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Canadian Journal of Anesthesia 53:646-652 (2006)
© Canadian Anesthesiologists' Society, 2006
General Anesthesia

Intraoperative infusion of dexmedetomidine reduces perioperative analgesic requirements

[Une perfusion peropératoire de dexmédétomidine réduit les besoins analgésiques périopératoires]

Alp Gurbet, MD, Elif Basagan-Mogol, MD, Gurkan Turker, MD, Fatih Ugun, MD, F. Nur Kaya, MD and Berin Ozcan, MD

From the Department of Anesthesiology and Reanimation, Uludag University Faculty of Medicine, Bursa, Turkey.

Address correspondence to: Dr. Alp Gurbet, Uludag, Department of Anesthesiology and Reanimation, University Faculty of Medicine, Gorukle, 16049 Bursa, Turkey. Phone: 90-224-4428039; Fax: 90-224-4428958; E-mail: agurbet{at}uludag.edu.tr


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: This prospective, randomized, double-blind study was designed to assess whether intraoperative infusion of dexmedetomidine provides effective postoperative analgesia. Postoperative pain scores and morphine consumption were compared in a treated group and a placebo group, both of which received patient-controlled morphine after total abdominal hysterectomy.

Methods: Fifty women were randomly assigned to two groups. Group D (n = 25) received a loading dose of dexmedetomidine 1 µg·kg–1 iv during induction of anesthesia, followed by a continuous infusion at a rate of 0.5 µg·kg–1·hr–1 throughout the operation. Group P (n = 25) received a volume-matched bolus and infusion of placebo (0.9% saline). For each case, heart rate, peripheral oxygen saturation, and systolic and diastolic blood pressure were recorded intraoperatively and for 48 hr postoperatively. Patients used a patient-controlled analgesia device to receive bolus doses of morphine after surgery. Total morphine consumption, pain scores, and sedation scores were recorded for the first 48 hr (two hours in the postanesthesia care unit and 46 hr on the ward).

Results: The groups were similar with respect to mean times to extubation of the trachea. Pain and sedation scores were also similar between groups at all corresponding times throughout the 48-hr period of observation. Group D patients consumed significantly less morphine in the postanesthesia care unit and on the ward (P < 0.05 and P < 0.01, respectively). Fewer patients in Group D experienced itching or nausea/vomiting (P < 0.05).

Conclusion: Continuous iv dexmedetomidine during abdominal surgery provides effective postoperative analgesia, and reduces postoperative morphine requirements without increasing the incidence of side effects.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
DEXMEDETOMIDINE is a highly selective {alpha}2-adrenergic receptor agonist that is most often used for short-term sedation in patients in intensive care who are on mechanical ventilation.1 The main advantage of this drug is that it does not cause serious respiratory side effects.2 In addition, it has an opioid-sparing effect.3,4 The analgesic, sedative/hypnotic and anxiolytic properties of dexmedetomidine make this drug potentially useful for painful surgical procedures.

Systemic administration of the {alpha}2-agonists dexmedetomidine and clonidine has been reported to cause sedative effects and reduce opioid requirements in the perioperative period.5–10 Such features are indirect evidence that these drugs have analgesic action. However, studies conducted in the perioperative period involve numerous confounding factors, and it is difficult to distinguish whether analgesic or sedative effects are responsible for the reduced opioid requirements.11 The analgesic activity of {alpha}2-agonists seems to be mediated by both supraspinal and spinal mechanisms. It is thought that central {alpha}2-adrenoceptors in the locus ceruleus (a supraspinal site) and in the dorsal horn of the spinal cord are involved in this activity.12,13 Dexmedetomidine has also been shown to have anti-hyperalgesic action in rats with neuropathic pain originating in the peripheral nervous system.14 This drug enhances the effects of analgesics without increasing the incidence of side effects.15

The aim of this study was to evaluate whether intraoperative infusion of dexmedetomidine provides effective postoperative analgesia. To address this question, we compared findings after intraoperative administration of dexmedetomidine or placebo to patients who underwent major abdominal surgery and then received morphine postoperatively via patient-controlled analgesia (PCA). Side effects related to dexmedetomidine were also investigated.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Institutional Ethics Committee approval was obtained for this prospective study, and all participants gave informed consent. The subjects were 50 women who underwent total abdominal hysterectomy and received morphine via PCA for postoperative pain control. All patients were ASA physical status I or II, and their ages ranged from 35 to 65 yr. The exclusion criteria were weight exceeding 100 kg, inability to use the PCA device, renal or hepatic dysfunction, cardiac failure, ischemic or valvular heart disease, long-term use of certain medications (ß-blockers, analgesics, sedatives or tricyclic antidepressants), psychiatric illness, alcohol abuse, and heavy smoking habit. The night before surgery, an anesthesiologist instructed each patient regarding use of the PCA device.

A computer-generated randomization table was used to assign each woman to the placebo group (Group P, n = 25) or the dexmedetomidine group (Group D, n = 25). An anesthesiologist (who was not one of the observers for the study) prepared injectable solutions containing either dexmedetomidine or 0.9% saline. The dexmedetomidine was supplied in 2-mL ampoules of 100 µg·mL–1 concentration (Abbott, Chicago, IL, USA), and this volume was diluted with 98 mL of normal saline to yield a final concentration of 2 µg·mL–1. For each patient in Group P, a 100 mL volume of 0.9% saline solution was prepared.

Routine monitoring consisted of non-invasive blood pressure, electrocardiography and peripheral oxygen saturation (SpO2) monitoring. Induction of anesthesia was achieved with thiopentone 3 to 5 mg·kg–1 iv and fentanyl 3 µg·kg–1 iv. Vecuronium 0.1 mg·kg–1 iv was given to facilitate tracheal intubation, and anesthesia was maintained with 0.5 to 2% (end-tidal concentration) sevoflurane in 60% nitrous oxide and 40% oxygen. In each case, the aim was to maintain mean arterial blood pressure (MAP) within 80–120% of baseline values. Mean arterial blood pressure rise of more than 20% above baseline was treated by administering a 2 µg·kg–1 iv bolus of fentanyl and raising the end-tidal sevoflurane concentration to 2%. Mean arterial blood pressure drop of more than 20% below baseline was treated initially with reduction of the end-tidal sevoflurane concentration to 0.5%. Supplemental boluses of vecuronium 0.05 mg·kg–1 iv were administered as required to maintain muscle relaxation during surgery.

Each Group D patient received an initial loading dose of dexmedetomidine1 µg·kg–1 over 30 min prior to induction, followed by an infusion started at 0.5 µg·kg–1·hr–1. The infusion was discontinued when surgery ended. Group P patients received the same volume of 0.9% saline as a sham loading dose, followed by a saline infusion. Heart rate, SpO2, and MAP were recorded at specific time points (zero, five, 15, 30, 60, 90 and 120 min) during the surgical procedure. The total amount of fentanyl administered during each operation was also recorded.

Upon completion of surgery, each patient was extubated when she was able to execute simple verbal commands. All subjects were transferred to the postanesthesia care unit (PACU), where they were monitored and received nasal O2 supplementation. Each woman was reminded of how to operate a PCA system (Abbott Pain Management Provider, Chicago, IL, USA) after receiving an initial bolus of morphine 3 mg iv. The PCA machine was set to deliver morphine boluses 1 mg iv with a lockout interval of five minutes. Morphine was delivered only via PCA; no morphine infusions were provided. This PCA regimen was continued for 48 hr (in the PACU and on the ward). Patients were encouraged to push the analgesic- demand button when they experienced pain, and to repeat until they felt pain relief. Diclofenac 75 mg iv was administered for rescue analgesia if the pain scores at rest remained higher than 3.

Each patient remained in the PACU for two hours, and was transferred thereafter to the ward. Data for pain scores (see details below), heart rate, MAP, and sedation scores (see details below) were recorded at ten, 20, 30, 40, 50, 60, 90 and 120 min in the PACU, at arrival on the ward, and at three, four, eight, 12, 16, 24, 32, 40 and 48 hr postoperatively. Each subject’s mean SpO2 value in the PACU was also recorded. Observers who recorded data were blinded with respect to patients’ group allocation. The observer was never the anesthesiologist providing clinical care of the patient.

Pain intensity was assessed using an 11-point visual analogue scale (VAS) on which 0 indicated no pain and 10 indicated the worst pain imaginable. At each assessment period after surgery, the patient assessed her pain at rest (VASR) and during movement (VASM). Sedation levels were also recorded at the same time intervals. The degree of sedation was assessed using the Ramsay sedation scale. In this system, 1 = agitated and uncomfortable, 2 = cooperative and orientated, 3 = can follow simple directions, 4 = asleep but strong response to stimulation, 5 = asleep and slow response to stimulation, and 6 = asleep and no response to stimulation.

Times to extubation of the trachea, and side effects possibly related to opioid or dexmedetomidine administration [nausea and vomiting, urinary retention, bradypnea (fewer than 8 breaths·min–1), and itching] were recorded for each case.

Statistical considerations
Based on previous data from Unlugenc et al.,9 23 patients per group would detect a 30% reduction in PCA morphine requirements, relative to the placebo group, during the first 24 hr with a 5% one-tailed type I error rate and 80% power. Kruskal-Wallis, Chi-square and Mann-Whitney U tests were employed as appropriate, and P values < 0.05 were considered significant.


   Results
TOP
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Five patients refused consent. A total of 50 patients consented to participate at the preoperative anesthesia visit and no patient was excluded at any stage of the study. Demographic and intraoperative outcomes are shown in the TableGo. Groups were similar with respect to age, body weight, height, proportions of ASA I and ASA II patients, and duration of surgery. There were no differences in intraoperative heart rate, MAP and SpO2 between groups. The mean amount of intraoperative fentanyl administered in Group D was significantly lower than that in Group P (P < 0.05). The intraoperative concentrations of sevoflurane were similar in both groups.


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  		TABLE Demographic and intraoperative data
 
Intergroup comparisons of MAP, heart rate and SpO2 findings in the PACU revealed no significant differences (Figure 1Go). The groups’ mean sedation scores at each time point in the PACU and on the ward were similar (Figures 2Go and 3Go). There were also no significant differences between the groups’ mean VASR scores at each time point assessed in the PACU and on the ward after surgery, and the same was true for the mean VASM scores (Figures 2Go and 3Go).


Figure 1
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  		FIGURE 1 Cardiorespirator y variables after surger y while in the PACU (mean ± SD). Group P = placebo group; Group D = dexmedetomidine group; B = preoperative baseline value; MAP = mean arterial pressure; SpO2 = peripheral oxygen saturation; PACU = postanesthesia care unit.

 

Figure 2
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  		FIGURE 2 Pain scores at rest and during movement, sedation scores and cumulative PCA morphine consumption in the PACU (mean ± SD). Patients receiving intraoperative dexmedetomidine consumed significantly less PCA morphine during the PACU stay (*p < 0.05). There were no significant differences in other end-points. Group P = placebo group; Group D = dexmedetomidine group; VASR = visual analogue scale at rest; VASM = visual analogue scale during movement; PCA = patient-controlled analgesia; PACU = postanesthesia care unit.

 

Figure 3
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  		FIGURE 3 Pain scores at rest and during movement, sedation scores and cumulative PCA morphine consumption while on the ward (mean ± standard deviation). Patients receiving intraoperative dexmedetomidine had significantly lower mean cumulative morphine consumption than placebo patients on the ward (*P < 0.01). There were no significant differences in other end-points. Group P = placebo group; Group D = dexmedetomidine group; A = arrival on the ward; VASR = visual analogue scale at rest; VASM = visual analogue scale during movement; PCA = patient-controlled analgesia.

 
The times from PACU admission to first analgesic (PCA) demand were similar in the two groups (8 ± 6 vs 9 ± 7 min, Groups P and D, respectively; P > 0.05). Group P had significantly higher mean cumulative morphine consumption than Group D (19.5 ± 1 vs 12 ± 0.7 mg, respectively; P < 0.05) during the PACU stay (Figure 2Go).

During the time patients were assessed on the ward (i.e., from arrival on the ward to 48 hr postoperatively), Group P patients had significantly higher mean cumulative morphine consumption than Group D patients (65.8 ± 20.6 vs 28.6 ± 10.7 mg, respectively; P < 0.01), (Figure 3Go).

A significantly higher number of patients in Group P experienced itching (13 vs 4 patients for Group P vs Group D, respectively; P < 0.05). Nausea and vomiting requiring treatment was also lower in the dexmedetomidine group (15 vs 6 patients, respectively; P < 0.05). Also, seven patients in Group P needed rescue analgesia in contrast to only two patients in Group D (P < 0.05). No patient in either group developed urinary retention or bradypnea. None of the patients in either group developed any opioid-related complications that delayed PACU or hospital discharge.


   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our findings indicate that intraoperative iv dexmedetomidine reduces PCA morphine consumption after total abdominal hysterectomy during the first 48-hr after surgery.

Animal studies have shown that iv dexmedetomidine significantly reduces sevoflurane anesthetic requirements.16 The analgesic effects of dexmedetomidine observed in our study correlate well with previous findings in both animals and humans. Experiments with thermal pain models in animals have shown that systemic administration of clonidine or dexmedetomidine has significant analgesic effects.17,18 Jaakola et al.4 evaluated analgesia after systemic administration of different doses of dexmedetomidine (0.25, 0.50, and 1 µg·kg–1) and fentanyl (2 µg·kg–1) in healthy volunteers, and found that dexmedetomidine had a moderate analgesic effect that was maximized at 0.5 µg·kg–1. In line with this, Cortinez et al.1 showed that a 0.6 ng·mL–1 target control infusion (equivalent to 0.5 µg·kg–1) of iv dexmedetomidine had analgesic effects in humans. These doses of dexmedetomidine are similar to the amounts which patients received in the current study.

Several experimental pain studies in human volunteers used the cold pressor test after administration of dexmedetomidine or clonidine. These investigations indicate a 20% to 30% decrease in pain VAS scores for subjects who receive either of these drugs at doses associated with moderate to severe sedation.2,18,19 However, conflicting results were documented in one study in an experimental model of secondary hyperalgesia, where volunteers who received clonidine at a dose known to produce moderate to severe sedation experienced no anti-hyperalgesic or anti-allodynic effects.20 Our results add to evidence that suggests dexmedetomidine does not have broad analgesic efficacy when administered systemically at doses that produce mild to severe sedation.

One study4 revealed that both dexmedetomidine and fentanyl have significant analgesic effects on ischemic pain induced by a sphygmomanometer cuff. The authors found that the analgesic action of dexmedetomidine was not dose-dependent; they observed an apparent ceiling effect at 0.5 µg·kg–1. In our study, we observed that an intraoperative loading dose of dexmedetomidine 1 µg·kg–1 followed by an infusion at a rate of 0.5 µg·kg–1·hr–1 provided good analgesia for at least 48 hr after total abdominal hysterectomy. This was reflected by the significantly lower requirements for iv PCA morphine analgesia in the dexmedetomidine group. Arain et al.5 examined the efficacy of dexmedetomidine vs morphine for postoperative analgesia after major inpatient surgery. Thirty minutes before the end of the surgery, one group received an initial loading dose of dexmedetomidine 1 µg·kg–1 followed by an infusion at a rate of 0.4 µg·kg–1·hr–1, discontinued at the end of surgery. Prior to the end of surgery, the other group received an iv bolus of morphine 0.08 mg·kg–1. Upon recovery from anesthesia, patients in both groups received morphine 2 mg iv whenever the VAS pain score was > 5. The groups had similar pain scores but the morphine group required 66% more morphine to achieve this analgesic effect. Similarly, in our study we observed no differences between the VAS pain scores (at rest or during movement) for the placebo and dexmedetomidine groups at any of the time after surgery. However, the patients who received dexmedetomidine required a lower cumulative amount of morphine during the first 48 hr after surgery.

Animal studies indicate that systemic administration of {alpha}2-adrenergic receptor agonists results in dose-dependent antinociception and sedation responses.21 Human data reveal a clear dose-response relationship for sedation, but not for analgesia, with systemic administration of these drugs.6,22 One possible explanation of the variances between animal and human studies is that many of the animal experiments involved drug doses several orders of magnitude larger than those used in human trials.3,18,19 In human research, it is usually not possible to administer systemic doses of {alpha}2-agonists that will provide effective analgesia, because such doses can heavily sedate subjects or even render them unconscious. In our study, we did not observe clinically important sedation in any patient who received intraoperative dexmedetomidine infused at a rate of 0.5 µg·kg–1·hr–1.

Previous research has shown that iv target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng·mL–1) decrease heart rate and blood pressure in a dose-dependent fashion. These cardiovascular effects are well documented for the plasma concentrations of dexmedetomidine that have been investigated to date.2 Arain et al.5 administered dexmedetomidine at an initial loading dose of 1 µg·kg–1 followed by an infusion at 0.4 µg·kg–1·hr–1 initiated 30 min before the end of elective inpatient surgery. Slower mean heart rates were observed in the dexmedetomidine-treated group during the early postoperative period. However, no patient who received dexmedetomidine in our study developed clinically important bradycardia, either during surgery or postoperatively.

Venn et al.23 investigated the postoperative effects of postoperatively administered dexmedetomidine in 119 cardiac surgery and general surgery patients who required mechanical ventilation and sedation in an intensive care unit. The patients were divided into two groups that received either dexmedetomidine or placebo. In both groups, midazolam and morphine were used for rescue sedation and analgesia, respectively. The authors found that dexmedetomidine had an analgesia-sparing effect and resulted in reduced need for rescue sedation. The elimination half-life of dexmedetomidine is two to three hours, and the authors speculated that the analgesic-sparing effect of dexmedetomidine would have persisted for up to 24 hr postoperatively. In our study, we observed that the dexmedetomidine group had significantly lower morphine requirements than the placebo group during the first 48 hr after abdominal surgery. One explanation for prolonged postoperative analgesia with dexmedetomidine may be the anxiolytic and thymoanaleptic properties of {alpha}2-agonists, which act on the emotional component of postoperative pain.24

In summary, our results indicate that intraoperatively administered dexmedetomidine has specific analgesic properties and provides effective visceral pain relief. We found that continuous infusion of dexmedetomidine during abdominal surgery significantly reduces the amount of PCA morphine that patients require to remain comfortable postoperatively, without affecting time to extubation. Intraoperative, systemically administered dexmedetomidine was also associated with fewer morphine-related side effects compared with placebo.


   Footnotes
 
Accepted for publication January 25, 2006. Revision accepted February 6, 2006.

Competing interests: None declared.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Cortinez LI, Hsu YW, Sum-Ping ST, et al. Dexmedetomidine pharmacodynamics: part II. Crossover comparison of the analgesic effect of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology 2004; 101: 1077–83.[Medline]

2 Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000; 93: 382–94.[Medline]

3 Aho MS, Erkola OA, Scheinin H, Lehtinen AM, Korttila KT. Effect of intravenously administered dexmedetomidine on pain after laparoscopic tubal ligation. Anesth Analg 1991; 73: 112–8.[Abstract/Free Full Text]

4 Jaakola ML, Salonen M, Lehtinen R, Scheinin H. The analgesic action of dexmedetomidine – a novel {alpha}2-adrenoceptor agonist – in healthy volunteers. Pain 1991; 46: 281–5.[Medline]

5 Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg 2004; 98: 153–8.[Abstract/Free Full Text]

6 Jaakola ML. Dexmedetomidine premedication before intravenous regional anesthesia in minor outpatient hand surgery. J Clin Anesth 1994; 6: 204–11.[Medline]

7 Marinangeli F, Ciccozzi A, Donatelli F, et al. Clonidine for treatment of postoperative pain: a dose-finding study. Eur J Pain 2002; 6: 35–42.[Medline]

8 Scheinin B, Lindgren L, Randell T, Scheinin H, Scheinin M. Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone and peroperative fentanyl. Br J Anaesth 1992; 68: 126–31.[Abstract/Free Full Text]

9 Unlugenc H, Gunduz M, Guler T, Yagmur O, Isik G. The effect of pre-anaesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patient-controlled morphine. Eur J Anaesth 2005; 22: 386–91.[Medline]

10 Lawrence CJ, De Lange S. Effects of single pre-operative dexmedetomidine dose on isoflurane requirements and peri-operative haemodynamic stability. Anaesthesia 1997; 52: 736–44.[Medline]

11 Angst MS, Ramaswamy B, Davies MF, Maze M. Comparative analgesic and mental effects of increasing plasma concentrations of dexmedetomidine and alfentanil in humans. Anesthesiology 2004; 101: 744–52.[Medline]

12 Guo TZ, Jiang JY, Buttermann AE, Maze M. Dexmedetomidine injection into the locus ceruleus produces antinociception. Anesthesiology 1996; 84: 873–81.[Medline]

13 De Kock M, Crochet B, Morimont C, Scholtes JL. Intravenous or epidural clonidine for intra- and postoperative analgesia. Anesthesiology 1993; 79: 525–31.[Medline]

14 Poree LR, Guo TZ, Kingery WS, Maze M. The analgesic potency of dexmedetomidine is enhanced after nerve injury: a possible role for peripheral alpha2-adrenoceptors. Anesth Analg 1998; 87: 941–8.[Abstract/Free Full Text]

15 Hayashi Y, Guo TZ, Maze M. Hypnotic and analgesic effects of the alpha2-adrenergic agonist dexmedetomidine in morphine-tolerant rats. Anesth Analg 1996; 83: 606–10.[Abstract]

16 Fragen RJ, Fitzgerald PC. Effect of dexmedetomidine on the minimum alveolar concentration (MAC) of sevoflurane in adults age 55 to 70 years. J Clin Anesth 1999; 11: 466–70.[Medline]

17 Kayser V, Desmeules J, Guilbaud G. Systemic clonidine differentially modulates the abnormal reactions to mechanical and thermal stimuli in rats with peripheral mononeuropathy. Pain 1995; 60: 275–85.[Medline]

18 Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ. Sedative, amnestic and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000; 90: 699–705.[Abstract/Free Full Text]

19 Hall JE, Uhrich TD, Ebert TJ. Sedative, analgesic and cognitive effects of clonidine infusions in human. Br J Anaesth 2001; 86: 5–11.[Abstract/Free Full Text]

20 Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 2003; 99: 152–9.[Medline]

21 Buerkle H, Yaksh TL. Pharmacological evidence for different alpha2-adrenergic receptor sites mediating analgesia and sedation in the rat. Br J Anaesth 1998; 81: 208–15.[Abstract/Free Full Text]

22 Eisenach JC, De Kock M, Klimscha W. Alpha2-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology 1996; 85: 655–74.[Medline]

23 Venn RM, Bradshaw CJ, Spencer R, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia 1999; 54: 1136–42.[Medline]

24 De Kock MF, Pichon G, Scholtes JL. Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anesth 1992; 39: 537–44.[Abstract/Free Full Text]




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