Comparison of morphine alone with morphine plus clonidine for postoperative patient-controlled analgesia

S. A. Jeffs*,1, J. E. Hall1 and S. Morris2

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
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Clonidine is an {alpha}2 adrenergic agonist with analgesic properties. This study aimed to see if the addition of clonidine to morphine when given by patient-controlled analgesia (PCA) would improve analgesia beyond the first 12 h after surgery.

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 kg–1 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 24–36 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: 424–7

Keywords: agonists, adrenergic; analgesia, patient-controlled; analgesics opioid, morphine; pharmacology, clonidine; pharmacology, morphine; vomiting, nausea, anaesthetic factors


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The morphine sparing effects of the {alpha}2-adrenoreceptor agonist, clonidine, have been well demonstrated at initial bolus doses of between 2 and 8 µg kg–1.17 Clonidine has been used successfully for supplementing analgesia intraoperatively,1 postoperatively2 and in intensive care,3 although most studies have looked either at its immediate effect or its effect during the first 12 h after surgery. Clonidine has largely been delivered either orally (as a premedication), or as an i.v. infusion.16 One study compared clonidine epidurally with patient-controlled analgesia (PCA) but as the sole analgesic medication.7 Oral and i.v. modes of delivery have potential problems for postoperative pain relief. The absorption of oral analgesic drugs is unpredictable in the perioperative period, especially after major surgery. In addition, it may not be desirable to give a bolus of a vasoactive drug in the immediate postoperative period. Intravenous infusions overcome the problem of bolus doses by being titratable (although this is more difficult with clonidine because of its long elimination half-life8), but this type of delivery needs greater nursing supervision, which may not be readily available on ordinary wards.

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
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
With local research ethics committee approval, 60 patients between the ages of 18 and 75 yr were recruited to a randomized double blind study. All patients were ASA grade I or II, undergoing major lower abdominal or gynaecological surgery. Patients were excluded if there was a history of hypertension, ischaemic heart disease or conduction disturbance, a history of depression or alcohol abuse, if they were taking antidepressants or ß-adrenoreceptor blockers, if they had impaired hepatic or renal function or a known sensitivity to opioids or clonidine.

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 kg–1, droperidol 1 mg, fentanyl 1 µg kg–1 and vecuronium 0.1 mg kg–1. Anaesthesia was maintained by 1–2% isoflurane in nitrous oxide and oxygen (ratio 2:1). Further boluses of fentanyl 1 µg kg–1 were given intraoperatively, up to a maximum of 4 µg kg–1, at the anaesthetist’s 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 kg–1 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 kg–1 h–1 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 Altman’s 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 Student’s unpaired t-test. The Mann–Whitney U test was used for pain, sedation and nausea and vomiting scores and {chi}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
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
There were no differences with respect to patient characteristics of the two groups (Table 1). Many more females than males were recruited as many were undergoing total abdominal hysterectomy. In the clonidine and morphine only groups, there were 23 patients having a gynaecological procedure, two female patients and five male patients undergoing a general surgical procedure. There was no difference in the dose of intraoperative fentanyl used between the two groups (Table 1). All patients were monitored fully throughout the study. No patients were withdrawn due to cardiovascular instability, and nor did any patient require intervention as a result of cardiovascular problems.


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Table 1 Patient characteristics and intraoperative fentanyl consumption (mean (SD or range) or ratio)
 
Pain scores were measured on movement in the bed and the worst score in the time period recorded. These were significantly lower in the first 12 h in Group C (Table 2), but thereafter there were no differences. The doses of morphine used by the two groups can be seen in Table 2. For the first 24 h, morphine consumption in the clonidine group was only marginally reduced and the reduction in consumption only achieved statistical significance during the final 12 h of the study. The incidence of postoperative nausea and vomiting was significantly reduced in Group C during the first 24 h (Table 3), although the severity scores were unchanged. There were no differences in the sedation scores between the two groups (Table 3). Patients’ satisfaction scores were significantly higher in Group C (median 4 (range 2–4), compared with 3 (1–4) in Group M; P<0.05).


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Table 2 Pain scores (median (range)) and morphine consumption and (mean (SD)) in each 12-h period. *P<0.05
 

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Table 3 Incidence and severity of nausea and vomiting, and sedation scores (median (range)) in each 12-h period. *P<0.05
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this study, the perioperative use of clonidine in addition to morphine produced improved analgesia during the first 12 h after major surgery. However, there was no improvement after this time. There was no significant reduction in the amount of morphine consumed. The combination of morphine and clonidine were associated with a reduction in postoperative nausea and vomiting, the effects of which were seen for 24 h after surgery. Presumably the combination of improved early pain relief and reduced nausea and vomiting in Group C led to the increased patient satisfaction in this group.

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 {alpha}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 {alpha}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
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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