Comparison of the analgesic effect of dezocine and esketamine in combination with sufentanil respectively after laparoscopic cholecystectomy: a prospective randomized controlled study

Acute cholecystitis, which is caused by gallstones, is a common clinical disease. Despite diverse treatment methods, laparoscopic cholecystectomy (LC) remains the gold standard for the surgical treatment of calculous cholecystitis [1]. Compared to traditional open cholecystectomy, LC is a minimally invasive surgical procedure that offers patients smaller incisions and reduced trauma. It is still traumatic to the body as some patients experience severe pain after surgery. The pain sources from the abdominal wall and internal organs, and the insufflation of carbon dioxide during the procedure can result in shoulder pain due to diaphragmatic traction and stretching [2]. Postoperative pain leads to complications such as increased heart rate, increased blood pressure, anxiety, sleep disorders, activation and release of inflammatory factors, inhibition of the immune system, and restriction of early postoperative activities and eating, causing lower perioperative patient comfortability and lower patient satisfaction, as well as increased duration of hospital stays and medical costs [3].

Patient-controlled intravenous analgesia(PCIA) has always been a hot topic of concern for anesthesiologists. As one of the most powerful opioid analgesics currently available, sufentanil is widely applied to PCIA due to its rapid peak and short half-life [4]. However, it still shares the common shortcomings of opioids, such as respiratory depression, nausea, vomiting, bradycardia, fainting, low blood pressure and astriction, restricting its application in clinical practice alone [5]. Therefore, sufentanil is usually used clinically in combination with one or more other analgesics to meet the analgesic needs of patients while reducing adverse reactions to all kinds of drugs.

Current studies regard dezocine as a partial agonist μ receptor and κ receptor, which has analgesic and sedative effects by inhibiting the reabsorption of norepinephrine and serotonin, and can reduce sufentanil-mediated hyperalgesia by restricting calmodulin-dependent protein kinase II (CaMKII.) [6, 7]. The combination of dezocine with other μ-receptor agonists significantly enhances the analgesic effect of the drug. Studies have indicated that the combination of dezocine and sufentanil can effectively relief postoperative pain in patients undergoing laparoscopic cholecystectomy [8]. However, this approach still involves the combination of two opioid drugs, which significantly increases the dosage of opioids administered to patients and still has an impact on patient prognosis.

As a new drug applied for clinical trials in recent years, esketamine is an N-methyl-D-aspartate (NMDA) receptor blocker and a dextroisomer of ketamine, which has twice the affinity with NMDA receptors as ketamine. Notably, esketamine has a variety of advantages over ketamine, including high bioavailability, rapid onset and metabolism, minimal side effects and others [9]. Esketamine has been successfully applied in clinical fields such as cancer pain control, antidepressant therapy and perioperative analgesia. It has become a frontline medication in anesthesia due to its widespread use and effectiveness.

Scientists both domestically and internationally have employed the combination of esketamine and sufentanil as a method of analgesia, which has advantages such as strong analgesic effects, antidepressant properties, and minimal side effects. However, due to a lack of clinical evidence, the effectiveness of this regimen for pain management in patients with LC has still not been fully established [10]. Therefore, we explored the effects of esketamine combined with sufentanil for postoperative pain management in LC patients and evaluated its impact on postoperative inflammatory factors by comparing it with the combination of dezocine and sufentanil as a PCIA regimen to provide a novel PCIA approach.

In total, this study recruited 58 patients who underwent laparoscopic cholecystectomy under general anesthesia, of which 2 patients were excluded due to contraindications to esketamine, 1 patient quit the study due to the duration of the surgery exceeding 2 hours, 1 patient quit due to a change to open cholecystectomy during the surgery and 2 patients quit due to complications(infection and bleeding). Finally, 52 patients completed this study (ES group, n=26; DE group, n=26) (Fig. 1).

The baseline features of patients in the two groups, including age, sex, BMI, duration of the surgery, and ASA classification, were not significantly different (P>0.05) (Table 1).

This study compared the esketamine and dezocine in combination with sufentanil to prevent the inflammatory pain after LC. We believe that 1.5 mg/kg esketamine in combination with sufentanil is better than 0.3 mg/kg dezocine in combination with sufentanil in terms of analgesic effects, improvement of postoperative sleep quality and reduction of inflammatory factor release, without increasing the incidence of adverse reactions.

The best time to manage postoperative pain is within 48 hours after surgery, especially within the first few hours. Considering the timeliness of the postoperative interview, we excluded patients whose data might have involved late at night or early in the morning. The VAS score is often used to evaluate the degree of acute postoperative pain in clinical practice. Based on the conclusions of previous studies, we defined a 1-point difference in VAS score as clinically meaningful [13]. Both PCIA plans showed excellent analgesic effects. We discovered that VAS scores at T1, T2, T3 and T4 after surgery were significantly lower in the ES group than in the DE group, and the number of analgesic pump presses, the number of analgesic supplements taken within 48 hours after the surgery and the initial bedside activity time in the ES group were lower than those in the DE group. This demonstrated that esketamine in combination with sufentanil has a better analgesic effect at the set dose. Zhu et al. suggested that dezocine can reduce postoperative pain to some extent by enhancing the analgesic effect of sufentanil [14]. Esketamine has demonstrated a notable superiority over dezocine in effectively reducing postoperative pain caused by laparoscopic surgery. As previous research noted, continuous infusions of low doses of esketamine infusion were effective in reducing postoperative pain [15]. Similarly, the administration of subanesthetic doses of esketamine during laparoscopic total hysterectomy has been shown to improve the treatment of postoperative depression and pain alleviation [16]. These findings further support our result that esketamine possesses potent analgesic effects after laparoscopic surgery. The powerful analgesic effect of esketaminem may be due to its prolonged antagonistic effect on NMDA receptors and the fact that its active metabolites also have an analgesic effect [17]. Notably, VAS score was greater in the ES group in our study than in previous reports at various time points. This discrepancy may be attributed to the higher esketamine infusion rate (0.3 mg/kg/h) used during the surgery, which significantly exceeded the postoperative infusion rate in our study. Despite these findings, patients expressed high overall satisfaction with the treatment protocol, indicating its clinical feasibility.

Postoperative sleep disorder (PSD) is related to postoperative delirium, cognitive dysfunction, pain and even cardiovascular accidents in severe cases, which significantly delay postoperative recovery [18]. The reasons are surgical stress response, pain, general anesthesia, and the usage of opioids. Therefore, improving postoperative sleep quality is an essential parameter that anesthesiologists need to consider. In this study, the PCIA regimen in the ES group demonstrated greater effectiveness in improving postoperative sleep quality, which indicated that esketamine, compared to dezocine, can more effectively enhance patients’ postoperative sleep quality and increase overall satisfaction. Similar to our observations, the results of Qiu et al. also concluded that esketamine can prevent PSD [19]. In this study, we found that the lower VAS scores in the ES group were associated with PSD, indicating that the effect of esketamine in improving sleep disorders is related to its ability to reduce postoperative pain.

Surgical trauma can induce various physiological stress responses, and surgical pain is closely associated with inflammatory factors. Several studies have shown that postoperative pain is primarily attributed to inflammatory factors. When the body is injured, it releases various inflammatory factors, with IL-6 and CRP being notable epresentative factors, which were commonly observed in surgeries such as cholecystectomy, appendectomy, and colon resection [20‐23]. The levels of inflammatory factors are related to the extent of surgical trauma, and the durations at which different inflammatory factors reach their peak are different. The peak times of IL-6 and CRP were 12-24h and 24-48h after LC, respectively [24]. Additionally, the inflammatory response triggered by trauma not only contributes to postoperative pain but exacerbates perioperative inflammation and immune suppression [25]. Therefore, postoperative administration of esketamine, as a potent analgesic, can effectively reduce both postoperative pain and inflammatory factor levels. Tu et al.’s study revealed that the application of esketamine during anesthesia induction for the elderly improved the postoperative inflammatory response [26]. To further investigate the analgesic effects of esketamine and the underlying causes of pain, we measured the levels of IL-6 and CRP in patients at 24 hours and 48 hours postoperatively. In this study, we found that IL-6 and CRP levels in the ES group at 24 hours and 48 hours postoperatively were lower than those in the DE group, suggesting that esketamine is capable of reducing inflammatory cytokine levels and that esketamine in combination with sufentanil is more effective in reducing the level of inflammatory factors at the set dose. In our current study, we found a consistent association between lower levels of IL-6 and CRP and lower VAS scores in postoperative patients. These findings indicated that postoperative pain is influenced by inflammatory factors, and that esketamine may reduce pain levels by mitigating the inflammatory response. Therefore, our study provides support for the idea that esketamine can effectively alleviate inflammatory pain.

Research has indicated that the combination of esketamine and dezocine, respectively, with sufentanil in postoperative PCIA can enhance the analgesic effect while reducing adverse reactions, thereby allowing for a reduction in sufentanil dosage [27, 28]. Compared to dezocine, the combination of esketamine and sufentanil has been found to effectively decrease the adverse effects associated with opioids. However, esketamine itself can produce certain side effects, such as vomiting, dizziness, and headaches, which are dose-dependent [29]. To minimize these adverse reactions, we opted for an esketamine dosage of 1.5 mg/kg (0.03 mg/kg/h). Nevertheless, considering the possibility of increased nausea and vomiting following esketamine administration, we closely monitored and observed the patients for adverse reactions. In our study, after administering esketamine at a dosage of 1.5 mg/kg (0.03 mg/kg/h), we found that the incidence of nausea and vomiting in this group was not higher than that in the control group, and there were no severe cases reported, suggesting the superiority of esketamine over dezocine.

Some limitations are obvious in this study. First, we applied scales to assess the intensity of pain and sleep quality, which was largely restricted by the subjective awareness of patients and follow-up staff, leading to potential bias in results. Second, it is unknown whether the dose of esketamine in this study is the optimal dose, and it needs to be further explored. And whether a dose of 1.5mg/kg is equivalent to dezocine at 0.3mg/kg is also unclear.The occurrence rate of postoperative nausea and vomiting and other adverse reactions remains high, and it may be necessary to consider implementing new experimental methods to further improve the management of postoperative nausea and vomiting. Finally, our observation period is limited to 48 hours, and the clinical significance of the observed effects over a longer duration is yet to be explored. Despite the widespread acceptance of esketamine in clinical practice, there are still many fields that require further investigation and exploration, necessitating the use of larger sample sizes and diverse research methodologies.

The combined administration of 1.5 mg/kg esketamine and sufentanil for postoperative PCIA in patients undergoing LC yielded significant improvements in pain relief and a reduction in inflammatory cytokine levels. Esketamine can reduce the expression levels of inflammatory factors, which is associated with alleviating inflammatory pain.