonary risks [8]. Sufentanil, a potent µ-opioid receptor agonist, is widely used but may heighten these risks. Oxycodone, a semi-synthetic opioid with mixed µ- and κ-receptor activity, has demonstrated comparable analgesia with potentially fewer respiratory effects in preclinical studies [9, 10]. Previous studies have reported that oxycodone compared with other pure μ-opioid receptor agonists may be associated with better postoperative analgesia, fewer opioids-related adverse reactions and lower incidence of postoperative pulmonary complications [11–13]. Animal studies suggest that κ-receptor activation alleviates oxidative stress in lung tissue by modulating inflammatory cytokine release, indicating that oxycodone may improve postoperative lung function through multimodal pathways [14]. Clinical evidence comparing these opioids in high-risk surgical populations remains limited. Specifically, whether oxycodone reduces PPCs in pulmonary dysfunction patients is unknown. We therefore conducted this RCT to test the hypothesis that oxycodone would lower PPCs incidence versus sufentanil in pulmonary-compromised patients undergoing laparoscopic gastrointestinal surgery.

Methods

Study design and participants

The study was approved by the ethics committee of The First Affiliated Hospital of Ningbo University (approval number: 2023-Research-007A) and registered at the Chinese Clinical Trial Registry (www.chictr.org.cn, Registration number: ChiCTR2500099262, Registration date: March 20, 2025. Retrospectively registered). Eligible patients were recruited between June 6, 2024 and June 30, 2025. All patients were provided with written informed consent to participate in the study. This manuscript adhered to the CONSORT guidelines.

Patients were eligible if they met all the following inclusion criteria: (1) scheduled for elective laparoscopic gastrointestinal surgery (including Da Vinci robot-assisted surgery); (2) had clear preoperative pulmonary function test results and pulmonary function tests showed varying degrees of pulmonary dysfunction (an FEV1 of 70%−79% of predicted value and FEV1/FVC of < 92% of predicted value indicated mild dysfunction; 60%−69% of predicted value indicated moderate dysfunction, 50%−59% indicated severe dysfunction); (3) planned to undergo general anesthesia with endotracheal intubation;(4) age between 18 and 80 years; (5) body mass index of 18 to 25 (calculated as weight in kilograms divided by height in meters squared) at screening; (6) American Society of Anesthesiologists physical status scale Ⅱ to III; and (7) capable of understanding the study and providing informed consent. Exclusion criteria were as follows: (1) refuse to sign informed consent; (2) have potential difficult airway problems; (3) have severe liver and kidney dysfunction; (4) have mental illness and communication disorders; (5) have allergies to any anesthetics or a history of allergy. Withdrawal criteria were as follows: (1) Patients who voluntarily withdraw informed consent. (2) patients who undergo open surgery during surgery. (3) patients whose surgery is canceled. (4) patients whose intraoperative blood loss is ≥ 30% of total blood volume. (5) patients whose core body temperature is lower than 35.5℃. (6) patients whose clinical researchers determine that they cannot participate in the study.

Randomization and blinding

The patients were randomly assigned to the oxycodone or sufentanil group according to the computer-generated random sequence, which was created with a 1:1 ratio by SPSS 22.0. Study statisticians were not involved in patient recruitment or the delivery of medication. An anesthetic nurse who was not otherwise involved in the study prepared the study agents in identical syringes according to treatment groups, with the group information contained in sequentially numbered sealed opaque envelopes. The surgeons and other health care personnel, the research staff who assessed the outcomes, anesthesiologists, and the patients themselves were all blinded to the group allocation.

Anesthesia management

There was no pre-operative medication. After admission into the operating room, all patients were given routine monitoring including heart rate (HR) and oxygen saturation (SpO₂). A radial artery puncture and catheterization were performed under local anesthesia to monitor the real-time blood pressure, a BIS monitor was connected to monitor the anesthesia depth and a neuromuscular monitoring was used to monitor the degree of residual muscle paralysis. Previous studies have established an equianalgesic dose ratio of 0.5 mg of oxycodone to 1 μg of sufentanil (all administered intravenously) [9]. Patients were given oxycodone 0.2 mg/kg for Group O or sufentanil 0.4 µg/kg for Group S, midazolam 0.04 mg/kg, etomidate 0.3 mg/kg and rocuronium 0.6 mg/kg during anesthesia induction. Tracheal intubation was performed 3 min later for mechanical ventilation. All patients received the same ERAS strategies throughout the perioperative period. Protective pulmonary ventilation strategies were applied to all patients (small tidal volume, 6–8 mL/kg (predicted body weight [PBW]); PEEP was set at 3–5 cmH₂O, the initial inspiratory oxygen fraction (FiO2) was set at 0.4 to satisfy the SpO2 greater than 95%) during surgery. During maintenance period, patients were given propofol 60–120 µg/(kg ·min), remifentanil 0.05–0.15 µg/(kg ·min) and rocuronium 0.3–0.8 mg/(kg ·h) and continuous inhalation of sevoflurane (0.8 to 1.0 minimum alveolar concentration) to maintain the BIS value at 40 to 60. The body temperature probe is placed to maintain the core temperature above 35.5 °C. The end-tidal carbon dioxide (ETCO₂) was properly maintained within the range of 35 to 45 mmHg and vasopressors were used to maintain the patient's blood pressure within 30% of the preoperative baseline value. Thirty minutes prior to the end of surgery, patients in Group O/Group S were given additional oxycodone 0.1 mg/kg/sufentanil 0.2 µg/kg and stopped the infusion of rocuronium. Both groups received 0.75% ropivacaine 10 ml incision infiltration at the end of the operation. Ondansetron, 4 mg, was administered intravenously to prevent postoperative nausea and vomiting. When TOF count was ≤ 2, sugammadex 2 mg/kg was given to antagonist the muscle relaxant. When TOF count was > 0.9, the patients were extubated and transferred to the PACU.

Postoperative analgesia protocol

Postoperative analgesia was delivered via an intravenous patient-controlled analgesia (PCIA) pump, which was prepared as follows:

• Drug formulation: Oxycodone 0.5 mg/kg (Group O) or sufentanil 1 μg/kg (Group S), combined with ondansetron 8 mg, diluted to a total volume of 100 mL with normal saline.

• PCIA programming: A continuous background infusion of 2 mL/h was set, with a patient-triggered bolus dose of 2 mL and a lockout time of 15 min (i.e., no additional bolus could be delivered within 15 min of the previous dose).

• Rescue analgesia: If the patient reported a Numerical Rating Scale (NRS) pain score ≥ 4 despite PCIA use, intravenous flurbiprofen axetil 50 mg was administered as rescue therapy, with a maximum daily dose of 200 mg. Flurbiprofen axetil, a non-steroidal anti-inflammatory drug (NSAID), was chosen as rescue analgesia to minimize opioid-related adverse effects while enhancing pain control No additional opioids were allowed unless approved by the acute pain service team.

Outcome measurements

The patients’ characteristics, duration of surgery and anesthesia, total dose of anesthesia drugs, fluids administered, bleeding and urine output (both corrected to the nearest 100 mL) were recorded. The primary outcome was the incidence of PPCs within 30 days after surgery, defined as respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis to be the composite measures according to the EPCO-recommended definitions [15, 16].

Secondary outcomes included time of first flatus, pain scores, postoperative opioid consumption (including total PCA consumption and number of PCA boluses), incidence of rescue analgesia, respiratory depression, postoperative nausea and vomiting (PONV), and length of hospital stay. The time to first flatus was recorded according to patient self-report, corrected to the nearest hour. Digital pain scores (0 for no pain, 10 for the most pain, 1–3 for mild pain, 4–6 for moderate pain, and 7–10 for severe pain) were recorded immediately (T1), 6 h (T2), 12 h (T3), 24 h (T4), and 48 h (T5) after surgery. The incidence of rescue analgesia and respiratory depression were assessed during the first 48 h after surgery. The presence of nausea, vomiting and other adverse events (such as myocardial infarction, allergic reactions, et,al) were assessed until hospital discharge. Independent researchers who were blinded to treatment group were responsible for collecting data. The physicians caring for patients did not participate in data collection.

Sample size calculation

The sample size was calculated based on an expected PPCs incidence of 50% in the sufentanil group and 26.5% in the oxycodone group. The expected 50% PPCs incidence in the sufentanil group was derived from our preliminary feasibility study of high-risk patients with preoperative pulmonary dysfunction undergoing similar procedures. This high baseline rate reflects our specific patient population rather than general surgical patients. Sample size calculation was performed using PASS 15.0, with a two-sided CI of 95% (α = 0.05) and a power of 80% (β = 0.2), and the ratio between the oxycodone and control groups was 1:1. Considering a dropout rate of 10%, we estimated that each group would require 71 patients, resulting in a total sample size of 142 patients for both groups.

Statistical analysis

Normally distributed data is analyzed by variance, and non-normally distributed data uses non -parameter rank and test. For continuous variables, data were reported as means with SDs or medians with IQRs according to the normality of distribution; for categorical variables, data were reported as numbers with percentages. The primary outcome, i.e., the incidence of PPCs, was analyzed by chi-square test, and differences between the two groups are expressed as the relative risk and 95% CI. For secondary outcomes, categorical data were analyzed by chi-square test or Fisher’s exact test, and the differences are expressed as the relative risk and 95% CI; in the analysis of continuous data, Student’s t test or Mann–Whitney U test was performed as appropriate, and the median difference with 95% CI was calculated. Statistical analyses were conducted using SPSS 22.0, and 2-sided P < 0.05 was considered statistically significant.

Results

A total of 180 patients were screened for eligibility, 38 were excluded, and 142 proceeded to randomization, with 71 patients randomized to receive oxycodone and 71 randomized to receive sufentanil (Fig. 1). Three patients in the oxycodone group and four in the sufentanil group withdrew informed consent before surgery, and thus no data were available and they could not be included in the ITT analysis. Additionally, four patients in the oxycodone group and two in the sufentanil group were converted to open surgery intraoperatively; as their data were complete, they were retained in the ITT analysis and analyzed according to the original group allocation. The remaining 135 patients (68 in the oxycodone group and 67 in the sufentanil group) were included in the final analysis.

Fig. 1.

CONSORT flow diagram

In total, 92 patients (68.2%) were male and 43 (31.8%) were female, with a median (IQR) age of 67.5(62.0–75.0) years. Baseline characteristics of the oxycodone and sufentanil groups were similar (eg, median [IQR] age, 69 [62.0–75.0] years vs 68.0 [62.0–75.0] years), respectively; 46 men [67.7%] vs 46 men [68.7%]), and there were no significant differences in American Society of Anesthesiologists status (eg, 19 patients [27.9%] vs 19 patients [28.4%] had class 3 status [indicating severe systemic disease]), or degree of pulmonary dysfunction (eg, 53 patients [77.9%] vs 54 patients [80.6%] had mild pulmonary dysfunction) (Table 1).

Table 1.

Patient characteristics and intraoperative data

Characteristic	No. (%) Oxycodone group	Sufentanil group
Total patients, no	68	67
Age, median (IQR), y	69.0 (62.0–75.0)	68.0 (62.0–75.0)
Height, mean (SD), cm	166.3 (7.83)	168.3 (7.45)
Weight, mean (SD), kg	62.4(8.86)	63.3(9.43)
BMI, mean (SD), kg/m2	22.4(2.11)	22.3 (2.26)
Sex, no. (%)
Male	46 (67.7)	44 (68.7)
Female	22 (32.3)	21 (31.3)
ASA classification, no. (%)a
Ⅱ	49 (72.1)	48 (71.6)
Ⅲ	19 (27.9)	19 (28.4)
Comorbidities
Diabetes mellitus, no. (%)	12 (17.7)	12 (17.9)
Hypertension, no. (%)	27 (39.7)	34 (50.8)
Coronary heart disease, no. (%)	3 (4.4)	2 (3.0)
Smoking, no. (%)	18 (26.5)	19 (28.4)
Degree of pulmonary dysfunction, no. (%)b
Mild	53 (77.9)	54 (80.6)
Moderate	11 (16.2)	11 (16.4)
Severe	4 (5.9)	2 (3.0)
PPCs risk, no. (%)c
Low	6 (8.8)	6 (9.0)
Moderate	48 (70.6)	49 (73.1)
High	14 (20.6)	12 (17.9)
Time, median (IQR), min
Surgical	175.0 (145.0–207.5)	185.0 (152.5–215.0)
Anesthetic	200.0 (173.8–235.0)	210.0 (175.0–247.5)
Type of surgery, no. (%)
Non-robotic laparoscopic surgery	32 (47.1)	32 (47.8)
Da Vinci robot-assisted surgery	36 (52.9)	35 (52.2)
Anesthesia drugs
Remifentanil, median (IQR), μg	1077.5 (890.9–1353.8)	1163.4 (946.2–1546.5)
Rocuronium, median (IQR), mg	113.0 (96.8–130.8)	113.0 (100.0–130.6)
Bleeding, median (IQR), mL	20 (20–30)	20 (20–50)
Infusion, median (IQR), mLd	1500 (1500–2000)	1500 (1500–2000)
Urine output, median (IQR), mLd	300 (250–350)	300 (200–350)

Abbreviations: ASA American Society of Anesthesiologists, BMI Body mass index (calculated as weight in kilograms divided by height in meters squared)

^aClass 1 indicates normal health; class 2, mild systemic disease; and class 3, severe systemic disease that is not life-threatening

^bAccording to preoperative pulmonary function testing results, an FEV1 of 70%−79% of predicted value and FEV1/FVC of < 92% of predicted value indicated mild dysfunction; 60%−69% of predicted value indicated moderate dysfunction, 50%−59% indicated severe dysfunction

^cAn ARISCAT score [17] less than 26 indicates low risk of postoperative pulmonary complications; a score between 26 to 44 inclusive suggests moderate risk; and a score greater than 44 signifies high risk

^dValues were rounded to the nearest 100 mL

There was no difference in surgical time (median [IQR], 175.0 [145.0–207.5] minutes vs 185.0[152.5–215.0] minutes) or anesthetic time (median [IQR], 205.0 [172.5–240.0] minutes vs 210.0 [175.0–247.5] minutes) between the oxycodone and sufentanil groups, respectively (Table 1). The short-acting opioid analgesic remifentanil (median [IQR], 1077.5 [890.9–1353.8] μg vs 1163.4 [946.2–1546.5] μg) and muscle relaxant rocuronium (median [IQR], 112.9 [96.8–130.8] mg vs 113.0 [100.0–130.6] mg) were comparable between two groups. The volumes of intraoperative bleeding (median, 20 mL [IQR, 20–30 mL] in the oxycodone group vs 20 mL [IQR, 20–50 mL] in the sufentanil group), the volume of intraoperative fluid administered (median, 1500 mL [IQR, 1500–2000 mL] in the oxycodone group vs 1500 mL [IQR, 1500–2000 ml] in the sufentanil group) and urine output (median, 300 mL [IQR, 250–350 mL] in the oxycodone group vs 300 mL [IQR, 200–350 ml] in the sufentanil group) were also comparable.

Primary outcome

PPCs occurred in 26/68 (38.2%) oxycodone recipients versus 38/67 (56.7%) sufentanil recipients (RR = 0.67; 95% CI 0.47–0.97; P < 0.05; Fig. 2).

Fig. 2.

Incidence of PPCs A, Pneumonia B, Atelectasis (C) and Pleural effusion (D)

Secondary outcomes

Oxycodone reduced PONV (16.2% vs 32.8%; RR = 0.49 [95% CI, 0.26 to 0.94]; P < 0.05; Table 2). Postoperative pain scores at each time point within 48 h were comparable between the oxycodone group and the sufentanil group. The median time to first flatus (median, 68.4 h [IQR, 57.5–71.7 h]vs 69.7 h [IQR, 53.7–92.5 h]) and length of stay (19 days [IQR, 15–26 days]) vs 18 days [IQR, 15–22 days]) were also comparable between the oxycodone and control groups (Table 2). Based on the 0.5 mg: 1 μg ratio stated in the manuscript, the total PCA consumption (42.5 mg [IQR, 35.0–48.5 mg] in the oxycodone group vs. 85.2 μg [IQR, 72.5–96.0 μg]in the sufentanil group) and the number of PCA boluses (21 vs. 22) showed no statistically significant differences. The incidence of RR < 12 breaths/min was lower in the oxycodone group (5.9% vs 17.9%, P < 0.05) (Table 3).

Table 2.

Secondary outcomes

Outcome	Median (IQR) Oxycodone group	Sufentanil group		z Score or χ2 value	P value
Total patients, No	68	67		NA	NA
Time to first flatus, ha	68.4 (57.5, 71.7)	69.7 (53.7, 92.5)		−0.56b	0.575
Pain scores
T1	3.00 (2.00, 3.00)	3.00 (2.00, 3.00)		−0.23b	0.821
T2	2.00 (2.00, 3.00)	3.00 (2.00, 3.00)		−1.87b	0.062
T3	2.00 (2.00, 3.00)	2.00 (2.00, 2.50)		−0.07b	0.947
T4	2.00 (2.00, 2.00)	2.00 (2.00, 2.00)		−0.87b	0.384
T5	2.00 (1.75, 2.00)	2.00 (2.00, 2.00)		−0.18b	0.856
PONV, No. (%)	11 (16.2)	22 (32.8)		5.07c	0.024
Length of stay, d	19 (15,26)	18 (15,22)	−1.73b		0.084

Abbreviation: NA Not applicable

^aValues were rounded to the nearest hour

^bz Score

^cχ² Value

Table 3.

Postoperative opioid consumption and pca usage (48 h)

Parameter	Median (IQR) Oxycodone group	Sufentanil group	z Score or χ2 value	P value
Total patients, no	68	67	NA	NA
Total PCA consumption	42.5 mg (35.0–48.5)	85.2 µg (72.5–96.0)	−0.56a	0.891
Number of PCA boluses	21 (17–24)	22 (18–26)	−0.56a	0.687
Incidence of rescue analgesia	27.9% (19/68)	40.3% (27/67)	2.29b	0.130
Incidence of RR < 12 breaths/min	5.9% (4/68)	17.9% (12/67)	4.70b	0.030

Abbreviation: NA Not applicable

^az Score

^bχ² Value

Adverse events

No patient had an allergic reaction during the perioperative period. In the oxycodone group, one patient developed a pulmonary embolism postoperatively, was transferred to the ICU for treatment, and was subsequently discharged successfully. Furthermore, none of the patients developed postoperative myocardial infarction, heart failure or death.

Discussion

In this single-center, double-blind, randomized, parallel controlled trial, we investigated the effects of the intraoperative administration of oxycodone on the PPCs in patients undergoing elective laparoscopic gastrointestinal surgery. The study’s findings demonstrated that compared with sufentanil, oxycodone decreased the overall incidence of PPCs among patients with preexisting pulmonary dysfunction undergoing laparoscopic gastrointestinal surgery. The results are in agreement with those of a study reporting that oxycodone attenuates vascular leak and lung inflammation in rat model of acute lung injury [18]. Our findings align with preclinical evidence that κ-receptor activation attenuates lung inflammation, providing a mechanistic rationale for PPCs reduction in clinical settings. Importantly, this benefit occurred without sacrificing analgesic efficacy—a critical consideration for patients with pulmonary dysfunction in enhanced recovery pathways.

The occurrence of PPCs results from the multifactorial interplay of mechanisms, including spanning mechanical injury, inflammatory cascade, neuroregulatory imbalance, drug side effects, and impaired patient compensatory capacity. In recent years, numerous experiments have shown that effective inhibition of inflammatory response and oxidative stress response can alleviate pulmonary injury caused by ischemia–reperfusion. Oxycodone has been shown to exert organ protective effects by inhibiting inflammation and oxidative stress or reduce cell damage and apoptos [19, 20]. Studies indicate that oxycodone suppresses pro-inflammatory cytokines (e.g., IL-6, TNF-α) by inhibiting the TLR4/NF-κB signaling pathway while upregulating anti-inflammatory IL-10 expression, thereby attenuating surgery-induced pulmonary inflammation [21]. For instance, in thoracoscopic lung cancer surgery, oxycodone combined with lung-protective ventilation strategies significantly reduces postoperative IL-6 levels and improves alveolar oxygenation. In contrast, sufentanil exhibits weaker modulation of inflammatory responses, potentially failing to block inflammatory cascade-mediated lung injury effectively.

Another plausible explanation for the reduced PPCs in the oxycodone group lies in its differential opioid receptor activity. Unlike sufentanil, a highly selective μ-opioid receptor agonist associated with dose-dependent respiratory depression and suppression of cough reflexes, oxycodone exhibits dual μ- and κ-opioid receptor agonism. Preclinical and clinical studies suggest that κ-receptor activation may mitigate μ-receptor–mediated respiratory depression while preserving protective airway reflexes. For instance, κ-receptor agonists have been shown to reduce bronchoconstriction and airway inflammation in animal models, potentially lowering the risk of atelectasis and pneumonia [18]. This receptor-specific effect may explain why oxycodone maintained adequate analgesia without exacerbating respiratory compromise in vulnerable populations. Furthermore, opioid-induced immunosuppression, a recognized risk factor for postoperative infections, may differ between these agents. Sufentanil, like other potent μ-agonists, has been linked to impaired neutrophil function and reduced cytokine production, which could predispose patients to pulmonary infections. In contrast, oxycodone’s κ-receptor activity may modulate inflammatory pathways more favorably [22]. Previous studies demonstrated that κ-agonists attenuate proinflammatory cytokine release (e.g., IL-6, TNF-α) in surgical patients, potentially reducing acute lung injury and infection risk [23]. This immunomodulatory effect aligns with our observation of fewer PPCs in the oxycodone group. Additionally, κ-receptor activation may suppress neurogenic inflammatory responses, mitigating airway hyperreactivity and further protecting pulmonary function [24].

Intraoperative pain stimuli activate the sympathetic nervous system, elevating adrenaline and cortisol levels, which trigger pulmonary vasoconstriction and microcirculatory dysfunction. According to previous studies, oxycodone’s preemptive analgesic effect markedly inhibits such stress responses, whereas sufentanil’ s shorter half-life may fail to cover the postoperative stress peak period adequately [25, 26]. As a dual µ- and κ-opioid receptor agonist, oxycodone provides superior inhibition of visceral pain compared to traditional µ-receptor agonists. Alleviating visceral pain can reduce diaphragm restriction and shallow rapid breathing caused by pain, thereby lowering the risk of atelectasis and hypoxemia. However, in our study, no significant difference was observed in postoperative pain scores, postoperative opioid consumption or PCA usage between two groups. These data confirm comparable analgesic efficacy and usage patterns between groups. This divergence in outcomes suggests the need for further mechanistic investigation, particularly regarding oxycodone’s receptor-specific actions and the limitations of pain assessment metrics. The comparable pain control between oxycodone and sufentanil aligns with their established equianalgesic properties. Previous studies confirm a potency ratio of 0.5 mg oxycodone to 1 μg sufentanil, indicating similar μ-opioid receptor (MOR) affinity at equivalent doses. Both drugs primarily mediate analgesia through central MOR agonism, explaining their parallel efficacy in acute postoperative pain. Oxycodone’s additional κ-opioid receptor (KOR) activity contributes minimally to somatic pain modulation but plays a pivotal role in mitigating PONV and PPCs, which is in agreement with our study’s findings. In addition, both groups achieved adequate pain control (mean VAS < 4), potentially masking subtle differences.

The observed PPCs incidence of 56.9% in the control group is notably higher than the 13.3% reported in ARISCAT moderate-risk patients [27]. Several factors explain this discrepancy:

1. Patient-specific factors: Our study exclusively enrolled patients with documented pulmonary dysfunction, representing a higher-risk subset than general ARISCAT cohorts. Reduced pulmonary function is one of the primary factors contributing to the occurrence of PPCs [28, 29].

2. Procedure-specific factors: Laparoscopic gastrointestinal surgery uniquely challenges pulmonary function through: (a) prolonged CO₂ pneumoperitoneum (median 3 + hours) causing diaphragmatic elevation and reduced functional residual capacity; (b) Trendelenburg positioning promoting atelectasis; (c) extensive surgical fields increasing inflammatory mediator release and ple effusion risk.

3. Diagnostic rigor: We applied EPCO definitions systematically followed by CT when clinically indicated.

4. Pneumonia prevalence: The high pneumonia rate (nearly 50%) reflects the synergistic effects of opioid-induced immunosuppression, impaired mucociliary clearance, and sputum retention in patients with compromised baseline lung function. The κ-receptor activity of oxycodone may specifically mitigate these μ-receptor-mediated immunosuppressive effects. Additionally, opioid-induced respiratory depression synergizes with shallow breathing patterns driven by pain, exacerbating sputum retention and atelectasis risks, particularly in elderly patients or those with pre-existing chronic lung conditions. The objective difference in respiratory rate supports our mechanistic hypothesis that oxycodone's κ-receptor activity may mitigate μ-receptor-mediated respiratory depression, preserving protective respiratory drive and cough reflexes crucial for preventing atelectasis and pneumonia.

This study has several limitations that warrant consideration. First, the generalizability of the study is limited due to its single-center design and focus on a surgical population of high-risk patients undergoing laparoscopic gastrointestinal surgeries. Larger, multicenter trials are needed to validate these results and assess the consistency of oxycodone’s pulmonary protective effects across diverse clinical settings. Second, the study population was restricted to patients undergoing elective laparoscopic gastrointestinal surgery, which may introduce selection bias. The exclusion of emergency surgeries, patients with severe comorbidities, or those with ASA Physical Status IV–V limits the applicability of the findings to higher-risk cohorts. Future studies should explore oxycodone’s effects in patients with more advanced pulmonary disease or undergoing emergency procedures. Third, while oxycodone demonstrated a significant reduction in pulmonary complications, the underlying mechanisms remain unclear. Biomarkers of pulmonary inflammation or oxidative stress were not measured, which could have provided mechanistic insights. Previous studies highlight the role of opioid receptor subtypes in modulating respiratory function and inflammation, but further pharmacodynamic investigations, including comparisons of inflammatory factors and pulmonary ischemia reperfusion injury, are warranted. Lastly, the study population was ethnically homogeneous (Chinese), and racial or genetic differences in opioid metabolism or pulmonary susceptibility to injury may affect the external validity of the results. Prior research has shown ethnic disparities in postoperative outcomes and drug responses, underscoring the need for validation in diverse populations. While oxycodone shows these advantages, it's important to note that the choice of analgesic should be tailored to individual patient needs and specific surgical procedures. Additionally, further research may be needed to confirm these findings across different patient populations and surgical contexts.

Conclusion

In patients with pulmonary dysfunction undergoing laparoscopic gastrointestinal surgery, oxycodone significantly reduced PPCs compared to sufentanil while providing equivalent analgesia. This supports its role as a lung-protective analgesic in enhanced recovery pathways. Integrating oxycodone into enhanced recovery protocols for high-risk surgical populations warrants further exploration. Future studies should further clarify its optimal timing of administration, dosage, and long-term pulmonary protective efficacy. Under strict compliance with anesthesia drug management regulations, oxycodone is poised to become a critical adjuvant medication for perioperative lung protection.

Abbreviations

PPCs

Postoperative pulmonary complications

PONV

Postoperative nausea and vomiting

ITT

Intention-to-treat

ERAS

Enhanced recovery after surgery

BMI

Body mass index

HR

Heart rate

ECG

Electrocardiography

IBP

Invasive arterial blood pressure

SpO2

Peripheral oxygen saturation

BIS

Bispectral index

PETCO2

Partial pressure of carbon dioxide

TOF

Train-of-Four

PCIA

Patient-controlled intravenous analgesia

NRS

Numeric rating scale

Authors’ contributions

Zhoutong Sun and Yijun Chen participated in the design of the experiment; Zhoutong Sun, Yuxing Tu, Xixi Chen, Jiahuan Chen, Yajun Ding, Shimeng Dong, Lu Sun and Juan Yi were involved in data collection; Zhoutong Sun and Yijun Chen conducted statistical analysis of the experimental data; Yijun Chen, Zhoutong Sun and Binbin Zhu were responsible for writing the manuscript. All authors have read and approved the final manuscript.

Funding

This work was supported by Enze Medical Research Projects for Pain Management, Bethune Charitable Foundation (grant no. ezmr2023-005) and Ningbo Top Medical and Health Research Program (No.2024010317).

Data availability

The datasets utilized and/or examined in the current study can be obtained from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the ethics committee of The First Affiliated Hospital of Ningbo University (approval number: 2023-Research-007A) and registered at the Chinese Clinical Trial Registry (www.chictr.org.cn, Registration number: ChiCTR2500099262, Registration date: March 20, 2025. Retrospectively registered). All patients were provided with written informed consent to participate in the study and all experiments were conducted in accordance with relevant guidelines and regulations.

Informed consent to participate was obtained from all of the participants in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.