The key findings of our study were that pretreatment with low-dose intranasal dexmedetomidine (IND) as an adjunct with the initiation of epidural labor analgesia provided a quicker onset of analgesia and lower pain scores caused by epidural puncture than conventional epidural labor analgesia (CON).

A number of studies have shown that administering DEX intranasally is safe, effective, more comfortable and convenient than an intravenous approach [16]. To the best of our knowledge, no study has investigated the efficacy of IND as an adjuvant for epidural labor analgesia to date. However, intravenous DEX was reported as an adjunct for labor analgesia and cesarean anesthesia in a parturient with a tethered spinal cord [6] and for labor analgesia in a parturient with preeclampsia [24]. The results showed that intravenous DEX improved analgesia and sedation without episodes of maternal hypotension, bradycardia or fetal heart rate distress [6, 24]. Uemura et al. used a clinically relevant dosing regimen (a bolus injection of dexmedetomidine 1.0 μg/kg) on pregnant ewes and suggested that intravenous DEX produces significant maternal sedation without altering the fetal physiologic status [7]. In addition, in vitro studies on human placentas have demonstrated low maternal fetal transfer of DEX, presumably due to its high lipophilicity [25]. These data suggest that intravenous DEX as an adjunct for labor analgesia is safe for the mother and fetus.

The nasal mucosa is rich in capillaries, and intranasal DEX administration results in the rapid entry of the drug into the bloodstream [13]. Compared to the intravenous route, IND has the same metabolic pathway but causes a more gradual ascending peak plasma concentration and hence better tolerability and convenience [26]. Previous studies found that IND was an easy and noninvasive route with a high bioavailability of 81.8% and more than 84% in pediatric patients compared with the intramuscular and oral routes [27]. Iirola et al. reported that IND had a bioavailability of 65% (35–93%) in healthy men [28].

This research showed that the median onset time of traditional PIEB with ropivacaine and sufentanil was 10.0 (8.5 to 11.5) minutes, consistent with the results of Song et al. [3]. The median onset time of IND combined with PIEB was 6.0 (4.9 to 7.1) minutes. DEX has sedative and analgesic properties through the activation of α2-adrenoreceptors and has been widely reported as an anesthesia adjunct to the intravenous and epidural routes to improve the effect of labor analgesia, reduce the total consumption of analgesics and lengthen the duration of analgesia without shortening the onset time [6, 8, 9, 29]. Li et al. [26] reported that the onset time of IND by atomizer (47.5 min, 95% CI, 25 to 135 min) and by drops (60 min, 95% CI, 30 to 75 min) was significantly longer than intravenous DEX (15 min, 95% CI, 15 to 20 min). However, the reported onset times of IND were inconsistent and ranged from 7 to 31 min in a systematic review reported by Poonai et al. [30]. According to the above literature, we designed the pretreatment time of IND as 15 min before the epidural puncture plus the time of the epidural puncture operation, which required 15–20 min. This study showed that the median onset time of epidural analgesia in the IND group was 6.0 min, which might be because we preadministered IND 15 min before the epidural puncture, providing preemptive and auxiliary analgesia. A recent study also reported that a combination of 0.1% ropivacaine with 0.25 μg/ml Dex + 0.25 μg/ml sufentanil yielded a shorter onset time than that of 0.1% ropivacaine + 0.5 μg/ml Dex or 0.5 μg/ml sufentanil in epidural labor analgesia [29]. Preemptive analgesia is an intervention prior to initiating painful stimuli by blocking the establishment of altered central processing of afferent input, which inhibits hyperalgesia and elevates the pain threshold after surgery to reduce or prevent subsequent pain [31]. The present study found that premedication with IND decreased procedural distress with greater compliance for the epidural puncture than traditional PIEB (CON) with preemptive analgesia and sedation. Poonai et al. reported that IND was likely more effective for procedural distress in children than oral chloral hydrate and oral midazolam [30]. Many parturients in labor are also anxious due to uterine contractile pain and the distress of the epidural puncture. DEX relieves anxiety and reduces plasma levels of stress hormones [32, 33]. In addition, it is necessary for the parturient to be able to cooperate with the health care staff while relieving pain. YUAN et al.’s study showed that IND combined with local anesthesia resulted in conscious analgesia, sedation and improved anesthetic effects during breast lumpectomy [16]. Here, IND was used to relieve maternal anxiety and did not affect cooperation during delivery. The RSSs of all parturients were less than 3 in this study, with no respiratory depression or reflux aspiration. Farghaly et al. [34] reported that DEX increased the pain threshold of nerve cells, which might be one of the mechanisms responsible for relieving procedural pain. Therefore, IND might alleviate procedural pain through preemptive analgesia, elevating the pain threshold and providing superior sedation.

The main purpose of this study was to observe the initiation of labor analgesia; therefore, the data were only collected during the first 60 min of this study. VAS scores were decreased in the IND group in the first 30 min, but no significant difference was seen 60 min post-analgesia, which suggested that IND improved the initiation of analgesia without affecting the maintenance of analgesia. A higher RSS was found in the IND group, which suggested that IND might reduce the stress and anxiety of parturients during labor. DEX has also been confirmed to improve sedation during the later stages of labor via epidural administration [8, 9]. YUAN et al. demonstrated that IND provided good clinical analgesia and sedation for at least 70 min after administration [16].

In this study, the median difference in the onset of analgesia between the CON and IND groups was 4 min. Wang et al. assumed that any difference should be at least 5 min to be clinically significant [2]. However, in our clinical practice, parturients who suffer from uterine contraction distress are eager to alleviate the pain as soon as possible. Hence, a median difference of 4 min was considered clinically meaningful, which was also supported by a recent study by Wang et al. [15]. In addition, although the effect of labor analgesia was significantly different between the two groups, the anesthesiologists took measures to meet the analgesic needs of parturients with the addition of analgesic drugs as necessary. Therefore, the maternal satisfaction score was as high as 9 in both groups. In the IND group, a lower bolus frequency of PCEA or physician rescue analgesia and less consumption of analgesic drugs were needed to achieve a high maternal satisfaction score, which suggested that pretreatment with IND as an adjunct of PIEB also improved the quality of labor analgesia maintenance.

DEX has a biphasic effect on SBP, as it decreases the heart rate and cardiac output via central anti-sympathetic action but increases vascular resistance via peripheral vascular α1-adrenoreceptor activation. Therefore, SBP is decreased and then elevated with increasing plasma concentrations in humans [35]. Li et al. considered that IND was associated with a longer onset than intravenous access. A more gradual onset avoided the α1-adrenoreceptor agonist effects seen with rapid intravenous access (hypertension and bradycardia) [26]. This study found that adverse effects such as maternal bradycardia, hypertension and hypotension were absent in both groups. There was no significant difference in FHR between the two groups, but there was a temporary decrease 5–10 min after the loading dose. Transient fetal bradycardia presented in 2 and 3 cases in the CON and IND groups, respectively, which might be associated with the loading dose of sufentanil [36]. No significant differences were detected in delivery mode, first and second stage duration, neonatal Apgar scores, umbilical blood gas analysis or side effects between the two groups, consistent with previous studies [2, 9].

Excessive uterine contractions might induce fetal distress or placental abruption. Several studies have suggested that DEX enhances uterine constriction [37, 38], and the potential detriment of changes in uterine contractions should be considered. The current literature about the impact of DEX on uterine contraction is inconsistent. As shown by Kimizuka et al. via in vitro studies, DEX presented a dose-dependent enhancement of myometrial spontaneous contraction in humans and rats without increasing oxytocin-induced uterine contractions by increasing the sensitivity of muscle fibres to calcium ions [38]. However, DEX was also confirmed to enhance oxytocin-induced myometrium contractions by in vivo studies [38]. In another in vitro study, Öcal et al. showed that DEX caused an increase in spontaneous contraction forces and frequency in early and middle pregnancy in rats but had the opposite effects in late pregnancy in a dose-dependent manner [37]. An in vitro study by Gertler et al. suggested that clinically relevant concentrations of DEX reduced uterine contractility by cell membrane hyperactivation and reducing the influx of ATP, norepinephrine, and calcium ions via a negative feedback mechanism [39]. Epidural analgesia was confirmed to inhibit uterine contraction by decreasing the secretion of endogenous oxytocin [40, 41], which could also counteract the effect of DEX on uterine contractions. In this study, we observed that the uterine contraction intensity in the IND group decreased briefly during the first 10 min and then recovered gradually, and there was no significant difference compared to the CON group. No episodes of fetal distress or placental abruption induced by excessive uterine contractions occurred, and no significant differences in delivery mode or first- and second-stage duration were detected. In summary, using a clinically appropriate concentration and dosage of DEX and epidural local anaesthetics are of paramount importance to avoid adverse effects on uterine contractions.

To identify the optimal intranasal dose for providing the best analgesia and sedation while minimizing side effects, three different intranasal doses (0.5, 0.8 and 1.0 μg/kg) were tested in a preliminary experiment according to methods used in previous studies. We found that dosages of 0.8 and 1.0 μg/kg reduced uterine contractions and extended the first stage of labor. This result was inconsistent with a previous study [16]. The first reason for this might be that most of the subjects were children, who have different pharmacokinetics and apparent volumes of distribution than adults. In addition, the optimal dose of IND is often related to the analgesic intensity produced by the subject drug and the degree of surgical trauma. In this study, PIEB played the major role in analgesia, and IND was used as an adjunct to improve analgesia and sedation. Uusalo et al. also demonstrated that intraoperative use of low-dose IND (0.5 μg/kg) yielded improved clinical sedation and analgesia and reduced opioid consumption in adults undergoing total hip arthroplasty (THA) [5].

This study had several limitations. First, the study was a single-centre study, and the sample was representative but not large. Second, the optimal dosage was not selected using a sequential method, which may reduce the power of the study. Third, the population was young women (27.9 ± 2.8 and 27.3 ± 2.9), which accounts for the majority of current primipara undergoing vaginal delivery, while the population of “older mothers” has increased in recent years and should be further studied. Finally, only data from 60 min post-IND were collected to assess the effect of IND on onset time and procedural pain. Whether IND has advantages in the maintenance of analgesia and breakthrough pain should be explored in future studies.

In summary, pretreatment with intranasal low-dose dexmedetomidine as an adjunct to a programmed intermittent epidural bolus might provide faster analgesia onset and less pain during the epidural puncture without increasing adverse effects compared to the traditional PIEB mode. These findings suggest that pretreatment with IND could be a useful adjunct for some patients during the initiation of epidural analgesia, and further investigation should be encouraged to determine its utility more fully.