Epidural analgesia is a widely practiced analgesic technique commonly used for postoperative analgesia, labor analgesia, and treatment of pain in the late stage of cancer, and has been demonstrated to improve postoperative outcomes and attenuate the physiological response to surgery [1–6]. Patient-controlled epidural analgesia (PCEA) is a common form of epidural analgesia that provides better analgesia, improves patient satisfaction, and reduces clinician workload compared to continuous infusion and intermittent bolus techniques [7]. Opioids are often used as adjuvants in combination with local anesthetics for epidural analgesia as this provides significant synergistic effects [8]. The combined application prolongs the duration of analgesia, reduces the concentration and dosage of local anesthetics, and increases patient satisfaction [9]. However, the combined use of opioids and local anesthetics increases the incidence of side effects such as itching, urinary retention, nausea and vomiting, and respiratory depression [10–12]. Therefore, the need for a more ideal adjuvant for local anesthesia, with better analgesic effects but fewer adverse effects, is growing. In recent years, several studies on the use of dexmedetomidine (DEX) as an adjuvant to local anesthetics for intravertebral anesthesia and analgesia have provided encouraging results.

DEX is a highly selective Alpha-2 receptor agonist with a variety of pharmacological effects including sedation, analgesia, and anti-sympathetic effects [13,14]. Several meta-analyses have demonstrated that the administration of DEX as an adjuvant in epidural anesthesia is well tolerated, acts synergistically, and provides an improved sedation and analgesic profile [15–18]. Notably, some studies have also shown that administering DEX as a local anesthetic adjuvant in spinal anesthesia [19] and epidural anesthesia [20,21] not only prolongs the duration of anesthesia and improves postoperative analgesia, but also reduces the incidence of itching compared with opioids. However, in the abovementioned studies, the administration of DEX was typically as a single dose with a short duration of action. However, when administering continuous infusions of DEX through the PCEA over a prolonged period, careful consideration of the efficacy of the cumulative dose and possible adverse effects is essential.

Unfortunately, our current understanding of the adverse effects and efficacy of DEX administered to patients in PCEA is limited. In several randomized controlled trials (RCTs), DEX has been compared with opioids as adjuncts to local anesthetics for PCEA; however, the results have been inconsistent and even contradictory. Therefore, a meta-analysis is needed to evaluate the adverse effects and efficacy of DEX versus opioids as adjuvants in PCEA to provide insights into clinical analgesic practices.

The protocol for this meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42022307670 on March 10, 2022. This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards [22].

This meta-analysis included seven studies, one of which (Cheng et al. [25]) contained two separate trials. The results of the present meta-analysis showed that DEX was superior to opioids in terms of pain relief and the incidence of nausea and vomiting and itching.

The VAS score is a critical parameter for evaluating the efficacy of potential analgesic therapies. This meta-analysis found that the addition of DEX resulted in lower VAS scores than the addition of opioids at 4–8 h, 12 h, and 48 h after surgery. One curious finding was that DEX was not significantly superior to opioids at reducing VAS scores in patients 0–4 h after surgery, which may be explained by the fact that researchers often administer the first dose of local anesthetics in the epidural space to expand the analgesic plane when linking the PCEA pump, thus masking the synergistic analgesic effect of the adjuvant considerably in the early postoperative period. The analgesic effects of DEX may be explained by several potential mechanisms. DEX opens the K⁺ channel on the cell membrane and strengthens the inhibitory effect of local anesthetics on the Na⁺ channel [32]. However, DEX can also inhibit the secretion of norepinephrine by the spinal cord, activate cholinergic nerves, and synergize with local anesthetics to enhance the analgesic effect [33]. In addition, DEX can induce local vasoconstriction by stimulating the Alpha-2 receptors of blood vessels, thereby delaying the absorption of local anesthetics and prolonging their duration [34]. In the meta-analysis, epidural DEX significantly reduced postoperative pain compared to opioids in terms of the VAS score; however, data on labor analgesia were not included, mainly because the time points for the VAS score evaluations in the included studies on labor analgesia varied and thus could not be integrated. In the study conducted by Zhang et al. [30], the progression of the cervical opening diameter was used as the observation point for the VAS score. Both Li et al. [26] and Cheng et al. [25] recorded VAS scores after anesthesia induction, but the observation time points were inconsistent. However, all included studies showed a tendency toward better pain control with DEX than with opioids for epidural labor analgesia. The results of the study conducted by Li et al. [26] demonstrated that the VAS scores were significantly lower in the DEX group than in the opioid group 10 min after epidural placement. Cheng et al. [25] showed the same results 15 min after anesthesia induction, and Zhang et al. [30] similarly showed lower VAS scores in the DEX group after cervical dilation > 3 cm. In a recently published meta-analysis [17] on epidural labor analgesia, the administration of DEX as a single shot or continuous infusion showed pain relief that was comparable with that of opioids. More high-quality research is needed in the future to draw clear conclusions on epidural labor analgesia.

The greatest concern with DEX administration in the epidural space is the potential for adverse effects, especially when used in PCEA because of its longer duration of action. DEX is associated with side effects such as hypotension, bradycardia, itching, dry mouth, shivering, nausea, and vomiting [35,36]. However, our analysis did not show a significantly higher risk of these side effects in the DEX group compared with the opioid group, except for dry mouth, though this is likely because an insufficient amount of studies reported the incidence of dry mouth. Furthermore, DEX significantly reduced the incidence of itching and nausea and vomiting compared with opioids. However, in our leave-one-out analysis, we found that the incidence of bradycardia was higher in the DEX group, whereas in the subgroup analysis of labor and postoperative analgesia, the incidence of bradycardia did not differ between the two groups. In another meta-analysis comparing DEX and placebo, Zhang et al. [15] found that the heart rate was lower in the DEX group; however, the incidence of bradycardia was not statistically significant. In conclusion, our results suggest that DEX is well-tolerated as an epidural adjuvant in PCEA and is superior to opioids in terms of the incidence of pruritus, nausea, and vomiting.

Our results indicate that DEX, when used as an adjuvant in PCEA, clearly increases the RSS scores in the early postoperative period. In studies comparing DEX with clonidine [37–39], DEX significantly improved the degree of sedation. Relevant studies have demonstrated that DEX can diffuse into the cerebrospinal fluid through the dura mater and combine with Alpha-2 adrenergic receptors in the blue nucleus of the brainstem to produce a sedative effect [40]. Moderately increased sedation can help reduce the patient’s stress response, reduce the body’s oxygen consumption, maintain hemodynamic stability, and reduce dependence on analgesics that depress respiration. However, excessive sedation may cause side effects such as hypotension, bradycardia, and respiratory depression. As the use of DEX may be complicated by its higher sedative effect, careful attention by physicians is imperative during its use. Moreover, the addition of DEX reduces the consumption of anesthetics and PCEA bolus doses, reflecting the superiority of its analgesic effect laterally. Furthermore, compared with opioids, epidural analgesia with DEX has no significant impact on the duration of the stages, mode of delivery, umbilical artery pH or PaO₂, or fetal heart rate. These findings are consistent with those of another previous study [17] that demonstrated that using DEX in epidural labor analgesia is safe for the fetus.

Previous meta-analyses have demonstrated that a single-shot injection of DEX into the subarachnoid or epidural space prolongs the duration of analgesia and decreases the requirement for rescue analgesia compared to placebo [15,16,18], opioids [41], or clonidine [42] in different surgical procedures. The most important difference between that study and the current meta-analysis is that the purpose of our study was to assess the safety and efficacy of continuous DEX infusions for epidural analgesia and thus, only studies involving continuous DEX infusions for epidural analgesia were included. Previous meta-analyses [17,41] have demonstrated that a single dose of DEX with epidural anesthesia significantly reduces the incidence of nausea and vomiting compared to opioids, which is consistent with our results. Qian et al. [41] found that, compared with epidural opioid administration, epidural DEX administration significantly reduces the incidence of shivering, though our results showed no significant difference. These authors also found that the incidence of dry mouth in the DEX group was significantly higher than that in the fentanyl group; however, the data from our included studies were insufficient to draw a definitive conclusion. In addition, the incidence of itching was significantly lower in the DEX group than in the opioid group in our study.

This meta-analysis has several limitations. First, data from the included studies were relatively insufficient. The VAS and RSS scores only included the postoperative analgesia population and may not be applicable for labor analgesia. Previous studies have reported that DEX may be associated with adverse effects, such as dry mouth and unstable hemodynamic changes. These results could not be synthesized or analyzed due to insufficient data in the studies included in this meta-analysis. Future studies should focus on these aspects. Second, this meta-analysis included studies using three different types of opioids (morphine, sufentanil, and fentanyl), which may have affected the results on pain relief and adverse events. Third, relatively high heterogeneity was found for some of our results, which may have resulted in bias; therefore, further research is required. The relatively high heterogeneity in this study may be explained by the different puncture segments among studies on epidural analgesia, different doses of DEX, and different PCEA parameter settings. Finally, DEX is a relatively new drug, particularly for epidural analgesia, and its long-term effects on the nervous system and maternal lactation are unknown. Therefore, suitable large-scale controlled trials to confirm these results are still necessary in the future.

In conclusion, the results of this meta-analysis showed that DEX is superior to opioids as a local anesthetic adjuvant in PCEA as DEX is associated with better pain relief and a lower incidence of nausea and vomiting and itching. However, some of the results of our meta-analysis should be interpreted with caution given the heterogeneity of the studies and insufficient data.