Dexmedetomidine and sufentanil combination versus sufentanil alone for postoperative intravenous patient-controlled analgesia: a systematic review and meta-analysis of randomized controlled trials

Postoperative pain is a common complication after surgery. Notably, effective management of postoperative pain is a core aspect of enhanced recovery after surgery, it reduces hospital stay and overall hospital cost, while enhancing recovery and reducing mortality after surgery [1, 2]. Intravenous patient-controlled analgesia (PCA) is an effective method for management of postoperative pain, because variable pharmacokinetic and pharmacodynamic parameters among patients and drugs can benefit from individual titration [3]. Of the variety of drugs available for postoperative acute pain, opioids are regarded as the preferred treatment. However, opioid use can result in numerous side effects, including excessive sedation, nausea, vomiting, pruritus, constipation, and respiratory depression [4, 5]; therefore, it is important to provide opioid- sparing analgesia. Multimodal pain management has been recommended to enhance pain relief and reduce the side effects of postoperative PCA [6].

Dexmedetomidine is a highly selective α-2 adrenergic agonist that exhibits hypnotic, sedative, analgesic, and anxiolytic properties [7–9]. Importantly, it does not cause respiratory depression [9, 10]. Dexmedetomidine has been reported to reduce the incidence of postoperative cognitive dysfunction [11] and to improve postoperative sleep quality [12]. A previous meta-analysis [13] suggested that dexmedetomidine could reduce opioid consumption in postoperative PCA. However, many types of opioids were used for postoperative PCA in that analysis, and opioid consumption was calculated by opioid equianalgesic conversion, which could introduce clinical heterogeneity. Sufentanil is a widely used analgesic drug that provides more intense analgesia with extended duration and milder respiratory depression, compared to equivalent doses of fentanyl or morphine [14]. In recent years, there has been a gradual increase in the number of reports involving the use of sufentanil for intravenous PCA. Therefore, we performed a meta-analysis of randomized controlled trials (RCTs) to quantify the effect of dexmedetomidine as an adjuvant for postoperative PCA with sufentanil.

This systematic review and meta-analysis was conducted in accordance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions [15], and was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16].

In this meta-analysis, we quantified the effect of dexmedetomidine as an adjuvant to sufentanil for PCA and found that dexmedetomidine improved postoperative pain intensity and reduced total sufentanil consumption. Furthermore, sufentanil-related side effects (e.g., postoperative nausea, vomiting, and pruritus) were reduced in the dexmedetomidine-sufentanil group; the incidences of dexmedetomidine-associated side effects (e.g., bradycardia and hypotension) did not increase.

In the past few decades, intravenous PCA has been commonly used for postoperative analgesia [34, 35]. Sufentanil is commonly used for the treatment of moderate to severe postoperative pain; however, the risk of adverse effects limits its use as a single method to manage postoperative pain [36–38]. Dexmedetomidine achieves ananalgesic effect by activation of α-2 adrenoceptors, thereby acting in a manner that differs from sufentanil; notably, combination of these drugs produces a synergistic analgesic effect without increasing the risk of respiratory depression [39].

Sufentanil-related complications were significantly reduced, while patient satisfaction was improved in the dexmedetomidine-sufentanil group, compared to the sufentanil group. These changes may be explained as follows: 1) Patients receiving dexmedetomidine-sufentanil combination for PCA used lower doses of sufentanil; and 2) Dexmedetomidine can decrease noradrenergic activity by inhibiting presynaptic α2 receptors in the locus coeruleus, or by reducing sympathetic outflow, which may induce postoperative nausea and vomiting [40].

With respect to the safety characteristics involved in the addition of dexmedetomidine to postoperative intravenous PCA, hypotension and bradycardia have been identified as the primary concerns [41]. In particular, for patients with stroke or coronary disease, the hypotensive or bradycardic actions of dexmedetomidine may be harmful. Upon administration of a high dose or rapid intravenous injection, dexmedetomidine produces hypertension by activating α-2 adrenoceptors on smooth muscle cells. When administered at clinically recommended concentrations, dexmedetomidine produces dose-dependent hypotension and bradycardia, due to the inhibition of neurotransmission in sympathetic nerves and reduction of sympathetic tone; this effect may also be mediated by the baroreceptor reflex and enhanced vagal activity [9, 10, 42]. In the present study, pooled results demonstrated no significant differences in the incidences of hypotension or bradycardia between the dexmedetomidine-sufentanil and sufentanil group; this might be a result of the small dose of dexmedetomidine used in these studies. Although no statistically significant difference was detected, there remains considerable concern with respect to the potential risks of hypotension and severe bradycardia associated with the use of dexmedetomidine. Moreover, dexmedetomidine could inhibit the release of corticosterone in response to adrenocorticotropic hormone stimulation after prolonged use or high dosage [43]. Enomoto et al. [44] reported that long-term dexmedetomidine administration might cause tolerance in infants, but there have been no reports of long-term use of dexmedetomidine for PCA in adults, likely because PCA is typically used for 2–3 days after surgery. Nonetheless, rebound hypertension and tachycardia after abrupt cessation of dexmedetomidine, as well as changes in tolerance and the potential for withdrawal syndrome, remain concerns when using dexmedetomidine.

The pooled results indicated that, regardless of the type of sedation score used, patients receiving postoperative intravenous PCA with dexmedetomidine-sufentanil combination exhibited higher sedation scores at 1 h postoperatively, compared with patients receiving sufentanil alone. However, interpretation of this result requires caution, because sensitivity analysis showed that there was no significant difference between the 2 groups. Notably, no oversedation events were reported in the included studies. Thus, the clinical significance of the outcome regarding postoperative sedation scores is unclear and further investigation is needed.

Peng et al. [13] found that patients receiving an opioid-dexmedetomidine combination for postoperative PCA experienced significantly greater pain relief and had significantly lower postoperative opioid consumption during the first 24 h postoperatively, compared with those receiving opioid alone. The results of the current meta-analysis were consistent with those findings, and provided evidence to support the safety of dexmedetomidine administration for more than 24 h. An updated meta-analysis by Peng et al. [45] also examined the safety of prolonged use of dexmedetomidine after surgery; our present findings are consistent with those of the updated analysis. However, previous meta-analyses included studies that used various opioids and were published before 2017. Although data regarding opioid equianalgesic conversion factors have been previously published, their pharmacokinetics and pharmacodynamics were not exactly same. In our meta-analysis, we solely included studies using sufentanil, which has a smaller volume of distribution, shorter elimination half-life, and more rapid recovery than either fentanyl or morphine [46]. Sufentanil exhibits a wider therapeutic index than other opioids for PCA [28], is the most potent available analgesic, and is the most commonly used for intravenous PCA. Six of 9 RCTs in our meta-analysis were published after 2017. When dexmedetomidine was added to PCA, previous meta-analysis [45] reported that the morphine-equivalent consumptions during the first 24 and 48 h after surgery decreased by 12.16 mg and 10.15 mg, respectively. This suggested that dexmedetomidine may be ineffective during the first 24 to 48 h after surgery. In contrast, our results showed that when dexmedetomidine was added to PCA, sufentanil consumption during the first 24 and 48 h postoperatively decreased by 13.77 μg and 20.81 μg, respectively. Our meta-analysis therefore indicated that the analgesic effect of dexmedetomidine continued throughout the first 48 h postoperatively.

There were several limitations in our meta-analysis. First, it included a small number of studies; however, we included all literature available. Second, all studies investigated Chinese adult patients, although they were reported in English. It remains unknown whether our findings are applicable to patients of other ethnicities. Third, surgery types and perioperative anesthesia protocols varied among studies, as did the doses of dexmedetomidine and sufentanil; thus, the included studies exhibited high heterogeneity. Fourth, the present study did not assess the dose-response effects for different types of surgeries. Additional RCTs are needed to identify the optimal doses of dexmedetomidine and sufentanil for different surgeries. Finally, publication biases and potential biases may influence our results.

Compared with sufentanil alone, dexmedetomidine- sufentanil combination for postoperative intravenous PCA may achieve better analgesia and patient satisfaction, thereby reducing sufentanil consumption and sufentanil-related complications.