1. Background

Orthopedic surgeries are often conducted under peripheral nerve blocks, which are highly effective methods for both anesthesia and analgesia. Peripheral nerve blocks can reduce systemic opioid use and potentially improve patient recovery after surgery.16 A single injection can provide analgesic effects for approximately 6 to 8 hours.1 However, some patients experience an exaggerated pain response when the block resolves, termed “rebound pain.” Recently, postoperative rebound pain after peripheral nerve block has been widely recognized.24 Rebound pain is defined as a transition from well-controlled pain during discharge from the operating room (numerical rating scale of pain [NRS] < 4 on an 11-point scale) to severe pain (NRS ≥7) within 24 hours after the block.31 This rebound pain primarily occurs between 12 and 24 hours after the peripheral nerve block is administered.17,18 This type of pain is a complex physiological and psychological response that potentially involves multiple factors, such as injection pressure, perineurium edema, myelin degeneration, and local inflammation.39,43 In addition, during the surgical procedure, peripheral nerve fibers and bones may be damaged or stimulated because of surgical irritation and tissue injury, resulting in enhanced postoperative pain.28 Postoperative rebound pain can decrease a patient's sleep quality, affect their appetite and mood, and diminish their overall recovery. Numerous studies have been conducted to investigate preventive strategies6,44,46; however, only a handful of interventions, including steroids and multimodal analgesia, have proven effective.41 Despite these measures, the incidence of rebound pain remains considerably high (approximately 20%).6,45 Thus, identifying new preventive strategies for this type of pain has become a new challenge for clinicians.44

Tropisetron is a 5HT-3 receptor antagonist and partial α7n-type acetylcholine (a7nAch) receptor agonist and has been frequently used for treating postoperative nausea and vomiting (PONV).36 Blocking 5HT-3 receptors35 and activating a7nAch receptors26 produce analgesic effects by decreasing inflammatory cytokine release. Activation of a7nAch receptors has been demonstrated to ameliorate ischemic–reperfusion injury and provide neuroprotection.32 In addition, we previously reported that tropisetron reduces inflammation and myocardial ischemic–reperfusion injury after heart valve replacement surgery.11 Moreover, antagonism of 5HT-3 receptors has been shown to have anxiolytic effects on animal models through modulation of the serotonergic system.7,21 Thus, simultaneously targeting these 2 receptors has the potential to suppress postoperative rebound pain and anxiety. Although many hospitals perform orthopedic surgery as an outpatient procedure, almost all orthopedic surgeries at our hospital involve inpatient surgery, enabling us to observe postoperative rebound pain and anxiety. Thus, we designed this randomized double-blind trial to explore the efficacy of tropisetron on postoperative rebound pain and anxiety after brachial plexus block.

2. Methods

The study was approved by the Ethics Committee of Xiangyang Central Hospital affiliated with Hubei University of Arts and Science, and it adhered to the tenets of the Declaration of Helsinki. The clinical study was registered at www.chictr.org.cn (ChiCTR2300069994). Written informed consent was acquired from all patients. The inclusion criteria were as follows: patients aged 18 to 70 years, American Society of Anesthesiologists (ASA) grade I–III anesthesia, and planned to receive upper extremity surgery under brachial plexus block anesthesia from April 2023 to July 2023 in our tertiary hospital. The exclusion criteria were as follows: had cognitive impairment, used other sedative and analgesic drugs in the past week, participated in other drug clinical trials within the past 3 months, or used a 5HT3 receptor antagonist before admission.

Before surgery, a medically trained biostatistician generated randomized numbers with a computer, allocated patients into the control group (5 mL of normal saline) or tropisetron group (5 mg/5 mL of tropisetron), and prepared the drug according to the number sequence. After the patient's admission to an operating room, a noninvasive blood pressure monitor, standard 5-lead electrocardiograph, and pulse oximeter were used for vital sign monitoring. Peripheral nerve block was performed by an experienced attending physician under ultrasound guidance, followed by analgesic effect evaluation 15 minutes after the injection. An anesthesia assistant who was blinded to the group allocation took the drug from the biostatistician and injected it after the start of the surgery. When patients provided informed consent, a patient-controlled analgesia (PCA) pump (100 mL filled with 200 μg of sufentanil) was used for postoperative analgesia. The local anesthetics used were 20 mL of 0.375% ropivacaine and 1% lidocaine for intermuscular sulcus or axillary blocking; 30 mL of 0.375% ropivacaine and 1% lidocaine in total for the intermuscular sulcus (15 mL) and axillary pathway (15 mL); and 30 mL of 0.375% ropivacaine and 1% lidocaine in total for the intermuscular sulcus (20 mL) and cervical plexus blocking (10 mL). If a patient felt pain and could not endure the incision or had an NRS > 3 during the surgery, the patient was considered to have an inadequate block. The recovery of sensory and motor functions was reported by the patients 24 hours after the brachial plexus block. Postoperatively, patients were educated to either press the PCA button or call for a physician if their NRS was equal to or higher than 4. The attending physician would then prescribe parenteral nonsteroid anti-inflammatory drugs (NSAIDs). In cases where the NRS remained ≥ 4, even 30 minutes after receiving the NSAID, an intravenous dose of dezocine was administered.

The demographic information of all the patients was collected, including age, sex, weight, height, smoking status, alcohol consumption, previous disease (cerebrovascular disease, cardiovascular disease, hepatic disease, pulmonary disease, diabetes mellitus [DM], and hypertension), pain before surgery, ASA classification, heart function (New York Heart Association standard), white blood cell (WBC) count, surgery site, bone surgery, length of incision, anesthesia injection site, intraoperative opioid use, intraoperative NSAIDs, dexmedetomidine, and PCA use. The patients' previous diseases were diagnosed through a combination of self-reported history and computed X-ray tomography, magnetic resonance imaging, blood tests, electrocardiography, and angiography. Our study's primary outcome was the incidence of postoperative rebound pain. The secondary outcomes, including visual analog scale of anxiety (VAA), postoperative NSAID use, opioid requirement, duration of sensory block and motor block (recorded in hours), inadequate blocking, postoperative nausea and vomiting (PONV), vertigo, and patient satisfaction, were measured 24 hours after the peripheral block was administered. The NRS scores and other secondary outcomes were measured by an assistant observer unaware of the group allocations. We used the NRS, an 11-point pain intensity score (0–10), to evaluate patient pain intensity, following our previous study. On this scale, “0” signifies no pain, and “10” represents the most intense pain imaginable.15 We also used the VAA, another 11-point score, to assess postoperative patient anxiety,25,47 as per our previous study.50 A VAA score of “0,” ≤3, ≥4, and <7 or ≥7 indicated no, mild, moderate, or severe anxiety, respectively. An independent investigator blinded to the group allocation recorded the patient demographic information and postoperative evaluations. All surgeons, anesthetists, patients, and postoperative evaluators were blinded to the group allocations.

2.1. Statistical analysis

The sample size calculation used PASS11 software. Based on a previous study, the incidence of rebound pain is about 50% after peripheral nerve block, and a 0.2 decrease of incidence is considered significant. The sample size was at least 39 patients in each group, with an alpha of 0.05 and a beta of 0.20.44 Considering that approximately 30% of patients are lost to follow-up, we included 115 patients in total. Continuous data are presented as the mean (SD) or median (interquartile) if they were normally or nonnormally distributed; 2 groups were compared using t tests or Mann–Whitney U tests. The categorical data are presented as numbers and tested using the χ2 or Fisher exact tests. The comparisons between groups were performed through intention-to-treat analysis. Univariate and multivariate logistic regression analyses were performed to explore the risk factors for postoperative rebound pain and moderate to severe anxiety (VAA ≥4). A P value <0.05 was considered to indicate a significant difference.

3. Results 3.1. Patients' baseline characteristics

During the study period, we screened a total of 376 patients and enrolled 115 patients. Among those patients, 56 (33 men) and 59 (34 men) patients were randomized to the tropisetron and saline groups, respectively. The trial flow chart is shown in Figure 1. None of the anesthesia procedures were converted to general anesthesia. One patient in the tropisetron group was discharged before the first visit and could not be contacted. The 2 groups showed no significant differences regarding demographic information, history, or NRS score before surgery (Table 1). There was no significant difference between the 2 groups regarding surgery-related information, including surgery location, bone surgery, or incision length (Table 1). In addition, no significant differences were found between the 2 groups regarding anesthesia-related information, including injection site, inadequate blocks, intraoperative NSAID, dexmedetomidine, or PCA use (Table 1). One patient reported an inadequate block; he could not endure the incision and had an NRS score >3 during surgery. The patient subsequently received sufentanil and dexmedetomidine for analgesia and sedation, respectively.

Figure 1.:

Trial flowchart.

Table 1 - Patient baseline characteristics. Control (n = 59) Tropisetron (n = 56) P Women (%) 26 (44.1) 22 (39.3) 0.741 Age (mean [SD]) 50.08 (14.24) 48.23 (15.19) 0.501 Weight (mean [SD]) 66.69 (11.59) 66.32 (12.47) 0.868 Height (mean [SD]) 165.81 (7.86) 165.36 (6.72) 0.739 BMI (mean [SD]) 24.16 (3.14) 24.15 (3.61) 0.989 Smokers (%) 10 (16.9) 5 (8.9) 0.318 Alcohol use (%) 20 (33.9) 15 (26.8) 0.531 Pain before surgery (median [IQR]) 5.00 (3.00–5.00) 4.00 (2.00–5.00) 0.282 Cerebrovascular disease yes (%) 4 (6.8) 5 (8.9) 0.935 Cardiovascular disease yes (%) 0 (0.0) 1 (1.8) 0.979 Pulmonary disease yes (%) 2 (3.4) 5 (8.9) 0.394 Hypertension yes (%) 10 (16.9) 11 (19.6) 0.895 DM (%) 3 (5.1) 3 (5.4) 1 Hepatic disease no/yes (%) 4 (6.8) 2 (3.6) 0.723 ASA (%) 0.4  II 48 (81.4) 41 (73.2)  III 11 (18.6) 15 (26.8) Heart function (%) 0.897  I 4 (6.8) 3 (5.4)  II 51 (86.4) 50 (89.3)  III 4 (6.8) 3 (5.4) WBC (mean (SD)) 7.21 (2.60) 7.31 (2.97) 0.846 Surgery site (%) 0.796  Hand 14 (23.7) 12 (21.4)  Front arm 25 (42.4) 24 (42.9)  Elbow 2 (3.4) 5 (8.9)  Upper arm 17 (28.8) 14 (25.0)  Shoulder 1 (1.7) 1 (1.8) Bone surgery (%) 47 (79.7) 38 (67.9) 0.219 Length of incision (median [IQR]) 7.00 (4.00–10.00) 10.00 (4.75–10.00) 0.324 Anesthesia injecting site (%) 0.718  Intermuscular sulcus 19 (32.2) 16 (28.6)  Axillary pathway 3 (5.1) 1 (1.8)  Intermuscular sulcus + axillary pathway 26 (44.1) 26 (46.4)  Intermuscular sulcus + cervical plexus 11 (18.6) 13 (23.2) Inadequate block (n) 0 1 0.979 Intraoperative opioid use (%) 30 (50.8) 31 (55.4) 0.766 Intraoperative NSAID use (%) 10 (16.9) 9 (16.1) 1 Intraoperative dexmedetomidine use (%) 58 (98.3) 55 (98.2) 1 PCA yes (%) 7 (11.9) 3 (5.4) 0.365

BMI, body mass index; DM, diabetes mellitus; NSAIDs, nonsteroidal anti-inflammatory drugs; PCA, patient-controlled analgesia; WBC, white blood cell count.

3.2. Postoperative primary and secondary outcomes

The intention-to-treat analysis of the primary outcomes revealed no significant differences between the tropisetron and saline groups regarding the incidence of rebound pain (tropisetron, 62.7%; control, 55.4%, P = 0.487) or NRS score (tropisetron, 7.00 [4.00, 8.00]; control, 7.00 [5.00, 8.00], P = 0.539) 24 hours after surgery (Table 2). However, the postoperative VAA score (tropisetron, 2.00 [1.00, 3.00]; control, 3.00 [2.00, 5.00], P = 0.006) and incidence of moderate to severe anxiety (tropisetron, 21.4%; control, 44.1%; P = 0.017) were significantly lower in the tropisetron group than those in the control group. The postoperative durations of sensory (tropisetron, 8.00 [7.00, 10.00]; control, 8.00 [7.00, 9.00], P = 0.860) and motor (tropisetron, 8.00 [7.00, 9.25]; control, 8.00 [7.00, 9.00], P = 0.997) blockages did not differ between the 2 groups. Similarly, the use of postoperative analgesia with NSAIDs (tropisetron, 96.4%; control, 100%; P = 0.453) and opioids (tropisetron, 8.9%; control, 8.5%; P = 1; did not include patient-use PCA) did not differ between the 2 groups. Moreover, there were no significant differences in terms of postoperative adverse events, including PONV (P = 0.113), postoperative headache (tropisetron, 0%; control, 3.4%; P = 0.499), or vertigo (tropisetron, 1.8%; control, 11.9%; P = 0.079). Importantly, the patients' analgesia satisfaction scores were similar between the 2 groups (P = 0.714).

Table 2 - Evaluation of postoperative primary and secondary outcomes. Control (n = 59) Tropisetron (n = 56) P Highest NRS within 24 hours after block (median [IQR]) 7.00 (5.00–8.00) 7.00 (4.00–8.00) 0.539 Rebound pain present (%) 37 (62.7) 31 (55.4) 0.487 Postoperative NSAID use (%) 59 (100.0) 54 (96.4) 0.453 Postoperative opioid use (%) 5 (8.5) 5 (8.9) 1 Duration of sensory block (median [IQR]) 8.00 (7.00–9.00) 8.00 (7.00–10.00) 0.860 Duration of motor block (median [IQR]) 8.00 (7.00–9.00) 8.00 (7.00–9.25) 0.977 VAA (median [IQR]) 3.00 (2.00–5.00) 2.00 (1.00–3.00) 0.006 Moderate to severe VAA (%) 26 (44.1) 12 (21.4) 0.017 Postoperative nausea and vomiting (%) 0.113  No 52 (88.1) 41 (73.2)  Mild nausea 5 (8.5) 9 (16.1)  Nausea and mild vomiting 2 (3.4) 6 (10.7) Analgesia satisfaction (%) 0.714  Medium 1 (1.7) 2 (3.6)  Satisfied 24 (40.7) 25 (44.6)  Very satisfied 34 (57.6) 29 (51.8) Postoperative headache (%) 2 (3.4) 0 (0.0) 0.499 Postoperative vertigo (%) 7 (11.9) 1 (1.8) 0.079

NSAIDs, nonsteroidal anti-inflammatory drug; NRS, numerical rating scale of pain; VAA, visual analog scale of anxiety.

3.3. Identification of factors associated with postoperative rebound pain and moderate to severe anxiety

Of the 115 patients, 114 had complete data, and the treatment and normal saline group patients' data were combined and used for associated factor analysis. Univariate logistic regression analysis revealed that preoperative pain, WBC count, bone surgery, and incision length were risk factors for postoperative rebound pain, and PCA was protective against this pain. Multivariate logistic regression analysis revealed that preoperative pain (4.8 [2.62, 10.93], bone surgery (8.5 [1.66, 56.32]), and incision length (1.6 [1.28, 2.13]) were risk factors, and PCA (0 [0, 0.04]) was protective against postoperative rebound pain (Table 3).

Table 3 - Univariate and multivariate logistic regression analyses of risk factors for postoperative rebound pain. No rebound pain (n = 47) With rebound pain (n = 67) P Univariate P Multivariate OR (95% CI) Tropisetron use (%) 25 (53.2) 30 (44.8) 0.487 Women (%) 15 (31.9) 33 (49.3) 0.098 Age (mean [SD]) 49.15 (14.00) 49.28 (15.33) 0.962 Weight (mean [SD]) 68.06 (10.90) 65.01 (12.23) 0.174 Height (mean [SD]) 166.34 (6.47) 164.97 (7.84) 0.326 BMI (mean [SD]) 24.52 (3.02) 23.79 (3.47) 0.25 Smokers (%) 5 (10.6) 10 (14.9) 0.7 Alcohol use (%) 17 (36.2) 17 (25.4) 0.302 Pain before surgery (median [IQR]) 2.00 (1.00–3.00) 5.00 (4.00–5.00) 0.001 <0.001 4.8 (2.62–10.93) Cerebrovascular disease (%) 4 (8.5) 5 (7.5) 1 Cardiovascular disease (%) 0 (0.0) 1 (1.5) 1 Pulmonary disease (%) 2 (4.3) 4 (6.0) 1 Hypertension (%) 8 (17.0) 13 (19.4) 0.938 DM (%) 2 (4.3) 3 (4.5) 1 Hepatic disease (%) 2 (4.3) 4 (6.0) 1 ASA (%) 0.343  II 34 (72.3) 54 (80.6)  III 13 (27.7) 13 (19.4) Heart function (%) 0.094  I 5 (10.6) 2 (3.0)  II 41 (87.2) 59 (88.1)  III 1 (2.1) 6 (9.0) WBC (mean [SD]) 6.58 (2.99) 7.75 (2.55) 0.027 0.345 0.89 (0.69–1.13) Surgery site (%) 0.572  Hand 10 (21.3) 16 (23.9)  Front arm 19 (40.4) 29 (43.3)  Elbow 5 (10.6) 2 (3.0)  Upper arm 12 (25.5) 19 (28.4)  Shoulder 1 (2.1) 1 (1.5) Bone surgery (%) 22 (46.8) 63 (94.0) <0.001 0.015 8.5 (1.66–56.32) Length of incision (median [IQR]) 4.00 (2.00–10.00) 10.00 (6.00–10.00) <0.001 <0.001 1.6 (1.28–2.13) Anesthesia site (%) 0.257  Intermuscular sulcus 19 (40.4) 16 (23.9)  Axillary pathway 2 (4.3) 2 (3.0)  Intermuscular sulcus + axillary pathway 17 (36.2) 34 (50.7)  Intermuscular sulcus + cervical plexus 9 (19.1) 15 (22.4) Intraoperative opioid (not used/used) (%) 19/28 (40.4/59.6) 34/33 (50.7/49.3) 0.37 Intraoperative NSAID use (%) 11 (23.4) 8 (11.9) 0.173 Intraoperative dexmedetomidine use (%) 46 (97.9) 66 (98.5) 1 PCA use (%) 8 (17.0) 2 (3.0) 0.023 <0.001 0 (0–0.04) Postoperative NSAID use (%) 46 (97.9) 67 (100.0) 0.858 Postoperative opioid use (%) 3 (6.4) 7 (10.4) 0.675

BMI, body mass index; DM, diabetes mellitus; NSAIDs, nonsteroidal anti-inflammatory drugs; PCA, patient-controlled analgesia; WBC, white blood cell count.

Univariate logistic regression analysis revealed that tropisetron use, female sex, age, height, alcohol consumption, and preoperative pain were associated with postoperative moderate to severe anxiety. Multivariate logistic regression analysis revealed that female sex (4.91 [1.99, 12.93]) and preoperative pain (1.37 [1.05, 1.84]) were risk factors, and tropisetron (0.29 [0.11, 0.75]) was protective against postoperative moderate to severe anxiety (Table 4). The forest plots for the relevant factors of rebound pain and moderate to severe anxiety are presented in Figure 2A and 2B, respectively.

Table 4 - Univariate and multivariate logistic regression analyses of risk factors for postoperative moderate to severe anxiety. No to mild anxiety (n = 77) Moderate to severe anxiety (n = 37) P Univariate P Multivariate OR (95% CI) Tropisetron use (%) 44 (57.1) 11 (29.7) 0.011 0.012 0.29 (0.11–0.75) Women (%) 23 (29.9) 25 (67.6) 0.001 0.013 4.91 (1.99–12.93) Age (mean [SD]) 47.05 (15.30) 53.76 (12.49) 0.022 0.087 1.02 (0.97–1.07) Weight (mean [SD]) 67.32 (11.65) 64.08 (11.82) 0.169 Height (mean [SD]) 166.49 (7.06) 163.54 (7.49) 0.043 0.321 BMI (mean [SD]) 24.21 (3.33) 23.84 (3.26) 0.576