British journal of Anaesthesia 1992; 68: 132-135
EXTRADURAL CLONIDINE AND BUPIVACAINE FOR POSTOPERATIVE ANALGESIA U. A. CARABINE, K. R. MILLIGAN AND J. MOORE
SUMMARY
KEY WORDS Analgesia: postoperative. Anaesthetic techniques: extradural. Anaesthetics, local: bupivacaine. Sympathetic nervous system, pharmacology: clonidine.
Since the discovery of an adrenergic pain modulating system in the spinal cord [1], the extradural analgesic potential of the alpha2 adrenergic agonists has been the focus of interest [2] as an alternative to opioids which, despite the risk of respiratory depression [3], are currently used widely in the management of severe pain. Clonidine, a partial alpha., adrenergic agonist, has been shown to produce analgesia of variable duration and intensity [4, 5], in both acute and chronic pain. It may also potentiate the effects of opioids [6] and local anaesthetic agents [7]. The main side effects of extradurally administered clonidine are hypotension and sedation [8]. Hypotension is rarely severe and is easily treated. Local anaesthetic agents also produce hypotension associated with sympathetic block [9]. The aim of this study was to compare the effects of extradurally administered clonidine with those of extradural bupivacaine, with particular emphasis on postoperative pain relief and haemodynamic state. In order to assess possible potentiation of analgesia, a combination of bupivacaine and clonidine was studied also. The dose of extradural clonidine was 150 ug, as this has been shown to produce analgesia [10]. The concentration of bupivacaine was chosen in an attempt to minimize sensory and motor block. PATIENTS AND METHODS
After Ethics Committee approval, we studied 95 ASA I or II patients aged 30-75 yr, undergoing total hip replacement under general anaesthesia. All patients gave informed consent to the study. Patients
U. A. CARABINE*, M.B., F.F.A.R.C.S.I.; K. R. MILLIGAN, M.D., F.F.A.R.C.S.I.; J. MOORE, M.D., PH.D., F.C.ANAES. ; Department of
Anaesthetics, The Queen's University and Musgrave Park Hospital, Belfast. Accepted for Publication: August 12, 1991. * Address for correspondence: Department of Clinical Anaesthesia, The Royal Victoria Hospital, Grosvenor Road, Belfast.
Downloaded from http://bja.oxfordjournals.org/ at University of Birmingham on June 8, 2015
We have assessed the use of clonidine and bupivacaine for postoperative analgesia. Both drugs were administered via the extradural route, and were given both alone and in combination. The analgesia produced by clonidine was superior to that of bupivacaine; a combination of the drugs resulted in significantly better and longer duration of analgesia than each drug administered alone. Cardiovascular changes and the incidence of side effects were similar in all three groups. The sedative effects of clonidine were not marked.
receiving medication other than oral analgesics were excluded, as were those for whom there were any contraindications to extradural block. All patients were premedicated with temazepam 20 mg 60-90 min before operation. In the anaesthetic room, a vein was cannulated and a pulse oximetry probe attached. Heart rate and arterial pressure were monitored using a Hewlett-Packard 78554A monitor. Before induction of anaesthesia, an extradural catheter was sited at Ll-2 or L2-3 using an aseptic technique with a standard 16-gauge Portex extradural minipack. In order to detect accidental intrathecal insertion of the catheter, 1.5% plain lignocaine 3 ml was administered down the catheter and sensation tested with ice to exclude a subarachnoid block. Subsequently, standard general anaesthesia was administered, with thiopentone 4 mg kg"1 and fentanyl l.Sugkg" 1 , vecuronium O.lmgkg"1, and 1-1.5% isoflurane with 65 % nitrous oxide in oxygen and intermittent positive pressure ventilation to maintain normocapnia. After insertion of the femoral component of the hip joint (approximately 30 min before the end of surgery), patients were allocated randomly to receive one of three treatments: clonidine 150 jxg (lml) diluted to 10 ml in 0.9% saline, 0.25% plain bupivacaine 10 ml or clonidine 150 |ig (lml) in 0.25 % bupivacaine 9 ml. At the end of the procedure, residual neuromuscular block was antagonized and the patient allowed to wake up quietly. After operation, arterial pressure and heart rate were recorded routinely at 10-min intervals for the first 1 h, and thereafter at 1-h intervals for 12 h. Systolic pressure of less than 85 mm Hg was treated with ephedrine 5 mg initially, and subsequent doses of 5 mg if required, to maintain arterial pressure in excess of 90 mm Hg. Heart rate less than 45 beat min"1 was treated with atropine in increments of 0.3 mg to achieve a rate of greater than 50 beat min"1. Blood loss was estimated by weighing of swabs and measurement of suction loss during the perioperative period, and replaced promptly with blood or plasma expanders as required.
EXTRADURAL CLONIDINE AND BUPIVACAINE
during the course of the anaesthetic. Immediately before the administration of the extradural drug, MAP was significantly less than the preinduction value in all groups, and remained significantly less in the postoperative period. MAP decreased in all the groups within 30-60 min of administration of the extradural drug, although the differences were not significant between the groups or compared with the preinjection value. Three patients in each of the bupivacaine and combination groups required active intervention to restore arterial pressure. The changes in heart rate were less marked, and the differences after administration of the extradural drug were not significantly different from baseline values. There were two patients in the combination and bupivacaine groups who received atropine for a heart rate less than 45 beat min"1 (table II). Sedation in the immediate recovery period was similar in all three groups. Twelve patients in each of the bupivacaine and combination groups and 13 in the clonidine group were assessed as drowsy 30 min after operation. One hour after operation, four, three and six patients in the combination, bupivacaine and clonidine groups, respectively, were considered drowsy (not significant). To ensure that pain assessment was carried out for all patients, even if they were too sedated to complete a VAS, both subjective and objective assessments were used. However, during the study, there were no patients who were unable to complete the VAS score satisfactorily. For observer assessment, there were no significant differences between groups at 15 and 30 min after operation. By 45 min, although both clonidine groups had lower pain scores than the bupivacaine group, this did not become statistically significant until 60 min, when the numbers of patients being assessed as having either no pain or mild pain were 29, 27 and 20 in the combination, clonidine and bupivacaine groups, respectively (P < TABLE I. Patient characteristics (mean (range or SD))
Age (yr) Weight (kg) Height (cm) Sex (M:F) Duration of surgery (min)
Clonidine group
Bupivacaine group
Combination group
62 (32-75) 70 (12) 159(10) 12:18 90 (20)
65 (30-74) 71 (13) 160 (9) 13:17 88 (14)
66 (31-75) 72(11) 159(11) 11:19 88 (17)
RESULTS
Results from 90 patients were analysed. Five patients were excluded from the study, two as a result of accidental removal of the catheter and three because of technical failure of the infusion pump; their randomization numbers were re-allocated. Patients were allocated equally to three groups. There was no difference between the groups in age, weight, height and preoperative cardiovascular measurements. The male to female ratios were similar in the three groups (table I). The intraoperative changes in mean arterial pressure (MAP) and heart rate were similar in all three groups, and there was a tendency for both to decrease
TABLE II. Haemodynamic data (mean (SEM))
MAP (mm Hg) Before induction Max. decrease Vasoconstrictor —(No-patients) HR (beat min"1) Before induction Max. decrease Atropine (No. patients)
Clonidine group
Bupivacaine group
Combination group
91(2) 19(4)
92(2) 20(3)
88(2) 20(3)
0
3
3
.. 73(2) 6(2) 0
73(2) 5(2) 2
73(2) 9(3) 2
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All the assessments of sedation and pain were made by one of two trained nurse observers who were unaware of the nature of the extradural injection. In the recovery ward, sedation was assessed on a three-point scale (awake, drowsy or asleep) at 15-min intervals for 1 h. Pain was assessed at 15-min intervals for 1 h by one of the trained nurse observers using a four-point scale (no pain, mild, moderate or severe pain). After objective assessment at 30 and 60 min, patients completed a 100-mm visual analogue scale (VAS) for pain, with no pain at one extreme and worst possible pain at the other. The duration of analgesia was measured from the time of extradural administration of the test drug during operation to the time of first request for analgesia. At this point, pain was assessed by both the observer and the patient. When analgesia was requested, a low-dose background extradural infusion of morphine was commenced at a rate of 0.1 mg h"1. The first request for analgesia was treated with systemic morphine administered i.v. in 1-mg increments until pain was controlled adequately. Further requests for analgesia were treated with morphine 5 mg i.m. and repeated as required. Analgesia was administered by nurses who were unaware of the nature of the study drug. The total morphine requirements for the initial 12 h after operation were recorded. The level of postoperative sensory block was assessed using ice. Motor impairment was assessed using the Bromage scale [11]. The times from administration of the extradural test drug to the return of full sensation and motor function were noted. Ventilatory frequency was recorded every 30 min during the study. Tissue oxygen saturation was monitored during the first 12 h after operation. The incidence of emetic symptoms and urinary retention requiring catheterization was noted during the first 12 h after operation. Results are presented as mean (SEM) for parametric data, and median and range for non-parametric data. Mean arterial pressure was calculated using the formula: diastolic arterial pressure plus one-third of the pulse pressure. Statistical analysis was by repeated measures analysis of variance (ANOVA), Student's t test, Mann-Whitney U test and chi square. Statistical significance was assumed at P < 0.05.
133
BRITISH JOURNAL OF ANAESTHESIA
134 TABLE III. Postoperative analgesia {mean (SEM) [range]). P < 0.05: * compared with bupivacaine group ; \ compared with clonidine group
Clonidine group VAS (mm) 30min 60 min Duration of analgesia (min) Morphine (mg) Extradural I.v. I.m. Total i.v. + i.m. None i.v. or i.m. (No. patients)
Bupivacaine group
clonidine group and four in the combination group reported a dry mouth in the early postoperative period. No other complications were noted.
Combination group DISCUSSION
20 [0-75] 20 [0-75]* 179(17)* [40-455]
24 [0-85] 36 [0-92] 122 (10) [30-255]
15 [0-72]* 9 [0-80]*t 257 (25)*f [30-690]
1.2
1.2
1.2
0.5 [0-5]* 5[0-16]* 6[0-16]*
2.2 [0-10] 8[0-24] 10 [0-27]
0.2 [0-5]* 4 [0-16]* 4[0-16]*
12*
3
15*
While extradural administration of opioids is associated with respiratory depression [3], clonidine administered via this route did not appear to have a marked effect on ventilation. Despite the tendency for extradural clonidine to produce hypotension [17], the changes observed in our study were comparable to those induced by bupivacaine. The fluid balance was similar in all three groups, and with active replacement of perioperative blood loss, the haemodynamic changes were likely to reflect the cardiovascular effects of the drugs. Although arterial pressure was less in the combination group in the
Downloaded from http://bja.oxfordjournals.org/ at University of Birmingham on June 8, 2015
0.05). On subjective assessment of pain, both the clonidine and the combination groups had significantly lower VAS scores than the bupivacaine group by 60 min and the combination had lower scores than the clonidine group (P < 0.05) (table III). At the time of first request for analgesia, there was a wide variation in the VAS scores recorded in all groups, but the differences between groups were not significant. The duration of analgesia was prolonged significantly in both the clonidine groups compared with the bupivacaine group (P < 0.05), and the combination of clonidine and bupivacaine produced a significantly longer period of analgesia compared with clonidine alone (P < 0.05) (table III). The background extradural morphine administered was similar in all the groups. However, the systemic requirements were significantly less in both the clonidine groups compared with the bupivacaine group (P < 0.05). The differences between the clonidine and combination groups were not significant. In addition, 15 patients in the combination and 12 in the clonidine groups required no supplementary systemic analgesia, compared with three patients in the bupivacaine group (table III). The incidence of urinary retention was similar in all three groups, nine patients in the clonidine group requiring catheterization compared with 12 in the bupivacaine and seven in the combination groups. There was no significant difference in the incidence of nausea and vomiting. Clonidine administered alone was not associated with either sensory or motor impairment. There was no significant prolongation of either sensory and motor block by the addition of clonidine to bupivacaine, and the maximum height and intensity of block were similar in both the bupivacaine groups. There were no significant differences between the groups with respect to either blood loss (mean (SEM) : bupivacaine 1570 (101) ml, clonidine 1576 (100) ml, combination 1383 (91) ml) or fluid replacement (bupivacaine 2988 (191) ml, clonidine 2770 (114) ml, combination 2591 (130) ml). Tissue oxygen saturation did not decrease to less than 90% during the study and no patient had a recorded ventilatory frequency of less than 10 b.p.m. One patient developed ventricular ectopic beats 30 min after extradural injection of bupivacaine; this responded to i.v. lignocaine. Five patients in the
This study has demonstrated that the analgesia produced by a bolus extradural dose of clonidine was superior to that produced by bupivacaine, and that by combining the drugs the duration of analgesia was prolonged significantly. Clonidine has been shown to prolong the sensory and motor block associated with intrathecally administered bupivacaine [17]. Our results indicate that clonidine prolonged the analgesia produced by bupivacaine, although there was no evidence of significant prolongation of sensory and motor block, which may be attributable to the relatively low dose of bupivacaine used. There is speculation on the interactions between clonidine and other analgesic agents. Clonidine has powerful vasoconstrictor properties and may reduce spinal cord blood flow [13], and initially this was thought to be the mechanism by which the effects of local anaesthetics were prolonged. However, vasoconstriction is unlikely to be the only explanation, as stimulation of the adrenergic mechanism in the spinal cord has greater effect on altering nociceptive thresholds than even the most powerful vasoconstrictors [14]. Despite the effects on spinal cord blood flow, there is no evidence of neuronal damage after extradural administration of clonidine [15]. Initially, it was thought that the mechanism of interaction with agents such as opioids was by crossreactivity at receptor level. It is now recognized that the two systems are separate [16]. Alpha2 adrenoceptors are located in the dorsal horn neurones of the spinal cord and local effects may include inhibition of the release of nociceptive neurotransmitters such as substance P. Alpha2 receptors occur also in many parts of the brain, including the locus coerulus, and play a role in modulating the descending pathways involved in nociceptive transmission. In an attempt to detect potentiation between morphine and clonidine, the rate of infusion of extradural morphine was deliberately slow and a loading dose was not given. The dose of extradural morphine used was based on the results from a pilot study. Although definite potentiation is difficult to demonstrate, patients receiving clonidine had significantly lesser requirements for analgesia in the postoperative period and a significantly larger number of patients requiring no systemic analgesia compared with the bupivacaine group.
EXTRADURAL CLONIDINE AND BUPIVACAINE
REFERENCES 1. Yaksh TL. Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacology and Biochemistry of Behaviour 1984; 22: 845-858. 2. Maze M, Segal I, Bloor B. Clonidine and other alpha 2 adrenergic agonists: strategies for the rational use of these novel anesthetic agents. Journal of Clinical Anesthesia 1988; 1: 146-157. 3. Rawal N, Arner S, Gustafsson LL, Allvin R. Present state of extradural and intrathecal opioid analgesia in Sweden. British Journal of Anaesthesia 1987; 59: 791-799. 4. Bonnet F, Boico O, Rostaing S, Saada M, Loriferne JF, Touboul C, Abhay K, Ghignone M. Postoperative analgesia with extradural clonidine. British Journal of Anaesthesia 1989; 63: 465-^69. 5. Kalia PK, Madan R, Batra RK, Latha V, Vardhan V, Gode GR. Clinical study on epidural clonidine for postoperative analgesia. Indian Journal of Medical Research 1986; 83: 550-552.
6. Vercauteren M, Lauwers E, Meert T, De Hert S, Adriaensen H. Comparison of epidural sufentanil plus clonidine with sufentanil alone for postoperative pain relief. Anaesthesia 1990; 45: 531-534. 7. Racle JP, Benkhadra A, Poy JY, Gleizal B. Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesthesia and Analgesia 1987; 66: 442-446. 8. Reid J. The clinical pharmacology of clonidine and related central antihypertensive agents. British Journal of Clinical Pharmacology 1981; 12: 206-302. 9. Howell P, Davies W, Wrigley M, Tan P, Morgan B. Comparison of four local extradural anaesthetic solutions for elective Caesarean section. British Journal of Anaesthesia 1990; 65: 648-653. 10. Van Essen EJ, Bovill GJ, Ploeger EJ, Schout BC. A comparison of epidural clonidine and morphine for postoperative analgesia. European Journal of Anaesthesiology 1990; 7: 211-218. 11. Bromage PR, Datta S, Dunford LA. Etidocaine: An evaluation of epidural analgesia for obstetrics. Canadian Anaesthetists Society Journal 1974; 21: 535-545. 12. Bonnet F, Brun Buisson V, Francois Y, Catoire P, Saada M. Effects of oral and subarachnoid clonidine on spinal anaesthesia with bupivacaine. Regional Anaesthesia 1990; 15: 211-214. 13. Gordh T, Feuk U, Norlen K. Effect of epidural clonidine on spinal cord bloodflowand regional and central hemodynamics in pigs. Anesthesia and Analgesia 1986; 65: 1312-1318. 14. Reddy SVR, Maderdrut L, Yaksh TL. Spinal cord pharmacology of adrenergic agonist-mediated antinociception. Journal of Pharmacology and Experimental Therapeutics 1980; 213:525-533. 15. Gordh T, Post C, Olsson Y. Evaluation of the toxicity of subarachnoid clonidine, guanfacine and a substance P antagonist on rat spinal cord and nerve roots. Anesthesia and Analgesia 1986; 65: 1303-1311. 16. Ossipov MH, Suarez LJ, Spaulding TC. Antinociceptive interactions between alpha., adrenergic and opiate agonists at the spinal level in rodents. Anesthesia and Analgesia 1989; 68: 194-200. 17. Lund C, Qvitzau S, Greulich A, Hjortso NC, Kehlet H. Comparison of the effects of extradural clonidine with those of morphine on postoperative pain, stress response, cardiopulmonary function and motor and sensory block. British Journal of Anaesthesia 1989; 63: 516-519.
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postoperative period, this was not clinically significant and may be attributable to either the central effects of clonidine on sympathetic outflow, or may simply reflect improved analgesia. Patients with a history of urinary symptoms were not excluded from the study and other factors may have contributed to the incidence of urine retention requiring catheterization. However, there was no difference in the incidence of urinary catheterization among the groups and" the use of clonidine in this study did not appear to result in an increased incidence of catheterization. In conclusion, the analgesic effect of extradural clonidine and its prolongation of the analgesic effects of bupivacaine with minimal sensory and motor effects, combined with an absence of ventilatory effects makes clonidine a potentially useful drug for postoperative pain management. Despite the decreased arterial pressure in the combination group, there were no marked contraindications to the administration of clonidine by this route.
135
EXTRADURAL CLONIDINE AND BUPIVACAINE FOR POSTOPERATIVE ANALGESIA U. A. CARABINE, K. R. MILLIGAN AND J. MOORE
SUMMARY
KEY WORDS Analgesia: postoperative. Anaesthetic techniques: extradural. Anaesthetics, local: bupivacaine. Sympathetic nervous system, pharmacology: clonidine.
Since the discovery of an adrenergic pain modulating system in the spinal cord [1], the extradural analgesic potential of the alpha2 adrenergic agonists has been the focus of interest [2] as an alternative to opioids which, despite the risk of respiratory depression [3], are currently used widely in the management of severe pain. Clonidine, a partial alpha., adrenergic agonist, has been shown to produce analgesia of variable duration and intensity [4, 5], in both acute and chronic pain. It may also potentiate the effects of opioids [6] and local anaesthetic agents [7]. The main side effects of extradurally administered clonidine are hypotension and sedation [8]. Hypotension is rarely severe and is easily treated. Local anaesthetic agents also produce hypotension associated with sympathetic block [9]. The aim of this study was to compare the effects of extradurally administered clonidine with those of extradural bupivacaine, with particular emphasis on postoperative pain relief and haemodynamic state. In order to assess possible potentiation of analgesia, a combination of bupivacaine and clonidine was studied also. The dose of extradural clonidine was 150 ug, as this has been shown to produce analgesia [10]. The concentration of bupivacaine was chosen in an attempt to minimize sensory and motor block. PATIENTS AND METHODS
After Ethics Committee approval, we studied 95 ASA I or II patients aged 30-75 yr, undergoing total hip replacement under general anaesthesia. All patients gave informed consent to the study. Patients
U. A. CARABINE*, M.B., F.F.A.R.C.S.I.; K. R. MILLIGAN, M.D., F.F.A.R.C.S.I.; J. MOORE, M.D., PH.D., F.C.ANAES. ; Department of
Anaesthetics, The Queen's University and Musgrave Park Hospital, Belfast. Accepted for Publication: August 12, 1991. * Address for correspondence: Department of Clinical Anaesthesia, The Royal Victoria Hospital, Grosvenor Road, Belfast.
Downloaded from http://bja.oxfordjournals.org/ at University of Birmingham on June 8, 2015
We have assessed the use of clonidine and bupivacaine for postoperative analgesia. Both drugs were administered via the extradural route, and were given both alone and in combination. The analgesia produced by clonidine was superior to that of bupivacaine; a combination of the drugs resulted in significantly better and longer duration of analgesia than each drug administered alone. Cardiovascular changes and the incidence of side effects were similar in all three groups. The sedative effects of clonidine were not marked.
receiving medication other than oral analgesics were excluded, as were those for whom there were any contraindications to extradural block. All patients were premedicated with temazepam 20 mg 60-90 min before operation. In the anaesthetic room, a vein was cannulated and a pulse oximetry probe attached. Heart rate and arterial pressure were monitored using a Hewlett-Packard 78554A monitor. Before induction of anaesthesia, an extradural catheter was sited at Ll-2 or L2-3 using an aseptic technique with a standard 16-gauge Portex extradural minipack. In order to detect accidental intrathecal insertion of the catheter, 1.5% plain lignocaine 3 ml was administered down the catheter and sensation tested with ice to exclude a subarachnoid block. Subsequently, standard general anaesthesia was administered, with thiopentone 4 mg kg"1 and fentanyl l.Sugkg" 1 , vecuronium O.lmgkg"1, and 1-1.5% isoflurane with 65 % nitrous oxide in oxygen and intermittent positive pressure ventilation to maintain normocapnia. After insertion of the femoral component of the hip joint (approximately 30 min before the end of surgery), patients were allocated randomly to receive one of three treatments: clonidine 150 jxg (lml) diluted to 10 ml in 0.9% saline, 0.25% plain bupivacaine 10 ml or clonidine 150 |ig (lml) in 0.25 % bupivacaine 9 ml. At the end of the procedure, residual neuromuscular block was antagonized and the patient allowed to wake up quietly. After operation, arterial pressure and heart rate were recorded routinely at 10-min intervals for the first 1 h, and thereafter at 1-h intervals for 12 h. Systolic pressure of less than 85 mm Hg was treated with ephedrine 5 mg initially, and subsequent doses of 5 mg if required, to maintain arterial pressure in excess of 90 mm Hg. Heart rate less than 45 beat min"1 was treated with atropine in increments of 0.3 mg to achieve a rate of greater than 50 beat min"1. Blood loss was estimated by weighing of swabs and measurement of suction loss during the perioperative period, and replaced promptly with blood or plasma expanders as required.
EXTRADURAL CLONIDINE AND BUPIVACAINE
during the course of the anaesthetic. Immediately before the administration of the extradural drug, MAP was significantly less than the preinduction value in all groups, and remained significantly less in the postoperative period. MAP decreased in all the groups within 30-60 min of administration of the extradural drug, although the differences were not significant between the groups or compared with the preinjection value. Three patients in each of the bupivacaine and combination groups required active intervention to restore arterial pressure. The changes in heart rate were less marked, and the differences after administration of the extradural drug were not significantly different from baseline values. There were two patients in the combination and bupivacaine groups who received atropine for a heart rate less than 45 beat min"1 (table II). Sedation in the immediate recovery period was similar in all three groups. Twelve patients in each of the bupivacaine and combination groups and 13 in the clonidine group were assessed as drowsy 30 min after operation. One hour after operation, four, three and six patients in the combination, bupivacaine and clonidine groups, respectively, were considered drowsy (not significant). To ensure that pain assessment was carried out for all patients, even if they were too sedated to complete a VAS, both subjective and objective assessments were used. However, during the study, there were no patients who were unable to complete the VAS score satisfactorily. For observer assessment, there were no significant differences between groups at 15 and 30 min after operation. By 45 min, although both clonidine groups had lower pain scores than the bupivacaine group, this did not become statistically significant until 60 min, when the numbers of patients being assessed as having either no pain or mild pain were 29, 27 and 20 in the combination, clonidine and bupivacaine groups, respectively (P < TABLE I. Patient characteristics (mean (range or SD))
Age (yr) Weight (kg) Height (cm) Sex (M:F) Duration of surgery (min)
Clonidine group
Bupivacaine group
Combination group
62 (32-75) 70 (12) 159(10) 12:18 90 (20)
65 (30-74) 71 (13) 160 (9) 13:17 88 (14)
66 (31-75) 72(11) 159(11) 11:19 88 (17)
RESULTS
Results from 90 patients were analysed. Five patients were excluded from the study, two as a result of accidental removal of the catheter and three because of technical failure of the infusion pump; their randomization numbers were re-allocated. Patients were allocated equally to three groups. There was no difference between the groups in age, weight, height and preoperative cardiovascular measurements. The male to female ratios were similar in the three groups (table I). The intraoperative changes in mean arterial pressure (MAP) and heart rate were similar in all three groups, and there was a tendency for both to decrease
TABLE II. Haemodynamic data (mean (SEM))
MAP (mm Hg) Before induction Max. decrease Vasoconstrictor —(No-patients) HR (beat min"1) Before induction Max. decrease Atropine (No. patients)
Clonidine group
Bupivacaine group
Combination group
91(2) 19(4)
92(2) 20(3)
88(2) 20(3)
0
3
3
.. 73(2) 6(2) 0
73(2) 5(2) 2
73(2) 9(3) 2
Downloaded from http://bja.oxfordjournals.org/ at University of Birmingham on June 8, 2015
All the assessments of sedation and pain were made by one of two trained nurse observers who were unaware of the nature of the extradural injection. In the recovery ward, sedation was assessed on a three-point scale (awake, drowsy or asleep) at 15-min intervals for 1 h. Pain was assessed at 15-min intervals for 1 h by one of the trained nurse observers using a four-point scale (no pain, mild, moderate or severe pain). After objective assessment at 30 and 60 min, patients completed a 100-mm visual analogue scale (VAS) for pain, with no pain at one extreme and worst possible pain at the other. The duration of analgesia was measured from the time of extradural administration of the test drug during operation to the time of first request for analgesia. At this point, pain was assessed by both the observer and the patient. When analgesia was requested, a low-dose background extradural infusion of morphine was commenced at a rate of 0.1 mg h"1. The first request for analgesia was treated with systemic morphine administered i.v. in 1-mg increments until pain was controlled adequately. Further requests for analgesia were treated with morphine 5 mg i.m. and repeated as required. Analgesia was administered by nurses who were unaware of the nature of the study drug. The total morphine requirements for the initial 12 h after operation were recorded. The level of postoperative sensory block was assessed using ice. Motor impairment was assessed using the Bromage scale [11]. The times from administration of the extradural test drug to the return of full sensation and motor function were noted. Ventilatory frequency was recorded every 30 min during the study. Tissue oxygen saturation was monitored during the first 12 h after operation. The incidence of emetic symptoms and urinary retention requiring catheterization was noted during the first 12 h after operation. Results are presented as mean (SEM) for parametric data, and median and range for non-parametric data. Mean arterial pressure was calculated using the formula: diastolic arterial pressure plus one-third of the pulse pressure. Statistical analysis was by repeated measures analysis of variance (ANOVA), Student's t test, Mann-Whitney U test and chi square. Statistical significance was assumed at P < 0.05.
133
BRITISH JOURNAL OF ANAESTHESIA
134 TABLE III. Postoperative analgesia {mean (SEM) [range]). P < 0.05: * compared with bupivacaine group ; \ compared with clonidine group
Clonidine group VAS (mm) 30min 60 min Duration of analgesia (min) Morphine (mg) Extradural I.v. I.m. Total i.v. + i.m. None i.v. or i.m. (No. patients)
Bupivacaine group
clonidine group and four in the combination group reported a dry mouth in the early postoperative period. No other complications were noted.
Combination group DISCUSSION
20 [0-75] 20 [0-75]* 179(17)* [40-455]
24 [0-85] 36 [0-92] 122 (10) [30-255]
15 [0-72]* 9 [0-80]*t 257 (25)*f [30-690]
1.2
1.2
1.2
0.5 [0-5]* 5[0-16]* 6[0-16]*
2.2 [0-10] 8[0-24] 10 [0-27]
0.2 [0-5]* 4 [0-16]* 4[0-16]*
12*
3
15*
While extradural administration of opioids is associated with respiratory depression [3], clonidine administered via this route did not appear to have a marked effect on ventilation. Despite the tendency for extradural clonidine to produce hypotension [17], the changes observed in our study were comparable to those induced by bupivacaine. The fluid balance was similar in all three groups, and with active replacement of perioperative blood loss, the haemodynamic changes were likely to reflect the cardiovascular effects of the drugs. Although arterial pressure was less in the combination group in the
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0.05). On subjective assessment of pain, both the clonidine and the combination groups had significantly lower VAS scores than the bupivacaine group by 60 min and the combination had lower scores than the clonidine group (P < 0.05) (table III). At the time of first request for analgesia, there was a wide variation in the VAS scores recorded in all groups, but the differences between groups were not significant. The duration of analgesia was prolonged significantly in both the clonidine groups compared with the bupivacaine group (P < 0.05), and the combination of clonidine and bupivacaine produced a significantly longer period of analgesia compared with clonidine alone (P < 0.05) (table III). The background extradural morphine administered was similar in all the groups. However, the systemic requirements were significantly less in both the clonidine groups compared with the bupivacaine group (P < 0.05). The differences between the clonidine and combination groups were not significant. In addition, 15 patients in the combination and 12 in the clonidine groups required no supplementary systemic analgesia, compared with three patients in the bupivacaine group (table III). The incidence of urinary retention was similar in all three groups, nine patients in the clonidine group requiring catheterization compared with 12 in the bupivacaine and seven in the combination groups. There was no significant difference in the incidence of nausea and vomiting. Clonidine administered alone was not associated with either sensory or motor impairment. There was no significant prolongation of either sensory and motor block by the addition of clonidine to bupivacaine, and the maximum height and intensity of block were similar in both the bupivacaine groups. There were no significant differences between the groups with respect to either blood loss (mean (SEM) : bupivacaine 1570 (101) ml, clonidine 1576 (100) ml, combination 1383 (91) ml) or fluid replacement (bupivacaine 2988 (191) ml, clonidine 2770 (114) ml, combination 2591 (130) ml). Tissue oxygen saturation did not decrease to less than 90% during the study and no patient had a recorded ventilatory frequency of less than 10 b.p.m. One patient developed ventricular ectopic beats 30 min after extradural injection of bupivacaine; this responded to i.v. lignocaine. Five patients in the
This study has demonstrated that the analgesia produced by a bolus extradural dose of clonidine was superior to that produced by bupivacaine, and that by combining the drugs the duration of analgesia was prolonged significantly. Clonidine has been shown to prolong the sensory and motor block associated with intrathecally administered bupivacaine [17]. Our results indicate that clonidine prolonged the analgesia produced by bupivacaine, although there was no evidence of significant prolongation of sensory and motor block, which may be attributable to the relatively low dose of bupivacaine used. There is speculation on the interactions between clonidine and other analgesic agents. Clonidine has powerful vasoconstrictor properties and may reduce spinal cord blood flow [13], and initially this was thought to be the mechanism by which the effects of local anaesthetics were prolonged. However, vasoconstriction is unlikely to be the only explanation, as stimulation of the adrenergic mechanism in the spinal cord has greater effect on altering nociceptive thresholds than even the most powerful vasoconstrictors [14]. Despite the effects on spinal cord blood flow, there is no evidence of neuronal damage after extradural administration of clonidine [15]. Initially, it was thought that the mechanism of interaction with agents such as opioids was by crossreactivity at receptor level. It is now recognized that the two systems are separate [16]. Alpha2 adrenoceptors are located in the dorsal horn neurones of the spinal cord and local effects may include inhibition of the release of nociceptive neurotransmitters such as substance P. Alpha2 receptors occur also in many parts of the brain, including the locus coerulus, and play a role in modulating the descending pathways involved in nociceptive transmission. In an attempt to detect potentiation between morphine and clonidine, the rate of infusion of extradural morphine was deliberately slow and a loading dose was not given. The dose of extradural morphine used was based on the results from a pilot study. Although definite potentiation is difficult to demonstrate, patients receiving clonidine had significantly lesser requirements for analgesia in the postoperative period and a significantly larger number of patients requiring no systemic analgesia compared with the bupivacaine group.
EXTRADURAL CLONIDINE AND BUPIVACAINE
REFERENCES 1. Yaksh TL. Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacology and Biochemistry of Behaviour 1984; 22: 845-858. 2. Maze M, Segal I, Bloor B. Clonidine and other alpha 2 adrenergic agonists: strategies for the rational use of these novel anesthetic agents. Journal of Clinical Anesthesia 1988; 1: 146-157. 3. Rawal N, Arner S, Gustafsson LL, Allvin R. Present state of extradural and intrathecal opioid analgesia in Sweden. British Journal of Anaesthesia 1987; 59: 791-799. 4. Bonnet F, Boico O, Rostaing S, Saada M, Loriferne JF, Touboul C, Abhay K, Ghignone M. Postoperative analgesia with extradural clonidine. British Journal of Anaesthesia 1989; 63: 465-^69. 5. Kalia PK, Madan R, Batra RK, Latha V, Vardhan V, Gode GR. Clinical study on epidural clonidine for postoperative analgesia. Indian Journal of Medical Research 1986; 83: 550-552.
6. Vercauteren M, Lauwers E, Meert T, De Hert S, Adriaensen H. Comparison of epidural sufentanil plus clonidine with sufentanil alone for postoperative pain relief. Anaesthesia 1990; 45: 531-534. 7. Racle JP, Benkhadra A, Poy JY, Gleizal B. Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesthesia and Analgesia 1987; 66: 442-446. 8. Reid J. The clinical pharmacology of clonidine and related central antihypertensive agents. British Journal of Clinical Pharmacology 1981; 12: 206-302. 9. Howell P, Davies W, Wrigley M, Tan P, Morgan B. Comparison of four local extradural anaesthetic solutions for elective Caesarean section. British Journal of Anaesthesia 1990; 65: 648-653. 10. Van Essen EJ, Bovill GJ, Ploeger EJ, Schout BC. A comparison of epidural clonidine and morphine for postoperative analgesia. European Journal of Anaesthesiology 1990; 7: 211-218. 11. Bromage PR, Datta S, Dunford LA. Etidocaine: An evaluation of epidural analgesia for obstetrics. Canadian Anaesthetists Society Journal 1974; 21: 535-545. 12. Bonnet F, Brun Buisson V, Francois Y, Catoire P, Saada M. Effects of oral and subarachnoid clonidine on spinal anaesthesia with bupivacaine. Regional Anaesthesia 1990; 15: 211-214. 13. Gordh T, Feuk U, Norlen K. Effect of epidural clonidine on spinal cord bloodflowand regional and central hemodynamics in pigs. Anesthesia and Analgesia 1986; 65: 1312-1318. 14. Reddy SVR, Maderdrut L, Yaksh TL. Spinal cord pharmacology of adrenergic agonist-mediated antinociception. Journal of Pharmacology and Experimental Therapeutics 1980; 213:525-533. 15. Gordh T, Post C, Olsson Y. Evaluation of the toxicity of subarachnoid clonidine, guanfacine and a substance P antagonist on rat spinal cord and nerve roots. Anesthesia and Analgesia 1986; 65: 1303-1311. 16. Ossipov MH, Suarez LJ, Spaulding TC. Antinociceptive interactions between alpha., adrenergic and opiate agonists at the spinal level in rodents. Anesthesia and Analgesia 1989; 68: 194-200. 17. Lund C, Qvitzau S, Greulich A, Hjortso NC, Kehlet H. Comparison of the effects of extradural clonidine with those of morphine on postoperative pain, stress response, cardiopulmonary function and motor and sensory block. British Journal of Anaesthesia 1989; 63: 516-519.
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postoperative period, this was not clinically significant and may be attributable to either the central effects of clonidine on sympathetic outflow, or may simply reflect improved analgesia. Patients with a history of urinary symptoms were not excluded from the study and other factors may have contributed to the incidence of urine retention requiring catheterization. However, there was no difference in the incidence of urinary catheterization among the groups and" the use of clonidine in this study did not appear to result in an increased incidence of catheterization. In conclusion, the analgesic effect of extradural clonidine and its prolongation of the analgesic effects of bupivacaine with minimal sensory and motor effects, combined with an absence of ventilatory effects makes clonidine a potentially useful drug for postoperative pain management. Despite the decreased arterial pressure in the combination group, there were no marked contraindications to the administration of clonidine by this route.
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