Biliary calculus, also known as gallstone, is a crystalline solid formed from bile concentration and composition changes caused by changes in diet, hormones, medications, or rapid weight loss or weight gain [27]. Laparoscopic cholecystectomy is the standard treatment for symptomatic cholelithiasis, especially when it is complicated by sharp, constant abdominal pain, fever, nausea, and vomiting [1, 2, 27]. Severe acute postoperative pain following LC is still prevalent due to the particularly complex nerve patterns distributed, electrocautery-associated injuries, incision injuries, and opioid-induced hyperalgesia [3,4,5]. Currently, the medications, preventing peri-and postoperative pain, mainly include opioid and non-opioid analgesics. Despite irrefutable clinical application in pain management, opioid use is sometimes restricted by many undesirable adverse effects, such as opioid dependence, tolerance, constipation, itch, or respiratory depression [28]. Opioid-free anesthesia modalities, represented by ketamine and ketamine, have become an attractive alternative for peri-and postoperative analgesia.

Esketamine, the S (+)-isomer of ketamine, a non-selective NMDA receptor inhibitor, possesses part of non-opioid analgesic properties and an analgesic effect twice that of racemic ketamine [29, 30], which is a dominant agent in opioid-free anesthesia for a long time [31]. Although esketamine has been demonstrated to be effective in controlling post-laparoscopy pain, many associated negative side effects may correlate with its dose intensity [21, 22, 31]. Therefore, we determine the ED50 of esketamine to explore an equilibrium point between the most excellent clinical effect and the lowest adverse reactions. For the starting dose selection, different studies use different dose settings, mainly including 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, and several other doses. For instance, the first child was given an esketamine dose of 0.1 mg/kg in order to explore the ED50 of esketamine for children to inhibit the response of gastroscope insertion in the study of Ming Su et al. [23]. Another study by Meiyun Tan et al. [32] used the Dixon sequential method to determine the effective dose of esketamine for mitigating pain during propofol injection, and the initial dose of esketamine was 0.2 mg/kg. In our study, we select 0.3 mg/kg esketamine as the initial dose recommended by the instructions. This dose is commonly used in clinical practice and many studies [25, 26].

A reasonable choice of drug dosage will be necessary for decreasing the rate of adverse effects while maintaining the efficacy of the treatment. In order to determine the optimal amount of esketamine for preventing postoperative pain, four groups were divided by Yan-ling Ren and colleagues according to the different doses of esketamine(0 mg/kg, 0.2 mg/kg, 0.4 mg/kg, 0.6 mg/kg), and it reported that intravenous injection of esketamine 0.4 mg/kg before anesthesia induction was a suitable dose to reduce pain sensitivity in patients undergoing thyroidectomy without increasing adverse reactions [33]. As is well known, up-down sequential allocation is a simple, robust, and efficient method of identifying the median effective dose (ED50). In our study, the ED50 and ED95 of esketamine for preventing early postoperative pain were 0.301 mg/kg (95%CI: 0.265-0.342 mg/kg) and 0.379 mg/kg (95%CI: 0.340-0.618 mg/kg) respectively. Interestingly, the ED95 in this study is highly similar to the esketamine 0.4 mg/kg, suggesting our result has wide applicability and clinical practicability. However, the study by Meiyun Tan et al. [32] concluded that the ED50 and ED95 of esketamine for mitigating pain during propofol injection were 0.143 (0.120, 0.162) mg/kg and 0.176 (0.159, 0.320) mg/kg, respectively. This dose range is significantly different from our conclusion, and may be closely related to the type of pain. Meanwhile, another literature reported that the ED50 of esketamine was 0.143 mg/kg (95% CI 0.047–0.398 mg/kg) when combined with 3 mg/kg propofol for successful sedation in pediatric gastroscope insertion [23], which is significantly lower than the dose we measured. The possible reason is that the observation targets are children, and the assessment criteria are sedative effect rather than analgesia effect.

Postoperative pain after LC consists of three components: incisional pain (somatic), deep abdominal pain (visceral) and opioid-induced hyperalgesia (OIH). Incisional pain is a unique and common form of acute pain that may involve nociceptive, inflammatory, and neuropathic pain [3, 34]. The literature suggested that incisional pain could be reduced by incisional local anesthetics and dexamethasone [35]. In our study, after the 0.5% ropivacaine was applied to the incision for local infiltration anesthesia during skin sutures, there were no statistically significant differences between the two groups in incisional pain-related VAS score at resting and movement, and ropivacaine wore off after 8–12 h, suggesting it could effectively relieve incisional pain and last for 8–12 h.

Local infiltration block provides excellent analgesia for incisional pain, but unfortunately, visceral pain and opioid-induced hyperalgesia are still evident. Visceral pain is a complex, unpleasant feeling caused by trauma and inflammation that is generally described as dull, diffuse, and poorly localized, mainly transmitted by the autonomic nervous system, and is frequently accompanied by malaise and strong autonomic reflexes [36,37,38]. Visceral pain after LC primarily involves two aspects: cutting injury-induced pain and hyperalgesia. The cutting injury-related pain is thought to be mainly caused by the dissection of the gallbladder off the liver bed by electric knives. Visceral hyperalgesia and central sensitization also have been validated as the two most important visceral pain-related characteristics [9, 10, 38]. A study [39] in healthy volunteers showed that acutely increased cortisol enhanced pain sensitivity and impaired pain-related emotional learning within the visceral, but not the somatic pain modality. However, visceral pain is difficult to manage effectively, largely due to the complexities of visceral innervation, which leads to visceral pain-related pathophysiological factors being poorly understood. On the other hand, remifentanil, a u-opioid receptor agonist, is widely used for intraoperative analgesia because of its unique rapid metabolism and elimination without delaying postoperative recovery [14, 40]. It can provide adequate intraoperative analgesia, attenuating hemodynamic fluctuations from noxious stimuli during surgery. In our study, using remifentanil effectively contributed to containing the reflex increase in the mean blood pressure and heart rate induced by noxious stimuli such as skin incision or gallbladder dissection. However, exposure to high doses of remifentanil may reduce the pain threshold and induce hyperalgesia. For instance, C.-H. Koo and colleagues [13] reported that the pain threshold was significantly lower in the high-remifentanil group than in the low-remifentanil group, and naloxone reduced remifentanil-induced postoperative hyperalgesia. Based on the above analysis, opioid-induced hyperalgesia and visceral pain to some extent can be considered hyperalgesia and possess similar mechanisms [9, 10, 15, 38]. The underlying mechanisms of hyperalgesia are likely to be associated with upregulation or alteration of N-methyl-D-aspartate (NMDA) or pain-related receptors. Although the intraoperative use of low-dose naloxone reduced postoperative hyperalgesia [13], it was unsuitable for routine clinical practice because opioid receptor antagonists could exacerbate pain.

Ketamine, which works as an NMDA antagonist, has been shown to reduce incisional pain, visceral pain and hyperalgesia [4, 17, 41], as well as the postoperative consumption of morphine. Theoretically, as a dextral resolution of ketamine, the esketamine may have the same effect on early postoperative pain (incisional pain, visceral pain and hyperalgesia). Feng Liu and colleagues [42] reported that esketamine-based anesthesia (1 mg/kg) can alleviate postoperative pain and regulate the inflammatory reaction in children undergoing endoscopic plasma adenotonsillectomy. In our study, we found that there was a significant decrease in the total VAS score at resting during the awakening period after extubation in the esketamine group when compared with the control group (p < 0.05), suggesting esketamine could prevent early postoperative pain effectively, including visceral pain and hyperalgesia. However, there were no statistically significant differences between the two groups for the total VAS score during cough and the numbers requiring rescue analgesia during the awakening period (p > 0.05), and there are three possible explanations for these: (1) the esketamine dose too low in some patients of the Group E; (2) the sample size is too small and insufficient number of events; (3) the cough reflex exacerbate the incisional pain and visceral pain.

Esketamine is a dissociative anesthetic with sympathomimetic and broncho-dilating properties, similar to ketamine. Recent reports found that 14/70 patients experienced treatment-emergent transient hypertension after intravenous esketamine, and it was significantly higher than the baseline value [43], which is mainly related to the sympathetic nerve-induced release of catecholamine [44]. In our study, there was a decrease in heart rate and mean arterial pressure in esketamine group at T1 compared to the basal values and control group, which did not increase due to using esketamine. The reasons for this may be multiple: (1) other anesthetics have vasodilatory effects; (2) lack of circulating blood volume due to fasting; (3) there was a more thorough blocking for the nociceptive stimuli after using esketamine. Therefore, the changes in vital signs during anesthesia need further study, when esketamine is combined with other anesthetics. On the other hand, using esketamine did not delay waking up after anesthesia and also did not increase the frequency of adverse reactions.

Our study has some limitations. Firstly, the sample size was set according to the up-down allocation methodology rather than the sample size estimation. Secondly, the comparison of VAS scoring between the two groups had some limitations because the esketamine group used different doses. Finally, this study only examined early postoperative pain to ensure adequate analgesia during the operation, and did not evaluate long-time postoperative analgesia of esketamine.