Dexmedetomidine is a highly selective α2-agonist with potent sedative, anaesthetic-sparing and analgesic effects [1,2]. It has not been associated with respiratory depression, despite its sedative effects [3-5]. In addition, dexmedetomidine has analgesic-sparing effects [2-7]. These properties make it an ideal pre-anaesthetic medication for painful surgical procedures.
Dexmedetomidine induces a centrally mediated reduction of sympathetic nervous system activity and may be useful in diminishing catecholamine release via its sympatholytic and analgesic properties . It enhances the effects of analgesics without increasing the incidence of side-effects [9-11]. This observation has led to the concept that a combination of opioids and α2-adrenergic receptor agonists may improve postoperative patient comfort.
Clonidine reduces fentanyl requirements by more than 50% and can attenuate haemodynamic changes . Two prospective, placebo-controlled, double-blind studies have demonstrated that a single pre-anaesthetic intravenous (i.v.) dose of dexmedetomidine reduces postoperative analgesic requirements [13,14].
The present prospective, randomized, double-blind, controlled study was designed to test whether dexmedetomidine could similarly reduce postoperative morphine consumption. We hypothesized that a single i.v. dose of dexmedetomidine, administered 10 min before induction of anaesthesia, would reduce morphine consumption administered by patient-controlled analgesia (PCA) compared with placebo in patients undergoing abdominal surgery.
Following Ethics Committee approval and informed patient consent, we recruited 60 ASA I-II patients between the ages of 18 and 64 yr, scheduled for elective abdominal surgery under general anaesthesia. Preoperatively, patients were instructed on the use of the PCA device and the verbal rating scale (VRS) for pain assessment. Exclusion criteria included inability to use the PCA device, long-term use of opioids and a history of chronic pain. No premedication was given except for the dexmedetomidine according to the study protocol. Intraoperative monitoring included pulse oximetry, automated non-invasive arterial pressure monitoring and lead II electrocardiogram.
Ten minutes before induction of anaesthesia, patients were allocated randomly to one of two groups using a computer-generated random number table. An anaesthetist, who was not one of the observers, prepared packages containing either dexmedetomidine (Abbott, Chicago, IL, USA) or 0.9% saline. Both the solutions were labelled ‘study drug’ and coded to maintain the double-blind nature of the study. Dexmedetomidine was supplied in 2-mL ampoules in a concentration of 100 μg mL−1, which was diluted with 98 mL normal saline to a final concentration of 2 μg mL−1. The placebo saline solution was prepared in a similar fashion.
Ten minutes before induction of anaesthesia, the patients in one group (n = 30) received an infusion of 1 μg kg−1 dexmedetomidine over 10 min and those in the other group (n = 30) received the corresponding volume of 0.9% saline. Scores for sedation and haemodynamic parameters (systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR) and peripheral oxygen saturation) were recorded by an anaesthetist who was blinded to the patient group, at times 0, 5 and 10 min during infusion of the study drugs.
Immediately after infusion of the study drug, anaesthesia was induced with thiopental (3-5 mg kg−1) until loss of eyelid reflex, and maintained with 1-2% sevoflurane in nitrous oxide/oxygen (2 : 1) according to haemodynamic, somatic and autonomic responses. Neuromuscular relaxation was induced by vecuronium bromide (0.1-0.2 mg kg−1) and maintained by bolus injections of 0.03 mg kg−1 at 30 min intervals.
An i.v. loading dose of morphine (0.1 mg kg−1) was given to all patients 20 min before the end of surgery. The tracheal tube was removed following antagonism of residual neuromuscular block with neostigmine (0.05 mg kg−1) and atropine (0.015 mg kg−1). No other opioids were administered intraoperatively.
Recovery from anaesthesia was assessed by the ability to open the eyes, grip a finger, obey simple commands and to breathe deeply on request. Thereafter, patients were allowed to self-administer morphine with a PCA device (Abbott Pain Management Provider, Class II, Type CF, Chicago, IL, USA). The bolus dose was set at 0.02 mg kg−1 with a lock-out time of 15 min with no background infusion or maximal dose. Ondansetron 4 mg and meperidine 0.4 mg kg−1 were prescribed i.v. on request as the rescue antiemetic and analgesic, respectively, for all patients to be repeated if necessary every 4 h. The PCA pump was removed 24 h after surgery, when i.v. dipyrone (metamizole), 3 g per day, was prescribed for pain management. The cumulative dose of morphine was recorded after recovery and at 1, 2, 6, 12 and 24 h after the start of PCA. Patients requiring any change in their analgesic regimen or resetting of the PCA pump were to be excluded from the study.
Scores for discomfort, pain, sedation, nausea, haemodynamic parameters and peripheral oxygen saturation were recorded at rest by an anaesthetist of the Pain Management Team, blinded to the patient group, after recovery and at 1, 2, 6, 12 and 24 h after the start of PCA.
Discomfort was assessed using a 11-point numerical scale from 0 to 10 (0: none, 10: extreme discomfort); pain was assessed by a VRS from 0 to 10 (0: no pain, 10: the worst pain imaginable); sedation was assessed on a 5-point scale with 1: alert and 5: deep sleep ; and nausea was assessed using a linear numerical scale of 1-5 (1: none; 2: mild, once in a 15-min period; 3: moderate, two or three times in a 15-min period; 4: severe, four or more times in a 15-min period; 5: worst nausea, persistent, severe nausea despite treatment with antiemetic).
The type of surgery, duration of anaesthesia, number of patients requiring supplementary meperidine, time to extubation, time to recovery and any side-effects (such as pruritus or urinary incontinence) associated with the procedure were also recorded.
The primary end-point was defined as a reduction in cumulative morphine consumption throughout the study period, a 30% reduction being regarded as clinically significant. The sample size was determined by power analysis; with a power of 0.8 and significance level of 0.05, 23 subjects per study group were required. However 30 subjects were recruited to increase the power. Statistical analyses were performed using the statistical package for the social sciences (SPSS) version 10.0. Data were reported as mean (95% confidence interval, CI), number (%) or median (range). A P-value <0.05 was accepted as statistically significant. Normality was checked for each continuous variable. For between-group comparisons, t-test and the U-test were used for normally and non-normally distributed variables, respectively. Wilcoxon signed rank sum tests were used to evaluate the within-group competitions between after recovery and each time intervals. The incidence of complications between the groups was compared by χ2-test.
Patient characteristics variables are shown in Table 1. There were no differences between groups with regard to sex, age or weight, type of surgery, number of patients requiring supplementary meperidine or duration of anaesthesia. Blood pressure decreased with time in both groups, but there was no significant difference between groups. However, after infusion of the study drugs, patients in the dexmedetomidine group had a lower mean HR at 10 min and a higher mean sedation score at 5 and 10 min (P < 0.05; Fig. 1).
Haemodynamic variables were similar between two groups in each study period after recovery. SPO2 remained within the normal range throughout the study period, with no differences between groups. Despite the long half-life of dexmedetomidine (100-150 min), the mean time to extubation at the end of anaesthesia and recovery time was similar in the two groups (Table 1). Both groups were alert and co-operative in the postoperative care unit. There were no adverse events in either group.
Pain and discomfort scores decreased with time in each group (P < 0.01) and cumulative morphine consumption increased with time (P < 0.05). Sedation and nausea scores did not change over time in either group after the PCA was started (Table 2). There were no significant differences between groups in mean pain, discomfort, nausea or sedation scores at any time (Table 2). However, patients given dexmedetomidine consumed 28% less morphine than controls in the first 24 h (Table 2) and had a lower cumulative morphine consumption at 6, 12 and 24 h after starting the PCA; 17.6 mg vs. 25.6 mg at 6 h (P < 0.001), 20.6 mg vs. 34.8 mg at 12 h (P < 0.001) and 23.8 mg vs. 44 mg at 24 h (P < 0.001) in the dexmedetomidine and saline groups, respectively.
Statistical analysis revealed that not only cumulative morphine consumption but also amounts of morphine consumed from the 2nd to 6th, 6th to 12th and 12th to 24th hour were significantly different between the groups (P < 0.001; Table 2).
Twelve patients (20%) complained of pain despite PCA morphine; five in the dexmedetomidine group and seven in the saline group. The type of pain that did not respond to the PCA morphine regimen was similar between the two groups (two patients with cholecystectomy, two with inguinal hernia repair and one with exploratory laparotomy in the dexmedetomidine group; three patients with cholecystectomy, two with inguinal hernia repair, one with splenectomy and one with exploratory laparotomy in the saline group). They were given a single i.v. dose of meperidine (0.4 mg kg−1) to reduce pain scores below 5 (Table 1). Six patients, four in the saline group and two in the dexmedetomidine group experienced nausea and were given ondansetron 4 mg. The incidence of nausea did not differ between the groups and no patient vomited during PCA therapy. Two patients in the saline group and one in the dexmedetomidine group complained of urinary retention. One patient in the saline group had pruritus that resolved spontaneously. No shivering was observed in either group.
The primary objective of this study was to determine whether a single i.v. dose of dexmedetomidine, given immediately before induction of anaesthesia, would reduce postoperative morphine consumption. We found a 28% reduction in morphine consumption during the first 24 h while maintaining comparable pain levels.
Possible mechanisms for this include an analgesic-sparing effect, a pre-emptive analgesic effect or a residual additive effect of dexmedetomidine.
The analgesic-sparing effect of dexmedetomidine has been described [3-6]. Given preoperatively, α2-adrenergic agonists potentiate morphine effects and reduce analgesic use after surgery by 10-15% . This effect is probably mediated via stimulation of α2-adrenoceptors in sympathetic nerve endings and the spinal cord . Arain and colleagues reported that patients receiving dexmedetomidine for sedation at the end of surgery had significantly lower pain scores and required less morphine . It is likely that the sedative and analgesic effects persisted into the recovery period, as the half-life is 2 h .
Venn and colleagues have reported that dexmedetomidine significantly reduces the requirements for rescue sedation and analgesia in a placebo-controlled trial in postoperative patients for up to 24 h . Although our methodology is different, our results are in accord with Venn's study . The combination of opioids and α2-adrenoceptor agonists may provide additive pain relief because the two drugs act at different sites, the opioid receptor and the α2-adrenoceptor . Analgesic effects of α2-adrenergic agonists have been demonstrated in animals [18,19] and human beings , which could explain the lower morphine consumption in the dexmedetomidine group.
Despite similar pain, discomfort and sedation scores, and side-effects, morphine consumption in the dexmedetomidine group was lower at 6, 12 and 24 h. This implies lower blood concentrations of morphine, although another possibility is that dexmedetomidine interferes with morphine metabolism. Further studies are needed to address this.
These data suggest that dexmedetomidine induces prolonged antinociception in the postoperaive period. Pre-anaesthetic administration of dexmedetomidine may have a pre-emptive analgesic effect, possibly emerging at 6-24 h postoperatively, after the effect of the intraoperatively administered morphine loading dose wore off. Further studies are needed to reveal this relationship. There may also have been a residual additive effect of dexmedetomidine, although this is unlikely in view of the half-life of dexmedetomidine.
Predictably, the sedation score increased and HR decreased immediately after the dexmedetomidine loading dose in Group D, but not in Group S. This might be avoided or reduced by giving the infusion more slowly [6,20]. Pre-anaesthetic administration of dexmedetomidine did not result in greater sedation than with saline, and patients were easily aroused in both groups after recovery. This property of dexmedetomidine has been noted previously [6,20]. Salivary flow and gastrointestinal motility are said to be reduced by α2-adrenergic agonists [21,22]. However, we found no significant differences between groups in nausea scores at any study period.
In this study, a single i.v. pre-anaesthetic dose of dexmedetomidine reduced postoperative morphine consumption. Opioid-induced side-effects were infrequent and caused few problems in either group. The reduction in the use of morphine is unlikely to have any financial benefits, since it would not reduce the number of unit doses of PCA medication. Indeed, the cost of the dexmedetomidine might exceed that of any savings in morphine costs.
In conclusion, a single dose of dexmedetomidine (1 μg kg−1) given 10 min before induction of anaesthesia significantly reduced PCA morphine consumption required for the same level of pain relief without affecting recovery times compared with saline placebo. There is no strong financial incentive for using dexmedetomidine in this way, but it seems reasonable that it could prove useful for patients undergoing major surgery associated with significant pain by reducing the amount of opioid required.
The authors gratefully acknowledge the assistance of nursing staff and would like to thank G. Seydaoğlu, PhD, for expert statistical advice. The study was not supported by external funds.
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