Propofol is the most widely used anesthetic drug for induction and maintenance of general anesthesia. Although propofol is an ideal anesthetic agent owing to its rapid onset and offset, the incidence of propofol-induced injection pain (PIP) has varied from 28% to 90% (Canbay et al., 2008). PIP is considered an unpleasant encounter in anesthesia practice (Jalota et al., 2011). Many techniques have been developed to reduce the incidence of PIP, including changing the temperature and concentration of propofol (Jeong and Yoon, 2016; Lu et al., 2021), controlling the injection speed, selecting large vein vessels (Canbay et al., 2008; Desousa, 2016), and transcutaneous electrical acupoint stimulation (Jin et al., 2022). The most common techniques are pre-treatment or mixed use of propofol with drugs such as lidocaine (Euasobhon et al., 2016; Hong et al., 2016; Jeong and Yoon, 2016; Sun et al., 2016; Zirak et al., 2016; Xing et al., 2018; Tian et al., 2021; Wasinwong et al., 2022), nonsteroidal anti-inflammatory drugs (Madan et al., 2016; Miniksar, 2022), dexmedetomidine (Yu et al., 2015; Lu et al., 2021), ketamine (Cheng et al., 2017; Akbari et al., 2018), nitrous oxide (Kaabachi et al., 2007), opioids (Kizilcik et al., 2015; Lee et al., 2016; Singh et al., 2016; Lee et al., 2017; Wang et al., 2020), benzodiazepines (Guan et al., 2021), and magnesium sulfate (Sun et al., 2016). All of these techniques or drugs attenuated PIP to varying degrees, but their drawbacks, such as laryngospasm (Batra et al., 2005; Kaabachi et al., 2007), emergence agitation (Kaabachi et al., 2007), gastrointestinal ulcer (Madan et al., 2016), pulmonary embolism (Davies et al., 2002), lengthy onset (Wang et al., 2020), and tinnitus or dizziness (Xing et al., 2018), limited their clinical use, and PIP could not be completely abolished.

Ketamine is an N-methyl-d-aspartate receptor (NMDAR) antagonist with analgesic effects. Appropriate use of ketamine reduces postoperative pain (Himmelseher and Durieux, 2005). Pre-treatment or mixed use with ketamine reduced the incidence of PIP by approximately 30% in pediatric patients (Barbi et al., 2003; Batra et al., 2005; Cheng et al., 2017; Akbari et al., 2018). Currently, ketamine is a racemic mixture of levo-ketamine and right-ketamine (esketamine). However, psychotropic adverse effects limit the clinical use of ketamine (Batra et al., 2005). The affinity for NMDAR and the analgesic effect of esketamine are twice those of ketamine and induce fewer adverse events. However, the efficacy of esketamine in relieving PIP remains unclear. We hypothesized that a mixture of esketamine and propofol would reduce the incidence of PIP in patients undergoing general anesthesia.

From July 5, 2021, to March 30, 2022, among 252 patients recruited for this study, six declined to participate, and two did not meet the inclusion criteria. A subset of 244 patients was randomly assigned to four groups, and 226 patients were analyzed (Figure 1). Overall, the demographic data were similar among the groups in terms of age, height, body weight, body mass index, male/female ratio, ASA score, and Mallampati score (Table 1).

The primary outcomes are presented in Table 2. The incidence of PIP was significantly lower in group ESK-20 (33.3%; p = 0.001, compared with NS; p = 0.002, compared with ESK-4) than in group NS (63.3%), group ESK-4 (62.2%), and group ESK-12 (49.1%). There were no significant differences between the ESK-12, ESK-4, and NS groups (p > 0.05). No significant difference was found in the incidence of mild PIP among the four groups (p > 0.05). The percentage of patients with moderate PIP was lower in group ESK-20 (6.7%; p < 0.0001, compared with NS; p = 0.015, compared with ESK-4) and group ESK-12 (7.5%, p = 0.001, compared with NS) than in group NS (33.3%) and group ESK-4 (22.6%). The percentage of patients with severe PIP was lower in group ESK-20 (0%; p = 0.119, compared with NS; p = 0.016, compared with ESK-4) and group ESK-12 (1.9%; p = 0.218, compared with NS; p = 0.093, compared with ESK-4) than in group NS (6.7%) and group ESK-4 (9.4%), although some of these differences do not reach statistical significance.

The characteristics of anesthesia and surgery are shown in Table 3. The time from induction to LOC in groups ESK-12 (82.0±31.1 s) and ESK-20 (89.3±35.2 s) was shorter than that in groups NS (98.7±35.4 s) and ESK-4 (95.3±35.7 s), but there were no significant differences. In addition, there were no significant differences in time from anesthesia induction to BIS ≤60, time from drug withdrawal to eye-opening, time from drug withdrawal to extubation, length of PACU stay and surgery, and distribution of surgery (p > 0.05). No significant differences were observed in the crystalloid infusion volume between the groups (p > 0.05).

The consumption of anesthetic and vasoactive drugs is shown in Table 4. Sedative use was recorded at different time points. There were no differences in the overall consumption of propofol, fentanyl, remifentanil, cisatracurium, or ephedrine among the four groups (p > 0.05).

No significant differences were found in systolic blood pressure, diastolic blood pressure, heart rate, SpO₂, or BIS values at any time point between the four groups (Figure 2; p > 0.05).

All adverse events were classified as mild or moderate. No serious adverse events or discontinuation due to adverse events were reported in any group (Table 5). There were no significant differences between the groups in terms of the incidence of hypotension, bradycardia, dysphoria, nausea, or vomiting (p > 0.05). None of the patients developed hypertension, tachycardia, or delirium in any of the groups.

To our knowledge, this study is perhaps the first to evaluate the efficacy of a mixture of esketamine and propofol in preventing PIP. Our results indicated that a mixture of esketamine (20 mg, 1 ml) and propofol (200 mg, 20 ml) dose significantly reduced the incidence of PIP in patients undergoing general anesthesia without severe side effects. There were no differences in the vital signs, characteristics of surgery and anesthesia, or adverse events between the groups.

However, the mechanism underlying PIP remains unclear. The primary mechanism is the direct irritation of afferent peripheral nerve fibers in the inner wall of the venous vessel. Peripheral nerve fibers sense nociceptive information and transfer it onward. Based on this mechanism, many techniques have been developed to reduce the incidence of PIP, such as changing the temperature and concentration of propofol (Jeong and Yoon, 2016; Lu et al., 2021), controlling injection speed, selecting large vein vessels (Canbay et al., 2008; Desousa, 2016), transcutaneous electrical acupoint stimulation (Jin et al., 2022), or pre-treatment or mixed use propofol with drugs, such as lidocaine (Euasobhon et al., 2016; Hong et al., 2016; Jeong and Yoon, 2016; Sun et al., 2016; Zirak et al., 2016; Xing et al., 2018; Tian et al., 2021; Wasinwong et al., 2022), nonsteroidal anti-inflammatory drugs (Madan et al., 2016; Miniksar, 2022), and dexmedetomidine (Yu et al., 2015; Lu et al., 2021).

The analgesic mechanism of N-methyl-d-aspartate (NMDA) receptor antagonists remains unclear. NMDA receptors are expressed in the primary afferent unmyelinated terminals that innervate the peripheral skin (Wang et al., 2000). Subcutaneous or intra-articular injection of NMDA receptor antagonists, such as ketamine, produced potent analgesia (Bai and Zhao, 1997; Lawand et al., 1997). These findings provide evidence of the potential role of peripheral NMDA in nociceptive transmission (Wong et al., 2014; Alhilou et al., 2021). Ketamine has been shown to have a local anesthetic action or additive hypnotic effect by acting on NDMA receptors in the vascular endothelium or central nervous system, respectively, when administered intravenously. For example, pretreatment with ketamine was effective in preventing PIP in children (Barbi et al., 2003; Tobias, 2004; Cheng et al., 2017) and adults (Tan et al., 1998; Suzuki et al., 2002; Zahedi et al., 2009; Wang et al., 2013; Thukral et al., 2015; Akbari et al., 2018). A propofol–ketamine mixture was more effective than ketamine pre-treatment in preventing PIP (Hwang et al., 2009). However, PIP was twice as high with a propofol–ketamine mixture than with a propofol–lidocaine mixture in children (Kaabachi et al., 2007). Moreover, the clinical use of ketamine is limited owing to its drawbacks, such as psychotomimetic/dissociative effects and abuse potential (Batra et al., 2005). Currently, ketamine is a racemic mixture of levo-ketamine and right-ketamine (esketamine). The affinity for NMDAR and the analgesic effect of esketamine are twice those of ketamine and induce fewer adverse events. In our study, the propofol–esketamine mixture (ESK-20 group) was effective in preventing PIP (decreased from 63.3% to 33.3%), and no patient reported severe pain. Pretreatment with esketamine (0.15–0.25 mg/kg) before injection of propofol significantly reduced the incidence of PIP (Li et al., 2022a; Fu et al., 2022). The mechanism by which esketamine reduces PIP may be related to its action on the peripheral NMDA receptors. The pH of the propofol–ketamine mixture was 5.84, while propofol had a pH of 7.86, supporting that pH changes are a more important cause of PIP (Hwang et al., 2009). We did not determine the pH of the propofol–esketamine mixture, and the change in pH may support our results. Esketamine is also a potent central-acting analgesic. The mechanism through which esketamine reduces PIP may be related to its central action too.

Mixing propofol with esketamine facilitated a simple and rapid injection sequence during anesthesia (Zheng et al., 2022). However, mixing them together may increase the risk of drug reactions. In the pilot study, no color change or immiscible surface layer was detected by visual inspection after mixing propofol with esketamine. In our study, we did not observe any adverse events after the use of the propofol–esketamine mixture.

The time from induction to LOC in groups ESK-12 and ESK-20 was shorter than that in groups NS and ESK-4, and the time from anesthesia induction to a BIS ≤60 was shorter in group ESK-12, although none of these effects reached statistical significance (p > 0.05). The consumption of propofol during the period of LOC and BIS ≤60 showed a trend toward lower values in group ESK-12 and group ESK-20, but the differences did not reach statistical significance (p > 0.05). The combined use of esketamine with propofol had no effect on the duration of anesthesia, did not reduce the total consumption of anesthetic drugs and vasoactive drugs, and had no effect on vital signs, which was inconsistent with previous studies in children (Zheng et al., 2022) and adults (Zhang et al., 2022). The interpretation may be that the doses we used were small, and different drugs such as midazolam were used in the other study (Zhang et al., 2022).

Emergence delirium or hallucinations are common drawbacks of esketamine or ketamine if either is used as the sole agent for sedation at higher doses (Zheng et al., 2022; Zhornitsky et al., 2022). Most psychiatric disorders associated with racemic ketamine come from (R)-ketamine (Tan et al., 2020), but not (S)-ketamine. Esketamine, the S-enantiomer of racemic ketamine, was approved for treatment of treatment-resistant depression in 2019. A lower dose of esketamine reduced these side events (Bornemann-Cimenti et al., 2016). No case of delirium was reported in our study; the combination of esketamine with propofol may have also attenuated this drawback (Hwang et al., 2009). Propofol has direct anti-emetic properties (Borgeat et al., 1992). Only one case of nausea/vomiting was reported in our study. Few patients in our study developed dysphoria. None of the patients had tachycardia or hypertension. No difference was found in the incidence of hypotension, bradycardia, dysphoria, nausea, or vomiting between the groups (Table 5). However, some studies revealed that 0.2 mg/kg esketamine for elderly subjects could maintain the stability of hemodynamics (Li et al., 2022b). This inconsistency may result in different uses of anesthetics such as etomidate, sufentanil, and inhaled anesthetics.

This study has several limitations. First, the inclusion of participants weakened the external validity of the trial. The study included only adult patients who underwent elective surgery. Therefore, our results may not be generalizable to other populations. Second, the number of participants in this study was relatively small. In the future, we will evaluate the efficacy of a mixture of propofol and esketamine in preventing PIP in children.

In conclusion, our current findings indicate that esketamine (20 mg) and 1% propofol (20 ml) admixture significantly reduced the incidence of PIP in patients undergoing general anesthesia without severe side effects.