Comparison between butorphanol and nalbuphine for alleviation of catheter-related bladder discomfort and emergence agitation in patients undergoing open spinal surgery: a randomized clinical trial

Abstract

Introduction

Opioid receptor agonist/antagonists have positive effects in the management of catheter-related bladder discomfort (CRBD). Whether the differences in κ receptor affinity will have different effects is still unknown. This study aims to compare the efficacy of opioid agents with varying κ receptor affinity profiles in alleviating CRBD and emergence agitation (EA).

Patients and Methods

A total of 120 patients undergoing open spinal surgery were randomly assigned into three groups: saline group, butorphanol group, and nalbuphine group. All drugs were injected intravenously 30 min before the end of surgery. The primary outcomes were the incidence of moderate to severe CRBD and EA at 5 min after tracheal extubation. Secondary outcomes included the severity of CRBD, numerical rating scales (NRS), Richmond agitation-sedation scale (RASS) at five time points after tracheal extubation, the need for rescue analgesia and the incidence of adverse events were also recorded.

Results

The incidence of moderate to severe CRBD was significantly lower in group B compared to group C (p < 0.001) at all the time points. Group B had significantly fewer patients with severe CRBD and lower NRS scores than both groups C and N (p < 0.001) at T1 and T2. Group B had lower RASS scores than groups N and C at T1, while at T2, T3 and T4, groups B and N continued to exhibit significantly lower NRS scores compared to group C (p < 0.001). The requirement for rescue analgesia decreased sequentially from group C to group N and then to group B (p < 0.001). The incidence of EA was significantly lower in groups B and N than in group C (p < 0.001).

Conclusions

Opioid receptor agonist/antagonists demonstrate efficacy in preventing CRBD and EA without significant adverse events. Butorphanol exhibits superior efficacy to nalbuphine in the early postoperative period.

Introduction

Preoperative indwelling urinary catheterization is a standard practice for patients undergoing general anesthesia, primarily to prevent postoperative urinary retention. To avoid discomfort associated with catheter insertion in conscious individuals, the procedure is typically performed after anesthesia induction. Upon emergence from anesthesia, catheter-related discomfort often manifests as urinary urgency and frequency, lower abdominal distension and pain, head shaking, body twisting, restlessness, and even confusion with attempts to remove the catheter [1,2]. The incidence of CRBD ranges from 47% to 90% during the postoperative period. In patients with urinary catheterization, CRBD may reduce postoperative satisfaction and increase the risk of complications such as surgical site infection or cardiovascular events [3]. Inappropriate management may diminish postoperative quality of life and exacerbate pain and agitation during recovery [4–6]. Consequently, preventive measures and early therapeutic interventions for CRBD are critically important for optimizing perioperative outcomes.

CRBD and postoperative wound pain often accompany the occurrence of EA; the three conditions develop alternately and influence each other. Pain is the most important risk factor associated with EA, and 63.5% of patients who experience EA have an indwelling urinary catheter [4,7]. Therefore, only by implementing comprehensive measures addressing all three aspects can effectively improve the quality of patient emergence.

Previous studies have revealed that opioids with varying affinities for μand κopioid receptors exert differential analgesic effects depending on pain modality [8]. κ Receptor agonism showed a potent analgesic effect and was well tolerated in patients experienced postoperative pain [9,10]. Butorphanol and nalbuphine, both classified as opioid receptor agonist-antagonists, exhibit distinct pharmacological profiles [11–13]. These agents demonstrate faster onset of action via intravenous administration, reduced addiction potential with single-dose use, and prolonged analgesic duration compared to pure μreceptor agonists [14,15]. Additionally, opioid agonist/antagonists demonstrate superior efficacy in visceral pain management while exhibiting a lower incidence of opioid-related adverse effects and addiction risk [12]. κopioid receptor agonism mediates potent anti-inflammatory and antioxidant stress effects, which may contribute to the alleviation of postoperative CRBD [16–18]. Pharmacological studies revealed that butorphanol exhibits a significantly stronger affinity for κreceptors compared to nalbuphine, whereas no significant differences were observed in their μopioid receptor binding affinities [19].

Whether this differential ofκreceptor affinity translates to clinically significant improvements in CRBD and perioperative recovery quality among catheterized patients remains unclear. This study aims to compare the efficacy of butorphanol versus nalbuphine in mitigating CRBD and EA in male patients undergoing spinal surgery.

Materials and methods

Study design and participants

This single-center, randomized clinical trial was approved by the Ethics Committee of Jingzhou Hospital Affiliated to Yangtze University on 23 Jan 2024 (No. 2024-003-01). The study was registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn, ChiCTR2400081300, Date of registration: 28 Feb 2024) and conducted at Jingzhou Hospital Affiliated to Yangtze University from 25 Mar 2024 to 31 Dec 2024. This research complied with the Declaration of Helsinki and CONSORT guidelines. Written informed consents were obtained from all patients or their guardians before enrollment.

Male patients scheduled for elective open spinal surgery under general anesthesia were selected. These patients required indwelling urinary catheters during the perioperative period until one day post-surgery. The inclusion criteria were: age between 18 and 70 years, BMI between 18 and 30 kg/m², and ASA-PS classification I-III. Exclusion criteria included: a history of urological diseases or surgeries (such as benign prostatic hyperplasia, neurogenic bladder, urinary tract obstruction, etc.), psychiatric disorders or use of psychotropic medications, central nervous system diseases, inability to communicate effectively, chronic pain, history of substance abuse, morbid obesity, severe hepatic or renal dysfunction, and any difficulties encountered during the catheter insertion process.

Randomization and blindness

All eligible patients were randomly assigned to one of the three groups in a 1:1:1 ratio using SPSS (version 26.0, USA) generated random sequence, group C (0.9% normal saline), group B (butorphanol 0.02 mg/kg), group N (nalbuphine 0.1 mg/kg), with 40 patients in each group.

The assignment number was sealed in an envelope. The first investigator who was not involved in any anesthetic care or data collection, opened the sealed envelopes containing the group assignments and prepared the study medication according to the allocated group. Before the end of the surgery, while placing a subcutaneous drainage tube, the second investigator administered the prepared medication to eligible patients intravenously which was prepared by the first investigator. The second investigator was responsible for anesthetic induction, management, and emergence. At the end of the surgery, after the patient regained spontaneous respiration and consciousness, the endotracheal tube was removed, and the patient was transferred to the PACU for observation with nasal oxygen supplementation. A third investigator assessed the patient’s CRBD, RASS, and NRS scores at various time points during the PACU and after transfer to the ward. All the investigators and patients, except the first investigators, did not know the group allocation until the data analysis were completed.

Previous studies have demonstrated that the analgesic efficacy of nalbuphine is comparable to that of morphine [20], whereas the analgesic potency of butorphanol is 3.5 to 7 times greater than that of morphine [21]. Taking the median value of 5 times, it was determined that 0.02 mg of butorphanol produces equivalent analgesic effects to 0.1 mg of nalbuphine. Based on this calculation, the equivalent doses of butorphanol and nalbuphine were calculated. Patients in group C, group B and group N were treated with 5 ml of 0.9% normal saline, 0.02 mg/kg butorphanol or 0.1 mg/kg nalbuphine, respectively.

Anesthesia and catheter insertion procedures

All patients fasted for at least 8 h preoperatively according to standard protocols. No preoperative medications, particularly those that might affect the assessment of CRBD, such as dexmedetomidine, scopolamine, tramadol, or pregabalin, were administered. All the patients were instructed on how to distinguish the surgical wound pain and discomfort related to the urinary catheter during a preoperative visit. Upon entering the operating room, an intravenous access was established in the upper limb, blood pressure (BP), heart rate (HR), electrocardiogram (ECG), and oxygen saturation (SpO₂) were applied to all patients. General anesthesia was induced using midazolam 0.05 mg/kg, propofol 2 mg/kg, sufentanil 0.5 µg/kg, and rocuronium 0.6 mg/kg. Once the patient was unconsciousness and satisfactory muscle relaxation was achieved, an endotracheal tube was inserted, and controlled ventilation was initiated. Subsequently, a urinary catheter was inserted transurethrally by a surgeon. Anesthesia maintenance: propofol was infused intravenously at a rate of 5–12 mg·kg⁻¹·h⁻¹, and remifentanil was administered at 0.1–0.2 µg·kg⁻¹·min⁻¹. Additional rocuronium 0.2 mg/kg was given as needed to maintain muscle relaxation, and sufentanil 10 µg per dose was administered to enhance analgesia. Volume-controlled ventilation was performed using an anesthesia machine, with a tidal volume set at 8–10 ml/kg and the respiratory rate adjusted to maintain end-tidal carbon dioxide between 35 and 45mmHg.

After successful tracheal intubation, all patients underwent urethral catheterization with a 16 F silicone catheter performed by a clinical surgeon with over 5 years of experience. Prior to insertion, the pubic symphysis area was thoroughly disinfected, and a layer of tetracaine hydrochloride jelly was used to lubricate the catheter. The insertion procedure was carried out gently to avoid trauma to the urethral mucosa. After successful catheterization, 10 ml of saline was injected into the catheter balloon, and the catheter was secured without tension on the inner thigh to prevent it from slipping or causing traction injury to the urethra.

Postoperative analgesia protocol and rescue analgesic

For postoperative analgesia, all patients received local infiltration of bupivacaine liposome injection at the surgical incision site at the end of the procedure. This study used tramadol for the rescue treatment of postoperative CRBD. When the postoperative CRBD score ≥3, tramadol 1 mg/kg was administered. When the postoperative NRS score was ≥4, sufentanil 0.1 µg/kg was given. If the patient experienced persistent agitation due to catheter-induced irritation symptoms, and the RASS score remained ≥3 after two consecutive assessments despite pharmacological rescue, the catheter could be removed in consultation with the surgical team, ensuring patient safety.

Outcome measurements

Baseline data were recorded for all patients. The severity of CRBD, NRS score, RASS score, and the occurrence of EA were assessed at five time points after tracheal extubation: 5 min (T1), 30 min (T2), 1 h (T3), 2 h (T4), and 6 h (T5).

The primary outcomes were the incidence of moderate to severe CRBD and the RASS score at T1 postoperatively. The severity of CRBD was assessed using a 4-point scale (none = patient did not complain of any CRBD symptoms even when asked; mild = urethral discomfort reported upon questioning; moderate = spontaneously reports lower abdominal fullness, urgency, or dysuria without behavioral abnormalities; severe = spontaneous complaint severe urgency, dysuria, or lower abdominal fullness that is intolerable, accompanied by behavioral abnormalities) [22]. RASS score was used to evaluate patients’ consciousness and agitation levels at T1, T2, T3, T4, and T5 postoperatively. The scale consists of 10 levels ranging from −5 to +4 (−5 = unarousable, −4 = deep sedation, −3 = moderate sedation, −2 = light sedation, −1 = drowsy, 0 = alert and calm, +1 = restless, +2 = agitated, +3 = very agitated, +4 = combative) [23]. RASS score ≥ +2 at T1 was defined as EA [24].

Secondary outcomes included the duration of surgery and the extubation time (from cessation of anesthetic maintenance drugs to tracheal extubation) were documented. Postoperative satisfaction, the needs for rescue analgesia, and adverse events such as nausea, vomiting, respiratory depression, dizziness, and drowsiness were also recorded. Postoperative satisfaction was assessed using a 5-point Likert scale at the time of catheter removal (1 = very dissatisfied, 2 = dissatisfied, 3 = neutral, 4 = satisfied, 5 = very satisfied) [25]. Postoperative pain was evaluated using the NRS (0 = no pain to 10 = worst imaginable pain) at T1, T2, T3, T4, and T5 postoperatively [26].

Statistical analysis and sample size

Statistical analyses were conducted using IBM SPSS (version 26.0, USA) and GraphPad Prism (version 9.2.0, USA). Levene’s test was used to assess the homogeneity of variances, and the Shapiro-Wilk test was used to check for normality. Normally distributed continuous data were presented as means ± standard deviation (SD), one-way analysis of variance (ANOVA) and LSD test were used to compare the differences among the groups. Non-normally distributed data were expressed as median (M) and inter-quartile range (IQR) and were analyzed by Kruskal-Wallis H test. Multiple comparison tests were adjusted by Bonferroni’s correction (p < 0.0167 was considered to be statistically significant when the post hoc test was used). Categorical variables were presented as frequencies (%) and compared using the Pearson’s chi-squared test or Fisher’s exact test. Spearman’s rank correlation coefficient was calculated to assess the strength and direction of association between two ordinal variables. Two-tailed p values of < 0.05 were considered statistically significant.

Sample size calculation was performed using PASS (version 15.0, USA). One of the primary outcome was the incidence of moderate to severe CRBD at T1 postoperatively. Based on preliminary observations, the incidence of CRBD in each group was as follows: 80% in group C, 15% in group B, and 50% in group N. With a significance level of α = 0.05, power of 1-β = 0.8, and a dropout rate of 10%, a total of 120 patients were planned to be included, with 40 patients in each group.

Results

Patient demographics and baseline characteristics

A total of 132 patients were screened for inclusion in this study from March 2024 to December 2024. Twelve patients were excluded due to failure to meet the inclusion criteria. The remaining 120 patients were randomly assigned to three groups in a 1:1:1 ratio. Before anesthesia induction, two patients in group C and three patients in group N declined to participate in the study. Ultimately, 38 patients in group C, 40 patients in group B, and 37 patients in group N were included for analysis (Figure 1). There were no statistically significant differences in the baseline characteristics of the three groups, including age, weight, BMI, ASA-PS classification, duration of surgery, and extubation time, consumption of sufentanil (p > 0.05) (Table 1).

Figure 1.

CONSORT diagram of the study.

Table 1.

Baseline characteristics of the patients and secondary outcomes.

Variable	Group C (n = 38)	Group B (n = 40)	Group N (n = 37)	F/χ2	p Value
Age (years)	56.53 ± 8.33	55.20 ± 8.85	58.00 ± 7.90	1.073	0.345
Weight (kg)	69.71 ± 8.92	70.45 ± 7.75	68.11 ± 8.95	0.749	0.475
BMI (kg/㎡)	24.80 ± 2.67	24.27 ± 2.54	23.81 ± 2.55	1.365	0.260
ASA-PS (n) (I/II/III)	5/19/14	7/21/12	4/24/9	2.464	0.651
Duration of surgery (min)	144.18 ± 36.19	152.65 ± 42.23	151.70 ± 33.17	0.586	0.558
Time to extubation (min)	9.21 ± 3.35	9.00 ± 3.40	9.57 ± 3.20	0.285	0.753
Consumption of sufentanil (ug)	31.45 ± 4.34	32.75 ± 4.93	31.49 ± 4.84	0.968	0.383

Data are presented as means ± standard deviation, or number of patients. Group C: saline group; Group B: butorphanol group; Group N: nalbuphine group. BMI, body mass index. ASA-PS, American Society of Anesthesiologists Physical Status.

Primary outcome

At each postoperative time point, the incidence of moderate to severe CRBD in groups C, B, and N was as follows: (T1: 81.6%, 17.5%, 45.9%; T2: 81.6%, 17.5%, 35.1%; T3: 39.5%, 5.0%, 24.3%; T4: 34.2%, 5.0%, 8.1%; T5: 15.8%, 0%, 2.7%). The occurrence of CRBD at each time point is shown in (Figure 2). At the whole observation points, group B had a significantly higher proportion of patients with no CRBD and a significantly lower proportion of patients with moderate CRBD compared to group C (p < 0.001). At T1 and T2, the number of patients with severe CRBD in group B was significantly lower than in groups C and N, while the number of patients with mild CRBD in groups B and N was significantly higher than in group C (p < 0.001). At T3, T4, and T5, the number of patients with no CRBD in group N was significantly higher than in group C (p < 0.001). At T3 and T4, there were no significant differences in the incidence of mild or severe CRBD between the three groups (p > 0.05). Specifically, at T1, group B had a significantly higher number of patients with none CRBD than group N, while at T3, the number of patients with moderate CRBD in group B was significantly lower than in group N. At T5, the number of patients with mild CRBD in group B was significantly lower than in group C (p < 0.001) (Table 2).

Figure 2.

Data are presented as percentage (%). Comparison of the incidence of severity CRBD between the three groups at T1, T2, T3, T4, and T5 postoperatively. Multiple comparison tests were adjusted by Bonferroni’s correction (p < 0.0167 was considered to be statistically significant). Compared with group C, *p < 0.0167; compared with group B, ^#p < 0.0167. CRBD, catheter-related bladder discomfort. Time points after tracheal extubation: 5 min (T1), 30 min (T2), 1 h (T3), 2 h (T4), 6 h (T5).

Table 2.

Incidence and severity of postoperative CRBD.

Variable	Group C (n = 38)	Group B (n = 40)	Group N (n = 37)	χ 2	p Value
T1
Incidence of moderate to severe	31 (81.6)	7 (17.5)	17 (45.9)	37.323	<0.001
None	2	15*	4#
Mild	5	18*	16*
Moderate	22	6*	11*
Severe	9	1*	6
T2
Incidence of moderate to severe	31 (81.6)	7 (17.5)	13 (35.1)	40.508	<0.001
None	1	16*	6
Mild	6	17*	18*
Moderate	25	7*	10*
Severe	6	0*	3
T3
Incidence of moderate to severe	15 (39.5)	2 (5.0)	9 (24.3)	26.816	<0.001
None	1	20*	12*
Mild	22	18	16
Moderate	15	2*	9#
Severe	0	0	0
T4
Incidence of moderate to severe	13 (34.2)	2 (5.0)	3 (8.1)	30.476	<0.001
None	4	26*	20*
Mild	21	12	14
Moderate	13	2*	3*
Severe	0	0	0
T5
Incidence of moderate to severe	6 (15.8)	0 (0)	1 (2.7)	20.380	<0.001
None	11	30*	23*
Mild	21	10*	13
Moderate	6	0*	1
Severe	0	0	0

Data are presented as number (%) of patients. Group C: saline group; Group B: butorphanol group; Group N: nalbuphine group. Data were compared using Pearson’s chi-squared test or Fisher’s exact test. Multiple comparison tests were adjusted by Bonferroni’s correction (p < 0.0167 was considered to be statistically significant). Compared with group C. *p < 0.0167; Compared with group B. ^#p < 0.0167. CRBD, catheter-related bladder discomfort. Time points after tracheal extubation: 5 min (T1), 30 min (T2), 1 h (T3), 2 h (T4), 6 h (T5).

Secondary outcome

At T1 and T2, the RASS scores of groups B and N were significantly lower than those of group C. At T1, the RASS score in group B was lower than in group N (p < 0.001). At the remaining time points, there were no significant differences in RASS scores among the three groups (p > 0.05) (Table 3).

Table 3.

RASS comparison between the three groups.

Variable	Group C (n = 38)	Group B (n = 40)	Group N (n = 37)	H	p Value
T1 RASS	2 (1,2)	0 (0,1)*	1 (0,1)*#	30.614	<0.001
T2 RASS	1 (0,1)	0 (0,0)*	0 (0,0)*	29.087	<0.001
T3 RASS	0 (0,0)	0 (0,0)	0 (0,0)	3.623	0.163
T4 RASS	0 (0,0)	0 (0,0)	0 (0,0)	0	1.000
T5 RASS	0 (0,0)	0 (0,0)	0 (0,0)	0	1.000

Data are presented as median (interquartile range). Compared with group C. *p < 0.0167. Compared with group B. ^#p < 0.0167. Multiple comparison tests were adjusted by Bonferroni’s correction (p < 0.0167 was considered to be statistically significant). RASS, Richmond agitation-sedation scale. Time points after tracheal extubation: 5 min (T1), 30 min (T2), 1 h (T3), 2 h (T4), 6 h (T5).

At T1 and T2, the NRS scores in group B were significantly lower than those in groups C and N. At T2, the NRS score in group N was lower than in group C (p < 0.001). At T3 and T4, the NRS scores in groups B and N were significantly lower than in group C (p < 0.001). At T5, there were no significant differences in NRS scores among the three groups (p > 0.05) (Table 4).

Table 4.

NRS comparison between the three groups.

Variable	Group C (n = 38)	Group B (n = 40)	Group N (n = 37)	H	p Value
T1 NRS	4 (3,4)	3 (2,3)*	3 (3,4)#	46.879	<0.001
T2 NRS	4 (4,4)	2 (2,3)*	3 (3,4)*#	63.718	<0.001
T3 NRS	4 (4,4)	3 (2,3)*	3 (3,3)*	48.823	<.001
T4 NRS	3 (3,4)	3 (2,3)*	3 (2,3)*	17.087	<0.001
T5 NRS	3.5 (3,4)	3 (3,4)	3 (3,4)	3.275	0.194

Data are presented as median (interquartile range). Compared with group C. *p < 0.0167. Compared with group B. ^#p < 0.0167. Multiple comparison tests were adjusted by Bonferroni’s correction (p < 0.0167 was considered to be statistically significant). NRS, numerical rating scales. Time points after tracheal extubation: 5 min (T1), 30 min (T2), 1 h (T3), 2 h (T4), 6 h (T5).

A significant positive correlation was observed between concurrent NRS scores and CRBD (r = 0.763, p < 0.001). Postoperative satisfaction scores progressively increased from group C to group N and then to group B (p < 0.05) (Figure 3). The incidence of postoperative dizziness was significantly higher in group B compared to group C (p < 0.0167). The requirement for rescue analgesia demonstrated a stepwise increase across groups C, N, and B (p < 0.001). Additionally, groups B and N exhibited significantly lower incidences of emergence agitation than group C (p < 0.001) (Table 5).

Figure 3.

Comparison the Likert scale between the three groups postoperatively. Multiple comparison tests were adjusted by Bonferroni’s correction (p < 0.0167 was considered to be statistically significant). Compared with group C, *p < 0.0167; compared with group B, ^#p < 0.0167.

Table 5.

The adverse events after extubation.

Variable	Group C (n = 38)	Group B (n = 40)	Group N (n = 37)	χ2	p Value
Nausea/vomiting	3	3	5	0.976	0.669
Respiratory depression	0	3	3	3.348	0.212
Dizziness	0	6*	2	6.495	0.021
Drowsiness	1	3	2	0.987	0.783
Rescue analgesia	29	4*	17*#	35.009	<0.001
EA	20	5*	6*	19.135	<0.001

Data are presented as number of patients. Data were compared using Pearson’s chi-squared test or Fisher’s exact test. Multiple comparison tests were adjusted by Bonferroni’s correction (p < 0.0167 was considered to be statistically significant). Compared with group C. *p < 0.0167. Compared with group B. ^#p < 0.0167. EA, emergency agitation.

Discussion

This randomized controlled clinical trial investigated the efficacy of opioid receptor agonist/antagonists in preventing CRBD and EA following spinal surgery. The results demonstrated that both butorphanol and nalbuphine significantly reduced the incidence of moderate-to-severe CRBD postoperatively. Notably, butorphanol exhibited superior efficacy to nalbuphine in preventing early postoperative CRBD, while concurrently improving emergence quality and patient satisfaction.

The precise risk factors for CRBD remain incompletely elucidated. Emerging evidence suggests associations with variables including gender, age, catheter size, balloon volume, surgical type, procedural duration, and prior catheterization history [27,28]. Previous research has predominantly focused on the incidence of CRBD following transurethral procedures. However, a significant diagnostic challenge stems from the clinical symptom overlap between CRBD and postoperative urethral trauma-related pain in this population. This overlap frequently leads to unreliable patient self-reporting of CRBD manifestations, impairing clinicians’ capacity to objectively evaluate discomfort and initiate targeted therapeutic measures. To address these diagnostic limitations, this study excluded patients undergoing transurethral procedures to enhance the precision of CRBD assessment. CRBD predominantly manifests during postoperative recovery, potentially attributable to cerebral cortical inhibition under general anesthesia that impairs both catheter perception and memory formation. Furthermore, surgical patients must undergo gradual emergence from anesthesia involving progressive reduction of anesthetic depth and restoration of sensorimotor functions before achieving recovery room discharge criteria. As a result, many patients have a poor tolerance to the catheter during the wake-up phase from anesthesia. Previous studies have shown that the incidence of CRBD after spinal surgery is 70% [22], but the study did not distinguish the gender of the patients. Male patients are at a higher risk of developing CRBD due to their longer and narrower urethra, which contains multiple bends and narrow segments, making them more susceptible to CRBD than female patients [29]. Ekasak et al. [30] showed that the incidence of CRBD after spinal surgery in male patients was 75%, which is consistent with the postoperative CRBD incidence in the control group of this study. Some studies have suggested that being over 50 years old is an independent risk factor for postoperative CRBD [31]. In this study, the average age of the patients was 56 years, which may partly explain the higher incidence of CRBD. Furthermore, some research indicates that preoperative education and explanation using images for patients who require catheter placement during the perioperative period can not only reduce the incidence of CRBD during the recovery phase but also decrease its severity [32]. Although patients were preoperatively instructed on distinguishing between wound pain and CRBD symptoms, the persistently high incidence of CRBD in the control group may have been partially attributable to the limited patient comprehension of this educational intervention.

This study found that within 30 min after surgery, the incidence of severe CRBD and the NRS scores in butorphanol group was significantly lower than control group and nalbuphine group. However, for moderate or mild CRBD symptoms, no difference was observed between the butorphanol and nalbuphine groups. These findings suggest that administering butorphanol intravenously 30 min before the end of surgery leads to better recovery quality for patients. The study also found that administering either butorphanol or nalbuphine 30 min could significantly reduce the overall incidence of postoperative CRBD. Both butorphanol and nalbuphine act as κ receptor agonists and μ receptor antagonists. The κ receptor is an important modulator of visceral pain, and its activation can downregulate the expression of cytokines and chemokines, exerting an anti-inflammatory effect, reducing nociceptive sensitization, and providing preemptive analgesia [18,33,34]. Peng et al. [19] conducted a comprehensive investigation into the pharmacological characteristics of butorphanol and nalbuphine, specifically comparing their respective affinities for κ and μ receptors. They found that the Ki value for butorphanol binding to the κ receptor was 0.079 ± 0.003, while for nalbuphine, it was 2.20 ± 0.01. The Ki value is an indicator of the affinity of a compound for a receptor; the lower the Ki value, the stronger the binding affinity of the compound for the receptor. The study also found that the κ/μ selectivity ratio for butorphanol was 3, whereas for nalbuphine, it was 0.4. A higher selectivity ratio indicates that the compound is more likely to bind to the κ receptor. The difference in affinity for the κ receptor between butorphanol and nalbuphine may explain butorphanol was more effective in managing postoperative CRBD than nalbuphine. There was no significant difference in the incidence of mild and severe CRBD among the three groups 1 h after surgery, due to most patients had already developed tolerance and adaptation to the catheter. However, for moderate CRBD symptoms, the butorphanol group still showed advantages over the nalbuphine group.

Studies have shown a strong correlation between postoperative pain and the severity of CRBD [35]. This study also analyzed this relationship and found a correlation coefficient (r = 0.763, p < 0.001) between NRS scores and CRBD after 5 min tracheal extubation. Clinicians often focus on alleviating postoperative wound pain based on their usual prescribing habits, which leads to the frequent use of high doses of opioid receptor agonists in the perioperative period. Given the increasing global use and misuse of opioids, a strategy that minimizes opioid consumption while achieving optimal pain relief should be a key consideration for clinicians [36]. While opioids are effective in relieving pain, but they often lead to postoperative complications such as nausea, vomiting, respiratory depression, and pruritus. Both animal and clinical studies have shown that the use of opioid receptor agonists for pain management during surgery increases sensitivity to postoperative pain stimuli [37]. In contrast, perioperative use of butorphanol can mitigate the hyperalgesia induced by opioid receptor agonists [38,39]. Both butorphanol and nalbuphine, perform better in postoperative analgesia than opioid receptor agonists, requiring less rescue analgesia, resulting in higher patient satisfaction, and lowering the risk of postoperative complications [40,41]. Notably, when managing visceral pain, the activation of κ receptors offers a more significant advantage [42,43], this is consistent with this study. However, the proportion of dizziness was higher in the butorphanol group than the control group, while the incidence of rescue analgesia and the occurrence of adverse events were significantly lower than in the control group. Patient satisfaction gradually increased from the control group to the nalbuphine and butorphanol groups, indicating that despite some minor side effects of these drug interventions, it is remained within an acceptable range.

EA is a common postoperative complication following general anesthesia, characterized by a combination of excitement, restlessness, and disorientation, along with involuntary movements, irrational speech, crying, or moaning. Postoperative pain, male gender, CRBD, and prolonged fasting time can increase the incidence of EA [24]. Previous studies have indicated that EA can cause severe harm to the patient and medical staff, even affecting the surgical outcome without promptly managed or treated [44]. Postoperative indwelling catheters are a common cause of EA. Spinal surgeries often involve prolonged exposure of the operative field, which combined with postoperative hypothermia, leads to a high incidence of postoperative shivering. Furthermore, the stimulation from wound pain and the systemic inflammatory response induced by surgical trauma further increase the incidence of EA. Previous research suggests that pain and postoperative shivering share similar neural pathways [45]. The perioperative use of butorphanol has been found to be effective in reducing postoperative shivering in elderly patients [46]. The analgesic and sedative effects of butorphanol can also effectively alleviate postoperative EA [47,48]. Compared to sufentanil, butorphanol significantly increases the level of IL-10 in circulation while reducing the levels of TNF-α and IL-1β, suggesting that butorphanol may have an inhibitory effect on the postoperative systemic inflammatory response, mitigating the stress response induced by surgery, and reducing the incidence of postoperative cognitive dysfunction [49]. Other studies have indicated that nalbuphine also demonstrates positive effects on postoperative EA [50], which aligns with the results of this study. However, due to the differing affinities of butorphanol and nalbuphine for the κ and μ receptors, the butorphanol group in this study exhibited better postoperative recovery quality.

Following intravenous administration, both butorphanol and nalbuphine exhibit peak pharmacological effects within 30 min, with an elimination half-life ranging from 3 to 4 h. These agents demonstrate significant clinical advantages, including potent analgesic efficacy, prolonged duration of pain relief, minimal gastrointestinal side effects, reduced respiratory depression, and low potential for drug dependence [51,52]. The highest incidence of CRBD in control group occurred 1h after extubation, while the highest incidence of moderate to severe CRBD occurred 30 min after extubation. This may be due to the analgesic medications used during the surgery not being fully metabolized at the time of extubation, which can partially alleviate the discomfort caused by the catheter. However, as the concentration of analgesic drugs in the body gradually decreases over time, patients without drug interventions experience an increase in the incidence and severity of CRBD. Therefore, the rational timing of drug administration, may help reduce the occurrence of moderate-to-severe CRBD.

It is noteworthy that the etiology of CRBD is multifactorial and complex. Previous studies have demonstrated that blockade of peripheral neural pathways can effectively reduce the incidence of CRBD [53,54]. However, CRBD, surgical incision pain, and EA frequently interact and mutually exacerbate one another, rendering single-modality treatment approaches insufficient to ensure stable recovery during the emergence phase. Currently, there are no established nursing standards or consensus guidelines for the management of CRBD. In the future, multimodal perioperative management strategies and multidisciplinary team-based approaches may represent important directions for advancement. For instance, the combined application of peripheral nerve blocks and opioid receptor agonist/antagonists may provide enhanced therapeutic efficacy.

Despite the above findings, this study has certain limitations. First, it is a single-center study with a limited number of participants. A multicenter study with a larger sample size would enhance the generalizability of the results and may reveal more significant findings. Second, this study only investigated a common dosage of butorphanol and nalbuphine. It remains uncertain whether higher doses of these trial medications would be more effective in managing CRBD and EA. Third, previous studies have shown that the incidence of postoperative CRBD is lower in female patients than in male patients, and CRBD in female patients is often overlooked postoperatively, so it remains unclear whether the results are applicable to female patients. Moreover, most of the outcome assessments in this study were based on patients’ understanding of CRBD, which can vary from person to person and may be subjective. In future studies, measurement of relevant biochemical markers in the blood and urine of patients may improve the accuracy and stability of the assessment.

Conclusions

Opioid receptor agonist/antagonists demonstrate efficacy in preventing CRBD and EA in male patients undergoing open spinal surgery with improved patient satisfaction, and without significant adverse events. In addition, butorphanol is more effective than nalbuphine in preventing CRBD and EA in the early postoperative period due to its stronger affinity for κ receptors.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data relevant to the study are included in the article. The data supporting the findings of this study are available from the corresponding author upon reasonable request.