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Effects of a continuous low-dose clonidine epidural regimen on pain, satisfaction and adverse events during labour: a randomized, double-blind, placebo-controlled trial

Wallet, Florent; Clement, Henri Jacques; Bouret, Carine; Lopez, Felix; Broisin, Françoise; Pignal, Corine; Schoeffler, Mathieu; Derre, Edith; Charpiat, Bruno; Huissoud, Cyril; Aubrun, Frédéric; Viale, Jean Paul

European Journal of Anaesthesiology (EJA): May 2010 - Volume 27 - Issue 5 - p 441–447
doi: 10.1097/EJA.0b013e3283365944
Postoperative Pain

Background and objective Epidural clonidine has been proposed as an adjunct for anaesthetic mixtures during labour. Administered as a bolus, clonidine may have side effects such as sedation and hypotension; its continuous infusion could be attractive in this respect. We, therefore, conducted a randomized, double-blind trial using patient-controlled epidural analgesia with a background infusion using a low dose of clonidine during labour.

Methods A total of 128 healthy parturients in active labour received a patient-controlled epidural analgesia solution of 0.0625% levobupivacaine and sufentanil 0.25 μg ml−1 with or without clonidine 2 μg ml−1. Ninety-five parturients were analysed. The pain score over time was evaluated as well as drug volume utilization; supplementation bolus and side effects were recorded. The primary endpoint was maternal satisfaction [ Identifier (NCT00437996)].

Results Three patients in the control group failed to achieve satisfactory epidural analgesia owing to a technical issue. Although the primary endpoint was not statistically significant, analgesia was more pronounced and obtained earlier in the clonidine group. The area under the curve for the visual analogue pain score was significantly lower in the clonidine group. In this group, hourly doses of levobupivacaine and sufentanil were reduced (13.9 ± 4.3 vs. 16.3 ml ± 4.0; P = 0.005) as well as rescue supplementation and pruritus incidence (18 vs. 46%; P = 0.004). Maternal blood pressure was significantly lower, over time, in the clonidine group but remained within the normal range. Sedation was similar in both groups (4.3 vs. 2.0%; not significant).

Conclusion The addition of clonidine to epidural levobupivacaine and sufentanil for patient-controlled epidural analgesia in labour improved analgesia, reduced the supplementation rate and reduced pruritus without improvement in maternal satisfaction. Blood pressure was significantly lower in the clonidine group over time but without clinical consequence.

From the Department of Anaesthesiology, Université de Lyon, Hospices Civils de Lyon, Hôpital Croix Rousse, Service d'Anesthésie Réanimation (FW, HJC, FL, FB, CP, MS, ED, FA, JPV), Department of Pharmacy, Université de Lyon, Hospices Civils de Lyon, Hôpital de la Croix Rousse, Lyon (CB, BC), Obstetrical Department, Université de Lyon, Hospices Civils de Lyon, Hôpital Croix Rousse, Service d'Obstétrique (CH), Inserm, EA4173 ERI 22, Agressions vasculaires et réponses tissulaires, UCBLyon1, Université de Lyon, Lyon (JPV) and Department of Anaesthesiology, Université Pierre et Marie Curie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié Salpétrière, Service d'Anesthésie Réanimation, Paris, France (FA)

Received 20 August, 2009

Revised 28 November, 2009

Accepted 6 December, 2009

Correspondence to Dr Henri Jacques Clement, Service d'Anesthésie Reanimation, Hospices Civils de Lyon, CHU de la Croix Rousse, Université de Lyon, Grande rue de la Croix Rousse, 69004 Lyon, France Tel: +33 4 72 07 25 10; fax: +33 4 72 07 19 85; e-mail:

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Current practice in obstetric analgesia is to combine local anaesthetics with adjuvant drugs in order to maintain high efficacy and comfort while reducing individual drug doses and thus side effects. Among the adjuvant drugs, clonidine has been proposed owing to its α-2 adrenergic agonist properties.1 Most studies reported a dose-sparing effect of local anaesthetic or opioid due to clonidine when administered as a bolus.2–4 However, some limitations arose due to side effects related to bolus administration such as hypotension or excessive maternal sedation.5–9 Continuous infusion of low-dose clonidine may reduce these side effects.2,10,11

Compared with continuous epidural infusion analgesia, patient-controlled epidural analgesia (PCEA) has been shown to improve analgesia and reduce the need for anaesthetic interventions12 and these effects are more pronounced when the PCEA is associated with a background infusion.13,14 Therefore, the aim of our study was to evaluate the role, on obstetric analgesia, of a continuous low dose of clonidine systematically added to a solution of low-dose levobupivacaine and sufentanil administered by PCEA.

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The present research was conducted at the Croix-Rousse Hospital, Hospices Civils de Lyon, France. The protocol was approved by the institutional review board – IRB (Comité de Protection des Personnes – CPP) and written informed consent was obtained from each patient [ Identifier (NCT00437996)]. One hundred and twenty-eight parturients (128) who underwent an uneventful course of pregnancy were included. Inclusion criteria were parturients classified as American Society of Anesthesiologists (ASA) physical status I or II, participants of 18–40 years of age, with singleton pregnancy of 37 weeks or more and vertex presentation. All women were in active labour with cervical dilatation of 3–8 cm and a visual analogue pain scale (VAPS) score greater than 30 mm. None was receiving intravenous analgesics before epidural placement.

Epidural catheters were inserted, with the patient in a flexed sitting position and the epidural space identified using the isotonic saline loss of resistance technique at the L2–L3 or L3–L4 level using a median approach with a 16G Tuohy needle. Before epidural puncture, the skin was infiltrated with 3–5 ml of 1% lidocaine. A multiport epidural catheter was advanced 3 cm into the epidural space. Afterwards, a test dose was given using 1% lidocaine 3 ml for subarachnoid testing. If no motor blockade occurred during the 5 min following injection, the catheter was considered to be in the epidural space. Monitoring for all patients included a noninvasive blood pressure measurement, electrocardiography, pulse oximetry and cardiotocography. Parturients were excluded for further analysis if delivery occurred within 90 min after epidural initiation or if parturients had an instrumental delivery or caesarean section. If epidural analgesia could not be obtained, patients were excluded. Classical epidural analgesia contraindications were also exclusion criteria (blood coagulation abnormalities, spine surgery, local or general sepsis).

Participants were allocated to one of two groups in a double-blind, randomized, prospective study design. Group assignment was performed by using a cluster random number table. The procedure of randomization and the preparation and handling of the treatment vials was the responsibility of the staff in the pharmacy at our institution. Participants were randomized to receive either a control solution (control group, levobupivacaine 0.0625% with sufentanil 0.25 μg ml−1) or the study solution (clonidine group, as the control and clonidine 2 μg ml−1). The anaesthetists performing the procedure and subsequent assessment were blinded to the solution used. Patients lay on their left side before injection of drugs.

The initial bolus was 15 ml of the allocated solution supplemented by a new 7 ml bolus 20 min later if there was no decrease in VAPS score under the threshold value of 30 mm. If this bolus failed to obtain a VAPS score lower than 30 mm, a new 10 ml bolus of 0.25% levobupivacaine was administered. If no decrease in VAPS score was noted after 15 min, the patient was excluded because of analgesia failure.

Once pain relief had been achieved (VAPS score lower than 30 mm), PCEA was made available using a disposable device (PCEA; Fresenius, Bad Homburg, Germany) that provides a 7 ml incremental bolus on demand with a 10 min lockout and a 3 ml h−1 background infusion (maximum infusion of 45 ml h−1).

During PCEA infusion, if analgesia was considered insufficient by the parturient, two boluses of 7 ml of the allocated solution were administered with a 10 min interval.

If these were insufficient, a new bolus of 10 ml levobupivacaine 0.25% was administered. If the VAPS score remained higher than 30 mm, the protocol was discontinued and analgesia was then managed by the anaesthesiologist in charge of the patient.

When blood pressure decreased by more than 20% of the initial value, the patients received a bolus of ephedrine 3–9 mg.

Our primary outcome was ‘maternal satisfaction’ at the time of delivery. Maternal satisfaction was defined as a painless delivery without motor blockade. A painful delivery or a painless delivery but with a motor blockade was considered as nonsatisfactory. Secondary outcomes were pain assessment over time from epidural injection to delivery, epidural analgesic consumption, motor blockade, pruritus and sedation incidence and newborn outcome. Pain was assessed with a 100 mm linear VAPS, on which 0 represented no pain and 100 the worst possible pain. Pain evaluation was carried out immediately before epidural injection and at 5 min intervals for the first 30 min after bolus injection, and then every hour until birth.

Pain during the first hour was also assessed by calculating the area under the curve (AUC) for VAPS values, as the sum of the values [(pain at t n+1 + pain at t n)/2) × (time (hour) between t n and t n+1] calculated for each interval between the observations. The primary outcome score was obtained less than 5 min after delivery by the nurse or the resident in charge of the parturient in order to measure the pain at delivery.

At 5 min following birth, the global satisfaction of the patients and midwives concerning analgesia during the whole labour was assessed on a visual analogue scale (VAS) by either the nurse or the resident in charge of the parturient. We performed this evaluation immediately after delivery because pain perception may decrease over time, as described by Robinson et al.15 Parturients and midwives were asked to ‘express their satisfaction about the analgesia obtained during the whole labour’ using a VAS. Midwives were unaware of the treatment given.

In addition to VAPS assessment, other data collected at the same time included maternal blood pressure and heart rate, Bromage score, sedation and pruritus. These data were collected immediately before epidural injection and at 5 min intervals for the first 30 min after bolus injection, and then every hour until birth.

Motor block was assessed using a modified Bromage scale (1 = complete motor block; 2 = able to move the feet; 3 = able to move the knees; 4 = detectable weakness of hip flexion; able to raise the legs, but unable to keep them raised; 5 = no detectable weakness of hip flexion). We did not assess the score 6 (able to perform knee-bend while standing) because it was difficult to stand the patients up with our monitoring and because the practice in our hospital is not to allow patients under epidural analgesia to stand during labour. For statistical analysis, motor block was defined as a modified Bromage scale equal to or lower than 4.

During epidural analgesia, we measured, with a 100 mm linear VAS, the side effects (pruritus, nausea and sedation).

Pruritus intensity was evaluated using a VAS scale from 0 (no pruritus) to 100 (worst pruritus possible). Pruritus was defined as a VAS of more than 0.

Sedation was assessed on a four-point scale (1 = wide awake, 2 = drowsy, 3 = dozing, 4 = awakening only when aroused).

Finally, we noted the time from epidural initial bolus administration until delivery, total volume of epidural solution used during that time (without the initial bolus of 15 ml), mode of delivery, and Apgar scores at 1, 5 and 10 min and venous cord pH of the newborn. The rescue volume of 0.25% levobupivacaine was noted elsewhere and was not included in the total volume of epidural solution infused.

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Statistical analysis

Data are presented as the mean (SD) or median [interquartile range (IQR)]. Normality was assessed using the Shapiro–Wilk test. Equality of variance was assessed using the Levene's test. Patient characteristics and obstetric data were analysed using the unpaired Student's t-test for the parametric variables, Fisher's exact test or χ 2 test for counts and proportions and the Mann–Whitney U-test for nonparametric data. Statistical analysis of continuous measurements was performed by one-way analysis of variance. A P value less than 0.05 was considered to be significant.

Statistical analyses were performed using SPSS for Windows v17.0 (SPSS, Chicago, Illinois, USA). Sample size was estimated before the study using the incidence of maternal satisfaction as the primary outcome, which is 70% in our institution. The sample size was calculated to detect a 20% increase in the percentage of women rating their delivery analgesia as fully satisfactory, with a power of 80% at a 5% type 1 error significance level.

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A total of 128 patients were enrolled in the study. Thirty-three patients (18 in the clonidine group and 15 in the control group) were excluded from data analysis (26%): 10 parturients delivered before 90 min, three patients experienced a failure of analgesia due to misplacement of the catheter (all in the control group), 10 patients required forceps for birth and 10 parturients required caesarean section. Thus, 49 patients in the clonidine group and 46 in the control group were suitable for further analysis. There was no significant obstetric or demographic difference between the two groups (Table 1). The modes of delivery were similar for the 128 parturients (Table 2). Eight parturients (12%) required instrumental delivery in the clonidine group compared with two parturients in the control group (3%; not significant). Five parturients (8%) in each of the groups required caesarean section (not significant).

Table 1

Table 1

Table 2

Table 2

The maternal satisfaction score did not differ between the groups. Seventy-one per cent of the parturients in the clonidine group experienced optimal delivery compared with 65% in the control group (not significant).

A lower VAPS score was observed in the clonidine group over time than in the control group (Fig. 1). At the time of delivery, the mean VAPS score was significantly lower in the clonidine group (22.4 ± 25.1) than in the control group (34.4 ± 28.0; P = 0.03).

Fig. 1

Fig. 1

Comparison of the AUCs between groups showed a lower value in the clonidine group during the first hour (19.13 ± 15.99) than in the control group (26.86 ± 15.11; P = 0.002).

Midwives' satisfaction scores were similar in both groups (86 ± 19 vs. 85 ± 16; P = 0.80).

The total volumes of anaesthetic solution used per hour of labour were significantly smaller in the clonidine group than in the control group: 13.9 ± 4.3 vs. 16.3 ml ± 4.0 (P = 0.005).

More patients in the control group required rescue levobupivacaine 0.25% bolus (37 vs. 12%; P = 0.01).

The incidence of motor block was not significantly different between the two groups (12 and 13% in the clonidine and control groups, respectively; P = 0.9). Only three parturients (two control, one clonidine) experienced a motor block with a Bromage score lower than 4.

Sedation rate (resulting in a sedation scale different from 1) was similar in the control and in the clonidine group (4.3 vs. 2.0%; P = 0.61).

Pruritus was present in 46% of the patients in the control group and in 18% in the clonidine group (P = 0.004), with a mean intensity of 33 ± 22 and 23 ± 22 mm, respectively (not significant). Nausea was present in 13% of the patients in the control group and in 4% of the patients in the clonidine group (not significant), with a mean intensity of 54 ± 32 and 17 ± 10 mm, respectively (not significant).

Neonatal Apgar scores and venous cord pH were also similar in both groups (Table 3).

Table 3

Table 3

The time course of systolic arterial pressure during epidural analgesia was different between groups (Fig. 2). Systolic arterial blood pressure was significantly lower in the clonidine group from 20 to 360 min after epidural infusion initiation. However, systolic pressure remained above 100 mmHg over time in both groups. Only one patient in the control group experienced a systolic blood pressure below 100 mmHg. More patients required ephedrine use in the clonidine group (26.5%) than in the control group (6.5%; P = 0.01). Maternal heart rate did not differ between groups. No adverse effect was observed during the whole study.

Fig. 2

Fig. 2

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The results of this study were that adding low-dose clonidine to local anaesthetics and opioids for labour analgesia was not associated with an improved maternal satisfaction at delivery, as evaluated by our primary outcome, but resulted in an improved VAPS score over time, a lower epidural mixture consumption and less pruritus. Moreover, these improvements were not associated with increased adverse effects.

Several studies have documented the potential benefit of spinal and epidural clonidine.3,16–20 This α-2-adrenergic agonist could be expected to be an efficient analgesic adjuvant by modulating pain perception at the spinal level.1,21,22 Clonidine also improves peripheral nerve blockade by local anaesthetics.23,24 The benefit of epidural clonidine administration in obstetrics has been evaluated in previous studies as an adjunct to local anaesthetics, opioids or both.2,3,8,18,25 This evaluation was made after bolus administration, usually 50–75 μg, up to 150 μg.26 Under these conditions, clonidine could exhibit several benefits, including the sparing of local anaesthetics and opioids, leading to less effect on motor function and opioid-induced respiratory depression, pruritus and nausea. Bolus administration of clonidine induced several side effects such as sedation and hypotension.2,8,25,27 Although pharmacodynamic studies suggest continuous infusions may be more appropriate, few studies have focused on continuous epidural clonidine administration during labour.6,7,28,29 This route of administration could be of value in respect to its simple use under clinical conditions.

In a previous study, the authors showed a local anaesthetic sparing effect, but with no change in the quality of analgesia.28 Furthermore, a subsequent study failed to show analgesic benefits, whereas the sedation scores were higher in the clonidine group.7 In the former study, the lack of analgesic or maternal satisfaction improvement was ascribed to the small power of the study. Our study confirmed the clinical advantage of this strategy based on maternal satisfaction and evaluated analgesia. However subjective, the maternal satisfaction assessment reflected the reduced requirement for rescue boluses and the lower incidence of pruritus. The large decrease in pruritus may be partially explained by the reduction in opioid administration.

A lower VAPS score was obtained in the clonidine group, whereas these patients received a reduced amount of epidural solution. This paradoxical result could have at least two explanations. Either the low level of pain of lower than 30 mm in both groups did not make the patients use the patient-controlled analgesia (PCA), or the side effects encountered in the control patients led these patients to trade a slightly higher pain score for less side effects.30 These results are in line with previous studies using bolus administration of clonidine and clearly show that a continuous infusion of low-dose clonidine has the same clinical advantage on pain, avoiding the side effects such as sedation and hypotension.2,3,29

Previous studies showed that sedation could occur after bolus administration of clonidine and that a minimum dose of 50 μg seemed to be necessary to induce sleep and dozing.8 In the present study, the total amount of clonidine injected during the initial dose of epidural solution was 30 μg due to the low clonidine concentration we used. After the initial dose, the mean clonidine infusion rate was 27.7 ± 7.5 μg per hour of labour. These results were consistent with those of the study by Paech et al.,7 who found a mean infusion rate of 28 μg h−1 in a PCEA bolus mode without background infusion. In the study by Tremlett et al.,28 no maternal sedation was observed whatever the clonidine infusion rate, 19 or 37 μg h−1. This suggests that there may exist a ‘threshold effect’ with a sedation effect observed at least above the value of 37 μg h−1.

The circulatory effect of clonidine could be of actual concern in the setting of labour analgesia.2,10,11 After epidural administration of clonidine, both bradycardia and hypotension could occur due to the reduced sympathetic outflow induced by stimulation of α-2-adrenergic receptors in the brainstem and intermediolateral column of the spinal cord.4,5,9 Blood pressure is usually reduced 15–20 min after epidural clonidine boluses and may remain lower for 90–120 min.31

Using a PCEA clonidine infusion, Paech et al. 7 found a significant reduction in systolic blood pressure over time in the clonidine group. However, systolic blood pressure always remained higher than 100 mmHg and no clinical significance was found. In our study, we found similar results. Although ephedrine was more frequently used in the clonidine group, no maternal or foetal consequences were noticed.

There were no adverse effects on the newborn infants. However, some authors found a higher number of foetal cardiotocographic traces with a reduced variability in the clonidine group.28 In this study, the variability and foetal cardiotocographic data were not specifically addressed, but the lack of difference in umbilical blood pH values and Apgar scores suggests that these effects, if any, have no consequence on newborn infants.

Motor blockade could also be of concern after clonidine administration as previously described.32 However, we did not find any difference in the motor blockade rate in either of the groups. This may be explained by the low dose of clonidine administered and the low dose of local anaesthetic used.

Thus, this study shows that low-dose continuous infusion of epidural clonidine resulted in excellent obstetric analgesia without significant adverse effects that may occur after a single epidural bolus injection.

Although this was a prospective double-blind randomized trial, some methodological aspects should be addressed and shortcomings or weaknesses of the study pointed out.

One major weakness is the high number of patients excluded from analysis (33 of 128 parturients; 26%). Although all secondary endpoints were significant, the primary endpoint (maternal satisfaction score) was not. This may be explained by the high number of exclusions, in which the primary endpoint could not be assessed.

Our study was, therefore, underpowered as our pretest maternal satisfaction was quite high and, thus, the difference between the control and treatment groups was low. However, we used some strong secondary endpoints that all supported a beneficial use of low-dose clonidine.

Another possible explanation is the nature of our primary endpoint itself: ‘maternal satisfaction score’. We decided to evaluate maternal satisfaction as this seemed an essential criterion in obstetric analgesia management. Indeed, for maternal satisfaction and obstetric management, not only analgesia but also the lack of motor blockade is essential for full maternal comfort.

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In conclusion, low-dose epidural clonidine (2 μg ml−1), self-administered and in combination with 0.0625% levobupivacaine and 0.25 μg ml−1 sufentanil, improved analgesia and reduced pruritus and supplementation delivery when compared with a similar PCEA solution without clonidine. We also observed a significant reduction in VAPS scores over time in the clonidine group. The maternal satisfaction score did not differ between the groups.

No difference was found in the sedation scores or in the motor blockade. As blood pressure was lowered, this effect, although, nonclinically relevant, warrants haemodynamic monitoring during the course of obstetric analgesia.

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The present work was supported by institutional funding (Hospices Civils de Lyon – BP 2251, 3 quai des Célestins, 69 229 LYON Cedex 02).

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clonidine; epidural analgesia; levobupivacaine; sufentanil

© 2010 European Society of Anaesthesiology