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Epidural Clonidine for Postoperative Pain After Total Knee Arthroplasty: A Dose–Response Study

Huang, Yuan-Shiou MD*; Lin, Liu-Chi MD; Huh, Billy K. MD, PhD; Sheen, Michael J. MD*; Yeh, Chun-Chang MD*; Wong, Chih-Shung MD, PhD*; Wu, Ching-Tang MD*

doi: 10.1213/01.ane.0000263284.34950.f4
Pain Medicine: Research Report

BACKGROUND: Combinations of epidural clonidine, local anesthetics, and opioids have improved postoperative analgesia after total knee arthroplasty. In this study we sought to determine the optimal epidural bolus dose of clonidine, which provides the best analgesia and fewest side effects.

METHODS: Eighty ASA I–III patients, who underwent total knee arthroplasty were randomly assigned to one of four groups of 20 patients each. Identical epidural anesthesia procedures were used for all groups. After surgery, groups C0, C1, C2, and C4 received patient-controlled epidural analgesia (PCEA) with clonidine (0, 1.0, 2.0, or 4.0 μg/mL, respectively) and morphine (0.1 mg/mL) in 0.2% ropivacaine. The analgesia effect was estimated by PCEA consumption volume and visual analog pain scale at rest and with movement at 1, 2, 4, 12, 24, 48, and 72 h after surgery. Systolic blood pressure, heart rate, sedation, and sensory and motor blockade were also recorded for 72 h after surgery.

RESULTS: The PCEA consumption volume for groups C0, C1, C2, and C4 were 71.8 ± 19.5 mL, 49.6 ± 12.3 mL, 48.1 ± 9.3 mL, and 39.4 ± 9.0 mL, respectively. The clonidine groups experienced less postoperative pain (P = 0.002). In the C4 group, four patients had prolonged sensory blockade and one patient had both severe sedation and prolonged sensory motor blockade. No significant statistical difference in analgesic consumption (P = 0.78) and pain intensity (P = 0.66) between groups C1 and C2 were noted.

CONCLUSIONS: The optimal amount of epidural clonidine in a solution of morphine and ropivacaine for postoperative pain management is 1.0 μg/mL.

IMPLICATIONS: In this double blind, randomized study, we demonstrated that 1.0 μg/mL of clonidine in an epidural mixture of morphine and ropivacaine resulted in the least use of supplemental analgesics, stable hemodynamic profiles, and minimal side effects during the 72 h period after total knee arthroplasty.

From the Departments of *Anesthesiology, †Orthopaedics, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, Republic of China; and ‡Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.

Accepted for publication January 29, 2007.

Supported by Tri-Service General Hospital of Taiwan, Republic of China (TSGH-C94-069).

Address correspondence and reprint requests to Ching-Tang Wu, MD, Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, #325, Section 2, Chenggung Road, Neihu 114, Taipei, Taiwan, Republic of China. Address e-mail to

Achievement of adequate postoperative analgesia in patients who undergo total knee arthroplasty (TKA) is often a challenging task (1). Severe pain is common after TKA, and can delay early commencement of physiotherapy, the most important determinant of successful postoperative knee rehabilitation (2). The current trend in postoperative pain management is multimodal analgesia (3).

Adding clonidine, an α2-adrenergic agonist, to a solution of ropivacaine and fentanyl improves postoperative analgesia for TKA (4). The dose-dependency of IV and intrathecal administration of clonidine has been demonstrated in patients after lumbar hemilaminectomy and TKA (5,6). Sveticic et al. (7) also demonstrated the optimal combinations of bupivacaine, fentanyl, and clonidine for postoperative continuous lumbar epidural analgesia. Our goal was to determine the optimal epidural clonidine dose to be included in a solution of 0.2% ropivacaine and 0.1 mg/mL morphine for postoperative pain management after TKA.

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This double-blind study was approved by our IRB. Written, informed consent was obtained from all patients enrolled in the study.

Eighty adult patients aged between 40 and 80 years, ASA physical status I–III, who underwent primary TKA were included in the study. A power analysis was performed using the volume of analgesic solution consumed during patient-controlled epidural analgesia (PCEA) as the primary variable and retrospective data from a surgical population at our institution that were representative of the study population. This analysis indicated that a sample size of at least 18 patients per group was necessary for a between-group difference of 15 mL in the mean volume of analgesic used during PCEA and a one-tailed type I error rate of α = 0.05 to be detected with a power of 90%.

Exclusion criteria were: history of allergic reaction and contraindications to any of the study drugs or to epidural catheter placement; use of opioids, nonsteroidal antiinflammatory drugs, corticosteroids or drugs for chronic pain 1 week preoperatively and during operation; inability to understand PCEA, the visual analog pain scale (VAS), or the study protocol; and diastolic arterial blood pressure more than 100 mm Hg.

Patients were randomly assigned to one of four study groups (C0, C1, C2, C4) of 20 patients each. All procedures were performed by the same surgeon. After the preoperative visit by the anesthesiologist, a lumbar epidural catheter was inserted at an L2–5 interspace and cephalic advanced 3–4 cm. Correct epidural catheter placement was confirmed using 1% lidocaine (6 mL) plus epinephrine (1:200,000) to establish a sensory level 1 day before surgery. Patients were familiarized with the VAS and were instructed on the use of the PCEA pump (Pain Management Provider; Abbott, Chicago, IL).

Epidural anesthesia was induced using 15 mL of 2% lidocaine plus epinephrine (1:200,000) and was maintained from 30 minutes thereafter by continuous infusion of the lidocaine–epinephrine solution at a rate of 8–10 mL/h until completion of surgery. After surgery, groups C1, C2, and C4 received PCEA with clonidine (1.0, 2.0, and 4.0 μg/mL, respectively) and morphine (0.1 mg/mL) in 0.2% ropivacaine (100 mL). Group C0 received PCEA with morphine (0.1 mg/mL) in 0.2% ropivacaine (100 mL). On arrival at the postanesthesia care unit, the patient’s epidural catheter was connected to the PCEA pump, which was set to dispense 4 mL of PCEA solution per delivery with a lockout time of 15 min and no 4-h limitation or continuous background infusion. All observations were made by a nurse who was blinded to the treatments throughout 72 h after operation.

We recorded side effects associated with morphine administration (pruritus, drowsiness, dizziness, nausea, and vomiting) at 1, 2, 4, 12 h after surgery and at 09:00 am on day 1, 2, and 3 after surgery, which were treated as necessary.

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Pain Evaluation

A 10 cm VAS with end points labeled “no pain” and “worst possible pain” was used to assess pain intensity at rest and after knee movement at 1, 2, 4, 12 h after surgery and at 09:00 am on day 1, 2, and 3 after surgery. Pain relief was estimated from the amount of PCEA analgesic solution consumed postoperatively.

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Hemodynamic Effects of Clonidine

Systolic arterial blood pressure (SBP), diastolic arterial blood pressure and heart rate (HR) were measured at 4 and 12 h after surgery and at 09:00 am on days 1, 2, and 3 after surgery. Hypotension was defined as SBP <80 mm Hg and was treated with 5 mg ephedrine administered IV. Bradycardia was defined as HR <50 bpm and was treated with 0.5 mg atropine IV.

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Effect of Clonidine on Sedation and Sensory and Motor Blockade

Sedation was scored at each interval (at 4 and 12 h after surgery and at 09:00 am on days 1, 2, and 3 after surgery) using the following scale: 1, awake and alert; 2, awake but drowsy, responsive to verbal stimulus; 3, drowsy but arousable, responsive to physical stimulus; 4, unarousable, not responsive to physical stimulus. Sensory blockade was assessed by pinprick and alcohol sponge. Lower limb motor blockade was graded according to the Bromage scale (8). All data collection was performed by people not involved inpatient care.

Complete recovery from the clonidine-induced prolonged sensory and motor blockade was documented in all patients.

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Range of Motion

Physiotherapy was initiated on the first postoperative day. The degree of active knee flexion (movement of the knee by the patient) and passive knee flexion (movement of the knee with the aid of a physiotherapist) tolerated by patients were recorded by the physiotherapist twice daily until patients were discharged from hospital. Patients were encouraged to get out of bed and walk with the aid of a walking frame.

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Management of Inadequate Analgesia, Morphine-Induced Pruritus, Nausea, and Vomiting

All patients received no other analgesics except PCEA. Catheter function was confirmed by alcohol sponge sensory level testing. If an effective sensory level was achieved and the patient complained of inadequate analgesia, 1–2 additional bolus PCEA doses were administered. If the patient still suffered from severe pain, meperidine 50 mg IV was administered. If patients required meperidine rescue, the catheter was removed and the patient was excluded from the study. Pruritus was treated with naloxone 0.1 mg IV. Nausea and vomiting were treated with prochlorperazine 5 mg IV.

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Statistical Analysis

Descriptive data were summarized as means (sd) or as percentages. Differences in mean age, height, weight, duration of operation, postoperative VAS score, and daily PCEA volume of analgesic consumed postoperatively were assessed by one-way analysis of variance and multiple comparisons. All analyses were done using SPSS® software.

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Analgesic Effects and PCEA Consumption

Means for demographic variables did not differ significantly among the four groups (Table 1). No patients required rescue meperidine. No patients were excluded from the study. Patients in the clonidine groups experienced significantly less knee flexion pain (8.14–12.61%, all P = 0.002) than those in the control group during the 72 h period after surgery (Fig. 1). Analgesic effects and volumes of analgesic solutions used for postoperative PCEA are shown in Figure 2. The cumulative volumes of analgesic solution consumed by the different groups during the study period were: C0, 71.8 ± 19.5 mL; C1, 49.6 ± 12.3 mL; C2, 48.1 ± 9.3 mL; and C4, 39.4 ± 9.0 mL. Group C4 used a significantly lower volume of analgesic solution (P = 0.013) and experienced less intense pain (P = 0.005) than the other groups during the first postoperative day. Groups C1 and C2 required a lower volume of analgesic solution (P = 0.004) and experienced less intense pain (P = 0.015) than group C0 during the first postoperative day. However, the volume of analgesic solution used by groups C1 and C2 during postoperative PCEA (P = 0.78) and the intensity of pain (P = 0.66) experienced by these two groups did not differ significantly.

Table 1

Table 1

Figure 1

Figure 1

Figure 2

Figure 2

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Hemodynamic Effects

Hemodynamic data are shown in Figure 3. SBP was more than 80 mm Hg and HR was more than 50 bpm for all patients at all sampling intervals during the postoperative period. Although SBP and HR were lower in the clonidine groups than in the control group, the difference was not statistically significant (Fig. 3).

Figure 3

Figure 3

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Effects of Clonidine on Sedation and Sensory and Motor Blockade

One patient in group C4 suffered from severe sedation (score 3). Five patients in group C4 and one patient in group C2 suffered from prolonged sensory blockade (for longer than 24 h). There were no clonidine-related side effects in group C1. Group C4 experienced a higher incidence of clonidine-related side effects than groups C1 or C2 (P < 0.05).

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Side Effects of Morphine

Morphine-associated nausea, vomiting, and pruritus in groups C1, C2, C4, and C0 were observed in four patients, three patients, four patients, and nine patients, respectively (P < 0.05 for clonidine groups compared with the control). Four patients in the control group were treated for vomiting and pruritus by IV administration of prochlorperazine (5 mg) and naloxone (0.1 mg).

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Knee Flexion

There were no significant differences among groups in the degree of knee flexion at any of the sampling intervals (Fig. 4).

Figure 4

Figure 4

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The main finding of this randomized study was that the optimal epidural clonidine concentration in a morphine and ropivacaine solution after TKA was 1.0 μg/mL. This combination resulted in excellent pain relief during the 72 h period after surgery and was not accompanied by significant hypotension, sedation, sensory blockade, or motor blockade. The highest concentration of clonidine (4.0 μg/mL; group C4) produced the best analgesia, but the degree of sedation and sensory and motor blockade were more severe and longer lasting than with lower concentrations of clonidine, which required careful monitoring of the patients.

Epidural analgesia after TKA improves postoperative rehabilitation and has an antithrombotic effect (9). When used as an adjunct to local anesthetic, epidural administration of opioid can improve the quality of analgesia. However, epidural opioid, especially morphine, is associated with dose-dependent side effects, including nausea, vomiting, dizziness, and pruritus. The addition of other adjuvant drugs, such as clonidine (4) or ketorolac (10), to solutions of analgesics may, through additive or synergistic mechanisms, results in better analgesia. This effect may reduce the dosage of drugs and thus decrease the incidence of dose-related side effects (11).

Clonidine induces dose-dependent spinal cord antinociception, mainly through stimulation of α2-adrenoceptors in the dorsal horn, mimicking the activation of descending inhibitory pathways (1,12,13). When clonidine alone was used for continuous epidural analgesia, dose rates as high as 100–150 μg/h were required to obtain satisfactory analgesia (14). Epidural administration of clonidine in combination with opioids or local anesthetics has been used in single bolus doses of 75–800 μg or continuous infusion rates of 20–50 μg/h (15). However, these dosages of clonidine are commonly associated with hypotension, bradycardia, and sedation (15). Although usually well tolerated by patients, these side effects are considered worrisome in the context of postoperative recovery. Mogensen et al. (16) demonstrated that thoracic epidural analgesia after hysterectomy is improved by administration of 18.75 μg/h clonidine in a mixture of bupivacaine (5 mg/h) and morphine (0.1 mg/h). Paech et al. (17) reported that clonidine (20 μg/h) in a mixture of bupivacaine (6.25 mg/h) and fentanyl (10 μg/h) improves postoperative thoracic epidural analgesia after abdominal gynecological surgery. Hemodynamic changes were observed by Mogensen et al. and Paech et al. Forster and Rosenberg (4) demonstrated that the addition of 2 μg/mL clonidine to a low-dose ropivacaine–fentanyl mixture reduced the need for opioid rescue pain medication after TKA and decreased arterial blood pressure and HR slightly without jeopardizing hemodynamics. Furthermore, Sveticic et al. (7) demonstrated that a combination of a low dose of clonidine (0.3–1.0 μg/mL) and bupivacaine (0.5–1.4 mg/mL), and fentanyl (1.4–3.0 μg/mL) provided good postoperative lumbar epidural analgesia after knee or hip surgery. Our study is consistent with these reports, in that epidural administration of combinations of local anesthetic, opioid, and low doses of clonidine resulted in significant improvement of analgesia after TKA.

After neuraxial or systemic administration, clonidine affects arterial blood pressure in a complex manner because of opposing actions at multiple sites. The α2- adrenergic agonists reduce sympathetic drive and arterial blood pressure through effects at specific brainstem nuclei and sympathetic preganglionic neurons in the spinal cord. Eisenach et al. (18) showed that 160 μg clonidine decreases arterial blood pressure by 18% and reduces HR by 5–20%, and concluded that epidural clonidine does not induce hemodynamic instability. Moreover, in our previous study (19), we found that addition of clonidine (1.5 μg/mL) to an epidural pain-control solution containing morphine and ropivacaine did not induce hemodynamic instability. In the present study, we also found that the lack of an obvious deleterious effect on SBP and HR might have been due to the small doses of clonidine (means: 49.6, 96.2, and 157.6 μg for groups C1, C2, and C4, respectively) received during the first 3 days after the operation and during lumbar epidural administration.

Motor and sensory blockade effects of local anesthetics were enhanced by clonidine. The effects of clonidine on the prolongation of nerve blockade are clearly dose-dependent (20,21). However, it has been demonstrated that addition of clonidine to local anesthetic for continuous femoral nerve blockade can delay recovery of motor function (22). For TKA, PCEA-related numbness and motor disturbance should be avoided because early postoperative mobility is important for successful rehabilitation and for decreasing the risk of deep vein thrombosis.

In our study, sensory and motor blockade were slight, enabling early postoperative mobilization therapy in all but one patient in the C2 group. However, five patients in the C4 group suffered from prolonged sensory blockade, which may have been caused by a synergistic effect of the high concentration of clonidine and ropivacaine. Sedation is frequently associated with the use of clonidine for postoperative analgesia and is often observed when clonidine is used in conjunction with opioids (1,15). In our study, there were no significant differences among groups in sedation; this may have been a result of the low dose of clonidine used. Furthermore, the degree of knee flexion did not differ significantly among treatments. It is clinically relevant in that even the higher clonidine concentration (4.0 μg/mL) added to ropivacaine did not cause significant motor deficit to the knee flexor muscles which allowed patients to participate in postoperative rehabilitation, even though sensory blockade had been enhanced by the higher clonidine concentration. Adding 1.0 μg/mL clonidine into 0.2% ropivacaine and 0.1 mg/mL morphine mixture did not cause clonidine-related side effects, but enhanced analgesia and decreased total morphine use.

A potential limitation of our study design was that the lowest concentration of clonidine tested was 1.0 μg/mL. Therefore, we cannot exclude the possibility that clonidine concentrations between 0.5 and 1.0 μg/mL might have had more favorable ratios of analgesic effects to side effects. Besides, epidural bolus time did not coincide with VAS, hemodynamic results, and side effects measurement. Assessment long after an epidural bolus may not have detected clonidine-induced hypotension, bradycardia, and sedation.

In conclusion, this study demonstrated that, when added to a lumbar epidural mixture of ropivacaine (2.0 mg/mL) and morphine (0.1 mg/mL), 1.0 μg/mL clonidine augmented analgesia after TKA surgery without significant adverse effects. Although the highest concentration of clonidine (4.0 μg/mL) produced the best analgesia, sedation and sensory and motor blockade were more severe and longer lasting than lower concentrations of clonidine, requiring careful monitoring of patients.

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