1 University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. 2 Department of Anaesthetics and Intensive Care Medicine, Llandough Hospital, Penlan Road, Llandough, Penarth, South Glamorgan, UK *Corresponding author
Accepted for publication: April 26, 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Sixty patients undergoing lower abdominal surgery were recruited into a randomized double blind study. At the end of surgery Group C received an infusion of clonidine 4 µg kg1 over 20 min, PCA clonidine 20 µg and morphine 1 mg bolus. Group M received an infusion of saline and then PCA morphine 1 mg bolus. Pain, sedation and nausea and vomiting were assessed after 12, 24 and 36 h, and satisfaction with analgesia was assessed at 36 h.
Results. Pain scores were significantly lower in Group C between 0 and 12 h, but thereafter there was no difference. Morphine consumption was the same for both groups until 2436 h. Nausea and vomiting was significantly reduced in Group C between 0 and 24 h. Patients in Group C were significantly happier with their pain relief (four-point scale).
Br J Anaesth 2002; 89: 4247
Keywords: agonists, adrenergic; analgesia, patient-controlled; analgesics opioid, morphine; pharmacology, clonidine; pharmacology, morphine; vomiting, nausea, anaesthetic factors
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
PCA has been used extensively over recent years to titrate analgesia to need9 thus avoiding the potential problems of overdose. PCA is widely used in ordinary ward situations. This randomized double blind study was designed to see if the addition of clonidine to morphine in a PCA device would reduce postoperative morphine consumption when compared with morphine alone. The study followed patients for 36 h after surgery to see how long any effect could be maintained. Any associated reduction in nausea and vomiting was assessed. Although reduced nausea and vomiting have been demonstrated with clonidine usage before,5 10 11 this study examined a very high-risk population i.e. females undergoing lower abdominal surgery.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients were given oral and written information about the study, and written consent was obtained. They were instructed in the use of the PCA device at the preoperative visit. An Abbott Provider 5500TM device was used to deliver the study drugs.
All patients were premedicated with temazepam 20 mg 1.5 h before surgery and a standard anaesthetic was given. After pre-oxygenation, anaesthesia was induced with propofol 2 mg kg1, droperidol 1 mg, fentanyl 1 µg kg1 and vecuronium 0.1 mg kg1. Anaesthesia was maintained by 12% isoflurane in nitrous oxide and oxygen (ratio 2:1). Further boluses of fentanyl 1 µg kg1 were given intraoperatively, up to a maximum of 4 µg kg1, at the anaesthetists discretion depending on the type and duration of surgery. The total amount of fentanyl administered to each patient was recorded.
Intraoperatively, patients were randomized into two groups: Group C received clonidine 4 µg kg1 in 100 ml of normal saline and Group M received 100 ml of normal saline. Both were given over 20 min when the surgeon started to close the abdomen at the end of the procedure. After surgery, patients in Group C received a bolus of morphine 1 mg and clonidine 20 µg with a 5 min lockout time and patients in Group M received a 1 mg morphine bolus, also with a 5 min lockout time. The PCA dose of clonidine was based on a 2 µg kg1 h1 infusion12 divided by seven (an audit was undertaken prior to commencing the study to assess the average number of PCA doses this group of patients needed in 1 h). Clonidine and morphine are physically and chemically compatible.13 Patients were studied for 36 h after surgery.
As soon as the patients were awake in the recovery room, their pain was assessed using a four-point verbal rating score (0, no pain; 1, mild pain; 2, moderate pain; 3, severe pain). If the pain score was 2 or above, a recovery nurse, who was unaware of the randomization, titrated morphine 2 mg at 5-min intervals until the pain score was below 2. The PCA device, containing the appropriate study drug, was then connected to the i.v. infusion. Patients were assessed at 12, 24 and 36 h after surgery and asked to score their worst pain since the previous assessment. These scores were all on movement in the bed. Morphine consumption at these times was recorded.
After surgery, sedation was assessed on a four-point scale (0, awake and alert; 1, drowsy; 2, mostly sleeping; 3, difficult or impossible to awaken). Sedation scores were recorded 12, 24 and 36 h after surgery.
The presence of nausea and vomiting was noted using a four-point scale (0, no nausea or vomiting; 1, mild nausea; 2, severe nausea; 3, retching or vomiting), with all incidents being noted on the data collection sheet as they occurred. Patients with a nausea score of 2 or 3 were given cyclizine 50 mg intravenously and odansetron 4 mg if this was unsuccessful. The number of patients who vomited and the severity of any episode in each 12 h time period were recorded. After 36 h patients were asked to score their level of satisfaction with their postoperative pain relief up to that time on a four-point scale (1, totally dissatisfied; 2, moderately dissatisfied; 3, reasonably satisfied; 4, totally satisfied with pain relief).
The power calculation for the study was based on morphine consumption between 12 and 24 h after surgery. A retrospective survey of morphine consumption in patients undergoing hysterectomy revealed a mean of 30 (SD 12) mg morphine between 12 and 24 h after surgery. Using Altmans Nomogram this gives a standardized difference of 0.83. To demonstrate a 30% decrease in morphine consumption between 12 and 24 h after surgery, 60 patients would be needed for a study with a power of 0.8 to show a significant difference at the P<0.05 level.
The patients were randomized by computer. Blinding was carried out by a doctor, not involved in the data collection, who made up syringes containing morphine with or without clonidine such that they appeared identical. Morphine consumption was analysed using Students unpaired t-test. The MannWhitney U test was used for pain, sedation and nausea and vomiting scores and 2 analysis was used for the number of patients who experienced nausea or vomiting. A probability level of <0.05 was considered to be statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The improved analgesia was not sustained past the first 12 h after surgery in this study. This may well have been because plasma clonidine concentrations were not sustained by the parameters set for the PCA device. Indeed, the enhanced analgesic effect may have been achieved by the clonidine loading dose alone. Future studies examining the use of clonidine analgesia after the first 12 h after surgery would probably benefit from measuring plasma clonidine concentrations.
The use of perioperative clonidine in this study significantly decreased nausea and vomiting in a group of patients at high risk of experiencing this problem. Nausea and vomiting is a major problem after surgery, affecting up to 75% of patients, depending on their age and the type of procedure carried out.14 The reduction in nausea and vomiting associated with clonidine has been reported previously.5 10 11 Clonidine has also been used to treat nausea and vomiting in a diabetic patient who had not responded to conventional treatment.15 In addition, it is known that patients undergoing chemotherapy experience anticipatory nausea and vomiting. This is thought to be due to noradrenergic activity. There have been pilot studies to look at this and, although differences were seen, further studies were thought to be needed.16 Anticipatory nausea and vomiting may also be a problem perioperatively, as many patients worry about feeling sick after their operation, especially if they have had the problem before. Again, it has been suggested that noradrenergic activity may be responsible for these symptoms. Plasma 3-methyl-4-hydroxyphenlglycol, a metabolite of norepinephrine, is elevated during anxiety. Clonidine, acting at presynaptic 2 adrenoreceptors, reduces noradrenergic activity17 and this may account for its effects on nausea and vomiting. Clonidine also has sedative effects. These are thought to be mediated by
2 adrenoreceptors in the locus coeruleus17 and it may be a combination of decreased norepinephrine activity and sedation that causes the antiemetic effect, particularly as midazolam and subhypnotic doses of propofol have a similar effect.18 The use of clonidine in a PCA may represent a strategy for dealing with a patient who states a history of previous severe nausea (with or without vomiting) that was resistant to treatment.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Bernard J-M, Hommeril J-L, Passuti N, Pinaud M. Postoperative analgesia by intravenous clonidine. Anesthesiology 1991; 75: 57782[ISI][Medline]
3 Lyons B, Casey W, Doherty P, McHugh M, Moore KP. Pain relief with low-dose intravenous clonidine in a child with severe burns. Intensive Care Med 1996; 22: 24951[ISI][Medline]
4 Benhamou D, Narchi P, Hamza J, Marx M, Peyrol M-T, Sembeil F. Addition of oral clonidine to postoperative patient-controlled analgesia with i.v. morphine. Br J Anaesth 1994; 72: 53740[Abstract]
5 Park J, Forrest J, Kolesar R, Bhola D, Beattie S, Chu C. Oral clonidine reduces postoperative PCA morphine requirements. Can J Anaesth 1996; 43: 9006[Abstract]
6 Flacke JW, Bloor BC, Flacke WE, et al. Reduced narcotic requirement by clonidine with improved hemodynamic and adrenergic stability in patients undergoing coronary bypass surgery. Anesthesiology 1987; 67: 119[ISI][Medline]
7 Bernard J-M, Kick O, Bonnet F. Comparison of intravenous and epidural clonidine for postoperative patient-controlled analgesia. Anesth Analg 1995; 81: 70612[Abstract]
8 Davies DS, Wing LMH, Reid JL, et al. Pharmacokinetics and concentration-effect relationships of intravenous and oral clonidine. Clin Pharmacol Ther 1977; 21: 593601[ISI][Medline]
9 Lehman KA. Patient controlled analgesia: An efficient therapeutic tool in the postoperative setting. Eur Surg Res 1999; 31: 11221[ISI][Medline]
10 Mikawa K, Nishina K, Maekawa N, Asano M, Obara H. Oral clonidine premedication reduces vomiting in children after strabismus surgery. Can J Anaesth 1995; 42: 97781[Abstract]
11 Kobayashi N, Ishii S. Effectiveness of clonidine in postoperative nausea and vomiting epidural versus oral administration. Masui 1997; 46: 53842[Medline]
12 Ryszard J, Zochawski, Wojciech Lada. Intravenous clonidine treatment in acute myocardial infarction (comparison to a nitroglycerin-treated and control group). J Cardiovasc Pharmacol 1986; 8 (suppl 3): S415
13 Christi JM, Jones CW, Markowsky SJ. Chemical compatibility of regional anesthetic drug combinations. Ann Pharmacother 1992; 26: 107880[Abstract]
14 Lerman J. Surgical and patient factors involved in postoperative nausea and vomiting. Br J Anaesth 1992; 69: 24S32S[Medline]
15 Soergel KH, Greenburger NJ. Nausea and vomiting in the diabetic patient. Hosp Pract 1998; 33: 4362
16 Fetting JH, Sheidler VR, Stefanek ME, Enterline JP. Clonidine for anticipatory nausea and vomiting: a pilot study. Cancer treat rep 1987; 71: 40910[ISI][Medline]
17 Bloor BC. General pharmacology of 2-adrenoreceptors. Anaesth Pharmacol Rev 1993; 1: 22132
18 Hvarfner A, Hammas B, Thorn SE, Wattwil M. The influence of propofol on vomiting induced by apomorphine. Anesth Analg 1995; 80: 9679[Abstract]