Perioperative and postoperative pain control, maintenance of hemodynamic stability, proper sedation and awakening are a major part of anesthetic management. The opioids such as fentanyl and remifentanil have been widely used in operating room and PACU. Dexmedetomidine, recently introduced, is often used as it has both analgesic potency and sedative effect.

Dexmedetomidine is the highly selective α₂-adrenergic agonist, which provides sedation, anxiolysis, hypnosis, analgesia, and sympatholysis (1). A loading dose of dexmedetomidine is 1 µg/kg over 10 minutes, and maintenance dose is 0.2-0.7 µg/kg/hr for procedural sedation. It has been used in the operating room and the intensive care unit (ICU) for sedation (2). It is not associated with respiratory depression, despite profound levels of sedation (3). It decreases sympathetic outflow of central nervous system in a dose-dependent manner and has analgesic effects best described as “opioid-sparing” (4). It has been known to reduce opioid requirements by 30% to 50% (5). Consistent with the pharmacological effect, dexmedetomidine decreases heart rate (HR) and arterial pressure. These hemodynamic changes are associated with reduction in norepinephrine plasma levels (6). The analgesic potential of α₂-agonists, however, does not approximate the potency of opioids. Nevertheless, in neuropathic pain in which opioid relief is suboptimal, α₂-agonists may offer specific advantages (7). These properties (sedation, lack of respiratory depression and analgesia sparing) of dexmedetomidine help reduce the significant postoperative pain and provide proper sedation after major surgical procedures, which can result in hemodynamic stability in PACU.

Although fentanyl and remifentanil have been commonly used for pain control and sedation in perioperative and postoperative period, dexmedetomidine can be an effective alternative as it has both analgesic and sedative effect like fentanyl and remifentanil. The aim of this study is to compare the efficacy of dexmedetomidine and opioids such as fentanyl and remifentanil with respect to hemodynamic stability, sedation and postoperative pain control after completion of total laparoscopic hysterectomy.

A total 93 patients were randomized into the study. One patient was excluded due to underpreparation, and 92 patients were allocated to intervention groups and received the allocated interventions. Of these, two patients were lost to follow-up due to change to open abdominal hysterectomy (Fig. 1).

The three groups had similar age, weight, height, ASA status, duration of the operation time and duration of the anesthetic time (Table 1). The patients in each group received a total of 137.7 ± 40.2 µg of DEX, 108.5 ± 29 µg of fentanyl, and 416.2 ± 37.2 µg of remifentanil.

Table 2 summarizes the adverse events during the study. There were no significant differences in the incidence of side effects among the three groups (Table 3). These adverse events were observed mainly during the immediate postoperative period. Dry mouth was reported in three patients in Group DK. Nausea, vomiting, shivering and bradycardia were reported in Group FK and Group RK.

Modified OAA/S scores of sedation were significantly lower in Group DK compared with other Groups at R0 (arrival at recovery room), and at R5 and R10 (Fig. 2A). VAS scores of postoperative pain were not significantly different among the three groups (Fig. 2B).

Changes in the BIS were not significantly different among the three groups at all times from t0 (before induction time) to t16-Rec-30 (30 minutes after arrival at recovery room; Fig. 3).

After starting the injection of study drugs in the three groups, SBP, DBP and HR were significantly lower in Group DK compared with other Groups from t6 (operation for 75 minutes) to t12-Rec-10 (10 minutes after arrival at recovery room; Fig. 4A and 4B).

After its approval by the Food and Drug Administration (FDA) in 1999, dexmedetomidine has become well-established as a sedative-hypnotic agent. Dexmedetomidine is chemically related to clonidine but its affinity for α₂-receptors is eight times higher (1,620:1) when it is compared with clonidine (200:1). It is now being used off-label outside of the ICU, in various settings such as maintaining airway, providing hemodynamic stability and adjunctive analgesia in the operating room, sedation in diagnostic and procedure units without the need for tracheal intubation, and prevention of withdrawal following the prolonged administration of opioids and benzodiazepines (9). It was also used for sedation in monitored anesthesia care (MAC) (10). Unlike other sedatives, dexmedetomidine-induced sedation allows the patients to open the eyes for response to verbal stimulation and communication, showing normal cognitive abilities. And after surgery or other procedures, it can be used without restrictions during physical examinations to identify the patient's general condition and neurological status (11).

Dexmedetomidine has sedative and analgesia-sparing effects via central actions in the locus coeruleus (LC) and in the dorsal horn of the spinal cord. The primary action of all α₂-adrenergic agonists is an inhibition of norepinephrine release causing an attenuation of excitation in the central nervous system, especially in the LC (12). To our knowledge, the α₂-adrenergic agonists have significant analgesic effects. Even though the opioids have more analgesic effects than dexmedetomidine, it is reported that dexmedetomidine can reduce opioid requirements by 30% to 50% and is a safer drug for sedation (13). Several studies have documented that it provides stable hemodynamics and has no effect on respiratory function (39).

The sedation produced by α₂-adrenoreceptor agonists, unlike the one by traditional sedatives, such as benzodiazepines, propofol, barbiturates and etomidate does not depend primarily on activation of the gamma-aminobutyric acid (GABA) system. Furthermore, the primary site of α₂-agonist action does not seem to be the cerebral cortex as would be the case with GABA-mimetic drugs. The α₂-adrenoreceptor agonists seem to target a different type of sedation compared with GABA-mimetic drugs (14).

A BIS monitor is a neurophysiological monitoring device which continually analyses a patient's electroencephalograms (EEG) during general anesthesia to assess the level of consciousness. The BIS monitor provides a single dimensionless number, the BIS value, ranging from 0 to 99 (15). We routinely use an intraoperative BIS monitor, and its target score is 40 to 60 during general anesthesia. In this study, we chose desflurane, which has very low partition coefficient, because it has little influence on the BIS score during and after surgery. As discussed earlier, the LC is the predominant noradrenergic nucleus in the brain which has a number of efferent connections, particularly to the frontal lobes. Thus, the LC plays a role as an important modulator of wakefulness. Farber et al. (16) reported that dexmedetomidine (20 µg/kg) and halothane (1%–2%) produced quantitatively similar EEG changes in chronically-instrumented cats. According to this study, halothane resulted in unconsciousness and a lack of response to tail clamping, whereas dexmedetomidine produced profound sedation with preservation of the tail-clamp response. Other study demonstrated that the infusion of dexmedetomidine at 0.6 µg/kg/hr produces EEG changes that correspond to a BIS of 60 (moderate to deep sedation) (2). These findings suggest that the BIS score based on EEG parameters may be influenced by the presence of α₂-agonists. As a result, the BIS score for dexmedetomidine and other opioids appear to show similar results in sedative doses.

Dexmedetomidine has also been used in adult patients having a high risk for coronary heart disease and it provides perioperative hemodynamic stability. There were reductions in total cost/patient, total length of stay in the hospital and days in the ICU with shorter duration of mechanical ventilation. The use of dexmedetomidine may also contribute to a lower incidence of shivering and morbidity (17).

Fentanyl and remifentanil are commonly used opioids not only for intraoperative analgesia but for postoperative pain control. In our institution, after surgery and arriving at the recovery room, all patients receive titrated doses of IV fentanyl with a loading dose of 25-100 µg, a continuous dose of 10-60 µg/hr, an intermittent dose of 10-50 ug and a lockout interval dose 6–8 minutes (range: 3-10 minutes) with PCA for postoperative pain control. After administration of an intravenous dose of 100 μg, its onset time of action is 1–2 minutes and its duration is 30–60 minutes.

Remifentanil is a selective, ultra-short-acting µ-opioid receptor agonist with an analgesic potency similar to that of fentanyl and a blood–brain equilibration time similar to that of alfentanil. Remifentanil is unique among the opioids as it undergoes metabolism via non-specific plasma and tissue esterases to inactive metabolites. Its pharmacokinetic properties are characterized by a small Vss of 0.3–0.4 L/kg, rapid clearance of 40–60 mL/min/kg and low variability compared with other i.v. anesthetic drugs. T_1/2α and t_1/2β are 1–2 and 8–20 minutes, respectively. Context-sensitive half-time is independent of the duration of infusion and is estimated to be about 4 minutes (18).

Remifentanil infusion can provide critically ill patients with analgesia and sedation (19). Low doses of remifentanil (up to 0.05 μg/kg/min) help critically-ill patients achieve calmness and sedation. But increasing remifentanil doses can cause respiratory depression and require controlled mechanical ventilation. Depending on clinical needs, sedation can be titrated to different targets, such as obtaining calmness, loss of consciousness (LOC), decreasing sympathetic tone or even inhibiting respiratory rate (20).

As the doses used in group FK and group RK were sedative ones, it may be insufficient to reduce severe pain. The analgesic potency of group DK was not significantly different from other opioid group. Furthermore, the patients in group DK had the ability to communicate with normal cognition and had reduced postoperative nausea & vomiting, as well as hemodynamic stability.

In conclusion, dexmedetomidine, at sedative doses, had the better postoperative hemodynamic stability than fentanyl or remifentanil and demonstrated a similar effect of pain control as fentanyl and remifentanil with patient awareness during sedation in the PACU.