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Anesth Analg 2004;98:1460-1466 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000111208.08867.3C
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Abstract |
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In this randomized, double-blind trial in 240 women, we investigated the analgesic efficacy and duration of subarachnoid fentanyl 15 µg with morphine, clonidine, or both morphine and clonidine for cesarean delivery. A dose-finding analysis showed similar postoperative efficacy and side effects for groups receiving morphine 100 µg with clonidine 60, 90, or 150 µg. Data from these groups were combined (MC60–150, n = 113) and compared with groups receiving morphine 100 µg (n = 39), clonidine 150 µg (n = 39), or morphine 100 µg plus clonidine 30 µg (n = 41). The four groups differed in the time to patient-controlled morphine use and cumulative morphine consumption (P < 0.0001 and P < 0.001, respectively), with the longest duration and smallest dose in MC60–150. Pain scores were significantly different among groups. Onset of sensory block, ephedrine requirement and incidence of hypotension, patient satisfaction, and recovery were similar. Groups receiving clonidine had greater sedation, those receiving morphine had more severe pruritus, and group MC60–150 showed a trend to more vomiting intraoperatively. Compared with morphine 100 µg or clonidine 150 µg alone, the combination of subarachnoid morphine 100 µg and at least 60 µg of clonidine was found to increase the duration of postcesarean analgesia, reduce opioid requirement, and increase intraoperative sedation.
IMPLICATIONS: A multimodal approach to postcesarean analgesia, using subarachnoid bupivacaine, fentanyl, morphine 100 µg, and clonidine 60 µg, improves pain relief compared with morphine 100 µg or clonidine 150 µg alone, but increases intraoperative sedation and may increase perioperative vomiting.
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Introduction |
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Subarachnoid morphine provides safe, high-quality postcesarean analgesia of variable duration. Although pain relief may exceed 12–18 h, up to 25% of patients seek supplementary analgesics within 6–12 h of surgery (1–3). When patient-controlled IV analgesia (PCIA) is made available, many women self-administer opioids within the first few hours and 10%–20% have large requirements (3,4). Dose-finding studies at cesarean delivery indicate that morphine 100 µg provides a ceiling analgesic effect (3,5). Concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDs) may allow effective use of smaller morphine doses, prolong analgesic duration, or reduce supplementary analgesic requirements (5–8). Larger doses of morphine increase the incidence and severity of opioid-related side effects without necessarily improving efficacy (1,3,5).
Despite demonstrated efficacy (9), subarachnoid clonidine is rarely administered as a component of spinal anesthesia for cesarean delivery. A 150-µg dose is associated with a frequent incidence of hypotension and a modest analgesic duration of 3–9 h (9,10). In animals, clonidine and morphine show at least an additive antinociceptive effect (11), but postoperative evaluation of this combination is limited to a single clinical trial after hip surgery, in which 500 µg of subarachnoid morphine was combined with a single dose of clonidine (12).
Spinal anesthesia is one of the most common approaches for cesarean delivery, so achieving high-quality postoperative analgesia of consistently prolonged duration is an attractive goal, provided the method used has an acceptable side-effect profile. The aim of this study was to investigate whether the addition of subarachnoid clonidine to a multimodal analgesic approach, using subarachnoid fentanyl and morphine and a systemic NSAID, increased the duration or efficacy of postcesarean analgesia, and if so, to determine an appropriate dose of clonidine.
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Methods |
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After obtaining institutional research and ethics committee approval, written informed consent for this randomized, double-blind trial was obtained from 240 healthy parturients with a singleton fetus, scheduled for elective cesarean delivery under spinal anesthesia. Exclusion criteria were preterm gestation, hypertensive disorders of pregnancy, multiple pregnancy, opioid exposure during pregnancy, and contraindications to regional anesthesia or the postoperative administration of NSAIDs. Because of "off-label" drug use, the trial was registered with the Drug and Safety branch of the Therapeutic Goods Administration under the Clinical Trial Notification Scheme in Australia.
Parturients were randomized to one of six groups using a computer-derived random-number sequence and sealed opaque envelopes. Preoperative aspiration prophylaxis consisted of oral ranitidine and sodium citrate, and IV crystalloid 10 mL/kg was administered before spinal anesthesia. The latter was performed at the lumbar 3-4 or 4-5 interspace using a 27-gauge pencil point spinal needle with the patient seated. Spinal anesthesia was achieved with hyperbaric 0.5% bupivacaine 2.5 mL plus fentanyl 15 µg, and all patients received a prophylactic IV ephedrine infusion (30 mg in 500 mL of crystalloid, titrated to maintain systolic blood pressure [SBP] within 20% of baseline). The study drugs were prepared in normal saline to a total volume of 2 mL by an anesthesiologist not involved in patient care or trial conduct. The study solution was injected immediately after the subarachnoid bupivacaine and fentanyl. The study solution contained morphine 100 µg (group M100); clonidine 150 µg (group C150); or morphine 100 µg plus clonidine 30 µg (group MC30), 60 µg (group MC60), 90 µg (group MC90), or 150 µg (group MC150).
Intraoperative assessments were performed by the attending anesthesiologist who was unaware of group allocation. The measured variables included onset of loss of sensation to cold at the fourth thoracic dermatome (T4); ephedrine dose; lowest SBP (using noninvasive automated oscillotonometry) and heart rate, recorded every 3 min; maternal sedation; the incidence of vomiting; and the neonatal Apgar scores. If supplementary intraoperative analgesia was required, nitrous oxide or ketamine was administered. All patients received naproxen 500 mg per rectum at the completion of surgery and twice daily orally thereafter. Postoperative analgesia was further supplemented with morphine PCIA (1-mg demand bolus; 5-min lockout, Abbott Provider pump, Abbott Australasia Pty. Ltd.), commencing in the postanesthesia care unit. There, scores for worst intraoperative pain, nausea, level of sedation, and for current pain at rest and on coughing were recorded. Visual analog scores for pain at rest, with coughing, and worst pain since the last assessment, were then recorded at 2, 4, 6, 12, 24, and 36 h postoperatively.
The time to first PCIA use and, at regular intervals, the cumulative morphine dose were noted. In addition, at 36 h, the presence of and need for treatment of pruritus, sedation, nausea, and the presence of side effects (dry mouth, dizziness, anxiety, and restlessness at any time) were sought by direct questioning. At 12, 24, and 36 h, opioid-related side effects were quantified using a visual analog scale for worst nausea, pruritus, and drowsiness in the preceding period and patients rated pain experienced using a 0–10 numerical rating scale. Other data recorded at 36 h included recovery time to ambulation, passage of flatus, food intake, micturition after urinary catheter removal (morning of first postoperative day), time to hospital discharge, and satisfaction with analgesia. All patients were asked if they were dissatisfied because of poor pain relief or the side effects experienced and whether they were willing to have the same anesthetic again. A research midwife or nurse, unaware of group allocation, performed all postoperative data collection.
The primary outcome was the duration of postoperative spinal analgesia, as determined by time from arrival in the postanesthesia care unit to activation of the patient-controlled analgesia (PCA) pump. Secondary outcomes were the pain scores and severity of sedation, nausea, and pruritus. The sample size had 90% power to detect a 50% increase in the duration of analgesia with the addition of clonidine to morphine (
0.05) based on a mean (SD) duration of spinal morphine of 14 (8) h (8). The data analyses were conducted using the SAS statistical package version 8 (SAS Systems, Cary NC). Numerical data that were normally distributed were expressed as mean and standard deviation, but otherwise as median and interquartile range (25th, 75th percentiles). Categorical variables were expressed as n (%). Comparisons among groups were made using 
2 tests for categorical variables, F tests for normally distributed variables, and Kruskal-Wallis tests for variables with nonparametric distributions, such as pain score. For comparisons of groups for the duration of analgesia, the Kaplan-Meier method was used, and pair-wise comparisons were only performed for this primary outcome. The log rank test was used to examine differences in time to an event among study groups. The level of significance was set at the 5% 2-sided level for the primary outcome and 1% for the secondary outcomes.
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Results |
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Two hundred forty patients were recruited. Data from 8 patients were not analyzed because of conversion to general anesthesia (n = 2), failure of data collection (n = 3), request for withdrawal at the time of anesthesia (n = 2), and major protocol violation (n = 1). This left 232 patients (group M100 n = 39, group C150 n = 39, group MC30 n = 41, group MC60 n = 38, group MC90 n = 38, group MC150 n = 37).
In an initial analysis, we examined a possible dose-related effect of clonidine (Fig. 1). Pairwise comparison showed a significant difference for duration of postoperative analgesia between group M and each group combining morphine and clonidine. There was a trend to a shorter duration of postoperative analgesia for group MC30 compared with each of groups MC60, MC90, and MC150 but no significant difference between groups MC60, MC90, and MC150 was seen. There were no significant differences between groups MC60, MC90, and MC150 for secondary efficacy or side-effect outcomes. Groups had similar cumulative morphine consumption at 24 h but group MC30 showed a trend to larger consumption by 36 h (31.5 [23.5, 47.5] versus 18 [11, 36], 25 [9, 39], and 22 [11, 36] mg for groups MC60, MC90, and MC150, respectively, P = 0.08). Group MC30 had the most frequency of dissatisfaction attributed to inadequate analgesia (23% versus 16%, 5%, and 3% for groups MC60, MC90, and MC150, respectively, P < 0.01).
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Based on the clinical decision to identify the smallest effective dose of clonidine, the results presented are thus a secondary analysis comparing 4 groups, namely groups M100, C150, MC30, and MC60–150 combined (n = 113). There were no differences among groups with respect to demographic and patient characteristics (Table 1).
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Efficacy
The time to first activation of the PCA pump was significantly different (175 [120, 201], 266 [183, 320], 240 [205, 269], and 300 [265, 349] min for M100, C150, MC30, and MC60–150, respectively, P < 0.0001; Fig. 2). Compared with group M, the time was significantly longer for both group MC30 and MC60–150, P < 0.0001 log rank test. There were significant differences among groups for cumulative morphine consumption in all time periods until 36 h postoperatively (Fig. 3, P < 0.001 at 24 h). At all times, group MC60–150 had received the smallest cumulative dose. Pain scores were significantly different in the first 14 h (P < 0.01 at 2, 6, 8, 10, and 14 h; Table 2 and Fig. 4). Pain at rest, with coughing (Fig. 4) and the worst pain experienced were significantly different in the first 4 h (dynamic scores higher in group M than group C than group MC30 than group MC60–150) and from 6–12 h. The scores during coughing at 12 h were higher among group C than group M than group MC60–90 than group MC30, but groups had similar scores at 24 h. Verbal pain ratings (0–10) were not significantly different (3 [2, 5], 4 [3, 6], 4 [2, 5], and 3 [2, 5], groups M100, C150, MC30, MC60–150, respectively, P = 0.04).
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Intraoperative Outcomes
Groups M100, C150, MC30, and MC60–150, respectively, did not differ in the time to loss of T4 sensation (8 [7, 10], 7 [6, 9], 8 [6, 10], and 8 [7, 9] min); the incidence of hypotension (28%, 38%, 37%, and 37%); the lowest SBP (95 [85, 105], 90 [80, 104], 91 [81, 105], and 93 [80, 107] mm Hg); or the median ephedrine requirement (30 mg all groups). There was also no difference in perioperative nausea scores, but a trend to a difference in the incidence of vomiting (8%, 8%, 10%, and 21% for M100, C150, MC30, and MC60–150, respectively, P = 0.012). Pain scores during surgery were similar (worst pain score 0 [0, 0] for all groups). Two women from group MC60–150 and 1 from each of the other 3 groups received ketamine analgesia during surgery. There was a significant difference among groups in the degree of sedation, with all groups receiving clonidine having higher sedation scores (10 [0, 38], 53 [8, 80], 30 [8, 54], and 44 [15, 63] for M100, C150, MC30, and MC60–150, respectively, P < 0.001).
Other Postoperative Outcomes
At 12–36 h, there were no differences in worst nausea or drowsiness score (P = 0.25 and P = 0.73, respectively, at 36 h). The incidence of antiemetic treatment did not differ (P = 0.28) and 41%, 23%, 39%, and 43% of M100, C150, MC30, and MC60–150, respectively, received an antipruritic drug (P = 0.05). However, worst pruritus was significantly different at 12 and 24 h (at 12 h 40 [15, 68], 0 [0, 20], 20 [0, 60], 30 [10, 63] for M100, C150, MC30, and MC60–150, respectively, P < 0.001). The times to ambulation, food intake, bowel activity, micturition after removal of the urinary catheter, and the incidence of recatheterization were similar.
The overall satisfaction score at 36 h did not differ (85 [75, 100], 80 [70, 100], 84 [70, 100], and 90 [75, 100] for M100, C150, MC30, and MC60–150, respectively, P = 0.68). The incidence of dissatisfaction attributed to inadequate pain relief, reported at 36 h, was similar (13%, 21%, 23%, 8% for M100, C150, MC30, and MC60–150, respectively, P = 0.07). Most patients were willing to have the same analgesic regimen again (92%, 81%, 83%, and 89% for M100, C150, MC30, and MC60–150, respectively, P = 0.48).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Subarachnoid fentanyl improves the quality of spinal anesthesia for cesarean delivery, but has a transient postoperative analgesic effect of two to three hours (2,13,14) and subarachnoid morphine is required if a prolonged analgesic duration is desired (2). Even after administration of recommended doses of subarachnoid morphine, supplemental analgesics are frequently required (3) and several adjuncts have been investigated in an attempt to achieve more prolonged high-quality analgesia. The analgesic effect of neuraxial clonidine is synergistic in animal models and additive in humans when combined with opioid (11), and pregnancy seems to increase the analgesic action of
2-adrenergic agonists (15). The only previous study to evaluate a combination of subarachnoid morphine and clonidine differed from our study in administering a fivefold larger dose of morphine to nonobstetric patients (12). We found that the addition of clonidine 60–150 µg to subarachnoid bupivacaine, fentanyl 15 µg, and morphine 100 µg significantly improved the quality and duration of spinal analgesia after cesarean delivery, but increased intraoperative sedation.
Subarachnoid clonidine has a potent antinociceptive effect mediated by 2-adrenergic receptors in descending modulatory pathways to the dorsal horn of the spinal cord. It is effective for both somatic and visceral pain (11) and the pharmacokinetic profile is consistent with rapid onset, brief duration, and limited segmental distribution (16).
Other studies have also found that subarachnoid clonidine does not alter the initial spread of sensory block or the quality of spinal anesthesia (10,12,17). Benhamou et al. (18), however, reported higher spread and less intraoperative pain with the addition of clonidine, probably because of a smaller dose of bupivacaine and the absence of morphine. Clonidine 150 µg added to a subarachnoid local anesthetic does not decrease postoperative pain scores or reduce patient-controlled morphine consumption and is a markedly inferior analgesic to subarachnoid morphine (10,19). Delayed onset of pain after the addition of clonidine is attributed to slower regression of sensory block (11,17). We confirmed that subarachnoid clonidine alone, in the dose range 75–150 µg, is not clinically satisfactory, having no effect on morphine requirements or on pain after the first 4 postoperative hours (19).
Epidural opioids and clonidine interact in an additive manner, with a reduction of the 50% effective dose of epidural clonidine when fentanyl is added (20). Preoperative oral clonidine 4 µg/kg does not cause hemodynamic instability during spinal anesthesia for cesarean delivery, but reduces postoperative morphine requirement (21). The addition of epidural clonidine 75 or 150 µg to epidural morphine increases the duration of postoperative analgesia and reduces supplementary morphine requirement (22). In orthopedic patients, the combination of subarachnoid clonidine and morphine did not affect analgesic requirements, pain, or arterial blood pressure between 2–5 hours postoperatively compared with subarachnoid morphine alone (12). However, in that study, only 1 dose of clonidine (75 µg) was investigated and the morphine dose of 500 µg is likely to have masked any potential effect. The dose of morphine we investigated (100 µg) is consistent with that currently recommended for patients undergoing cesarean delivery (3) and we did not include >150 µg of clonidine because this dose alone provides 6–8 hours of analgesia but causes undesirable sedation, dry mouth, and hypotension (9). Our postulate was that the interaction of smaller doses of clonidine with morphine might improve analgesia without altering sedative or hemodynamic effects. After orthopedic surgery, subarachnoid clonidine 15–75 µg significantly improves spinal anesthesia and postoperative pain relief, but doses of 25–75 µg are associated with greater sedation and reduction of arterial blood pressure (23,24).
The most important clinical finding of our study was that clonidine in doses of 60–150 µg, combined with subarachnoid morphine 100 µg, improved the efficacy of subarachnoid morphine and decreased supplementary analgesic requirement. The apparently short duration of effect in all groups is consistent with previous studies using similar methodology (3,25). Studies showing initial supplementation many hours after subarachnoid morphine did not permit PCA supplementation. A limitation of our study was that we did not assess the regression of sensory block after surgery, making it impossible to determine whether better early postoperative analgesia and reduced supplementation in groups receiving clonidine was attributed to an extension of sensory block or an analgesic effect. However, regression of spinal bupivacaine anesthesia commences within 90–120 minutes, even in the presence of subarachnoid clonidine and fentanyl (18). The improved analgesic outcomes we observed several hours postoperatively are thus likely to have reflected the spinal analgesic activity of clonidine. We opted for a multimodal approach, including subarachnoid fentanyl for its intraoperative benefits (13,14,26) and perioperative NSAID because of a potential effect on duration of analgesia or dose-sparing of supplementary opioid (5–8). It is possible that subarachnoid fentanyl may also have influenced subarachnoid morphine analgesia, because lower early pain scores and rescue analgesic use are reported when subarachnoid morphine alone is administered (2).
Sedation is generally considered undesirable during regional anesthesia for cesarean delivery. Mild or moderate drowsiness is common after administration of spinal clonidine in doses of 
150 µg, especially in the presence of opioid (10,18). Drowsiness was increased in all clonidine groups in our study, and although no one complained of being excessively sleepy, this is a potential disadvantage in this setting. Spinal clonidine 150 µg has been reported to decrease blood pressure and heart rate and to increase the incidence of nausea at cesarean delivery (10). In contrast, we found that clonidine 30–150 µg did not increase the incidence of hypotension or reduce the lowest SBP, which supports the assessment that the hypotensive effect of clonidine is not usually clinically important in the presence of extensive sympathectomy from spinal anesthesia (11). Clonidine inhibits preganglionic sympathetic activity centrally, mainly mediated at a thoracic level, but large doses (>200 µg) cause a biphasic response, with initial peripheral pressor effects before a decrease in arterial blood pressure toward baseline (11).
Although there was no apparent effect on nausea, we found a trend to a more frequent incidence of intraoperative vomiting with clonidine 60 µg. This occurred despite the fact that no difference in hemodynamic variables or increase in ephedrine requirement was seen in these groups. It has been suggested that nausea after intraspinal clonidine may represent an accumulating effect of acetylcholine at the chemoreceptor trigger zone (10). Finally, although the neonatal effects of clonidine were not evaluated in this study, it has been reported that there are no significant effects associated with perioperative clonidine in infants of breast-fed mothers (19,22,27).
In conclusion, a combination of subarachnoid morphine 100 µg and clonidine for spinal anesthesia for cesarean delivery significantly improves postoperative pain relief, but increases intraoperative sedation and may increase perioperative vomiting. Because there was no difference in primary or secondary outcomes among groups receiving morphine with clonidine 60–150 µg, we conclude that the minimal effective dose range of subarachnoid clonidine, when combined with bupivacaine, fentanyl 15 µg, and morphine 100 µg, is 30–60 µg.
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Acknowledgments |
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This study was supported by a grant from the Women and Infants Research Foundation, Western Australia.
We thank the operating room and postnatal nursing staff and our colleagues, but in particular research midwives Desiree Osgood and Tracy Bingham who coordinated the trial.
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References |
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