This single-center, randomized, double-blind, parallel-controlled trial was conducted at The First Affiliated Hospital of Anhui Medical University in Hefei from November 2020 to January 2021. Institutional review board approval (PJ2020-12-41) was obtained from the Ethics Committee of The First Affiliated Hospital of Anhui Medical University. Written informed consent was obtained from all participants and the trial was registered at Chinese Clinical Trial Registry (ChiCTR2000040243). The study was performed in accordance with the Declaration of Helsinki.
First-trimester women undergoing elective painless surgical abortion complying with the state laws and regulations were screened for eligibility for the trial. The inclusion criteria included patients aged between 18 and 45 years, American Society of Anesthesiologists physical status I or II, and a gestational age below 12 weeks. Patients with severe hepatic and renal dysfunction, history of chronic pain, preoperative use of nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids, psychiatric disorders, allergies to nalbuphine or other anesthetic drugs, and emergency re-operations at the time of enrollment, were excluded.
Randomization and Blinding
Eligible participants were randomly allocated at a 1:1 ratio to the sufentanil group and the nalbuphine group by a statistician using SPSS (version 23.0, SPSS Inc., Chicago, IL, USA). The statistician was not involved in patient recruitment or the delivery of medication. The group assignments were contained in sequentially numbered sealed envelopes. An anesthetic nurse who was not involved in the study prepared the study agents in identical 20-ml syringes according to the group assignments. Attending anesthesiologists assigned the intervention to participants using the prepared, identical looking study agents. All patients, surgeons, attending anesthesiologists, and follow-up anesthesiologists were blinded to group assignments. The randomization code was revealed after the follow-up ended or for patients with severe adverse events.
All the participants fasted for 8 h and were deprived of water for 2 h before surgery. When patients arrived in the outpatient operation room, intravenous access was established with an 18-G intravenous catheter in dorsal hand vein by the same senior nurse, and no premedication was administered. Standard monitoring including electrocardiograph, heart rate (HR), noninvasive blood pressure (BP), and pulse oxygen saturation were established, and the vital signs pre-induction were recorded. Patients received preoxygenation at a flowrate of 3 l/min with a fiscal mask.
Patients in the sufentanil group received sufentanil 0.1 μg/kg  and patients in the nalbuphine group received nalbuphine 0.1 mg/kg for anesthesia induction. Two minutes later, the attending anesthesiologists manually injected 0.5 mg/kg propofol over a period of 15 s. After evaluating the propofol injection pain, an additional amount of propofol (dose of 1.0 mg/kg) was injected to complete the surgical abortion. When patients lost consciousness, the surgical gynecological procedure began. If patients exhibited body movements during the procedure, an additional propofol injection (dose in the range of 0.4–0.8 mg/kg) was administered. Patients were transferred to the recovery room after the end of surgery to recover consciousness.
The primary outcome was postoperative pain. We evaluated the degrees of postoperative pain at 15 min, 30 min, 1 h, and 6 h following the operation based on a numerical rating scale. A score of 0 indicates no pain and a score of 10 indicates the most severe pain. Secondary outcomes included propofol injection pain and an intraoperative analgesic effect. Propofol injection pain was evaluated by a study-blinded follow-up anesthesiologist based on a four-point verbal rating scale : a score of 0 indicated no pain, a score of 1 indicated mild pain (only reported pain in response to questions without behavioral signs), a score of 2 indicated moderate pain (reported pain spontaneously without question or accompanied by behavioral signs), and a score of 3 indicated severe pain (strong vocal response or accompanied by arm withdrawal, facial grimacing, or tears). Intraoperative pain intensity was assessed based on the modified behavioral pain scale (BPS) for non-intubated patients (BPS-NI) (Table S1 in supplementary material) . The modified BPS-NI included three parts: facial expression, movements of the upper and lower limbs, and vocalizations. A total score > 5 indicated that patients experienced intolerable pain during the procedure.
Tertiary outcomes included perioperative hemodynamic changes, adverse events, and patient satisfaction scores. We recorded systolic and diastolic BP, mean arterial pressure (MAP), and HR at T1 (before anesthesia induction), T2 (cervical dilation), T3 (suction aspiration), and T4 (end of the surgery). The occurrence of perioperative adverse events, including tachycardia (> 100 beats per minute [bpm]), bradycardia (< 50 bpm), hypertension (BP > 20% increase from baseline or MAP > 110 mmHg), hypotension (BP > 30% decrease from baseline or MAP < 60 mmHg), respiratory depression (respiratory rate < 8 bpm or partial oxygen saturation < 90%), dizziness, and postoperative nausea and vomiting (PONV) were recorded. The presence of PONV was scored according to the following states and scores: no nausea (0), slight nausea (1), moderate nausea (2), or vomiting (3). The degree of satisfaction was assessed 6 h following surgery based on a scale from 0–3: not satisfied (0), somewhat satisfied (1), moderately satisfied (2), and highly satisfied (3).
Sample Size Calculation
According to our pilot data, we estimated that the mean pain score at 30 min following surgery was 2, and the standard deviation (SD) was equal to 1. With a two-tailed α value of 0.05, power of 90%, and boundaries of efficiency 0.5, a total of 86 patients in each group were required to detect the advantage of nalbuphine. Owing to skewed distribution of the pain score, a nonparametric test for analysis should be used. The sample size needed for a Mann–Whitney U test would be expanded by 1.053 times because the power efficiency of this was expected to be approximately equal to 95% compared with the Student’s t test . Considering a 10% follow-up rate loss, the sample size needed to be expanded by 1.1 times. Finally, we needed 200 patients to detect possible superior outcomes of nalbuphine.
We used the Shapiro–Wilk test to investigate data for normality. The data which satisfied the normal distribution were presented as mean ± SD, and the comparison between groups was performed by a two-tailed Student’s t test. Continuous variables of a non-normal distribution were presented as medians (interquartile range [IQR]), and comparison between groups was performed by the Mann–Whitney U test. For categorical variables, data were described with numbers (frequency), and the χ2 test was used for statistical comparisons. The Mann–Whitney U test was also used for ranked data, such as intensity of propofol injection pain, severity of PONV, and degree of satisfaction. The statistical analyses were performed with SPSS. Two-sided p values < 0.05 were considered statistically significant.