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Anesth Analg 2003;96:1083-1088 © 2003 International Anesthesia Research Society
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Abstract |
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Postoperative pain after total knee arthroplasty (TKA) is severe and can complicate early physical therapy. We tested the hypothesis that intrathecal clonidine would improve postoperative analgesia for TKA using a hyperbaric bupivacaine spinal anesthetic. In a double-blinded, placebo-controlled protocol, 81 ASA physical status I–III patients undergoing either a single or bilateral TKA were randomized into 4 groups with the following 2-mL solutions added to 15 mg of hyperbaric bupivacaine: 1) sterile saline, 2) morphine (250 µg), 3) morphine (250 µg) with clonidine (25 µg), and 4) morphine (250 µg) with clonidine (75 µg). At 1, 2, 4, 6, 12, and 24 h postoperatively, we measured visual analog scales (VAS), cumulative IV morphine consumption, hemodynamics, nausea, ancillary drugs, and side effects. Our primary comparison was between the clonidine with morphine groups versus the morphine group. We found that the combined administration of intrathecal clonidine and morphine decreased 24 h IV morphine consumption by 13 mg (P = 0.028) when compared with intrathecal morphine alone. This corresponded to a decrease in the VAS score of 1.3 cm at 24 h postoperatively (P = 0.047). Adverse side effects were similar among all groups with the exception of more relative hypotension in the clonidine groups through postoperative hour 6. We conclude that the coadministration of intrathecal clonidine and morphine decreases the 24-h IV morphine consumption and improves the 24-h VAS score when compared with intrathecal morphine alone.
IMPLICATIONS: In this prospective, randomized, double-blinded, and placebo-controlled trial, we identify an effective postoperative analgesic approach in total knee replacement surgery. Intrathecal morphine (250 µg) combined with clonidine (25 or 75 µg) provided superior analgesia compared with intrathecal morphine alone.
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Introduction |
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Achieving adequate postoperative analgesia after total knee arthroplasty (TKA) is often a challenging task. Pain is rated as severe in the majority of patients who undergo TKA (1). This can easily hinder early physical therapy, which is the most important factor for successful postoperative knee rehabilitation (2). Postoperative pain control is complicated by rehabilitation and the recovery goal of continuous movement of the joint. In addition, immediate anticoagulation limits the options for epidural analgesia. Many approaches have been proposed and include IV patient-controlled analgesia (PCA), continuous nerve blocks, and neuraxial techniques (3–5) .
The analgesic neuraxial effect of the 
2-adrenergic agonist clonidine is well described (6–10) . In addition, intrathecal morphine is a well described modality for providing prolonged postoperative analgesia. Unfortunately, both drugs are limited by their unique side effect profiles (11,12) .
The purpose of this prospective, randomized, double-blinded, and placebo-controlled study was twofold. First, we hypothesized that the combined administration of intrathecal morphine and clonidine would provide superior postoperative analgesia in patients undergoing TKA when compared with standard IV PCA or intrathecal morphine. In addition, taking advantage of the potential synergy between neuraxial morphine and clonidine, we hypothesized that the doses of these drugs could be reduced, therefore minimizing their side effect profiles.
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Methods |
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The study was reviewed and approved by the Dartmouth College Committee for the Protection of Human Subjects. After giving written informed consent, 81 ASA physical status I–III patients undergoing either single or bilateral TKA were enrolled in this clinical study. Patients were excluded if they were <18 yr of age, were pregnant, or had a history of any of the following: chronic obstructive lung disease, allergy to a study drug, chronic pain syndrome, chronic opioid use, rheumatoid arthritis, or contraindications to spinal anesthesia.
Patients were premedicated with 1–2 mg of midazolam at the discretion of the anesthesia team. All 81 patients underwent a spinal anesthetic with 15 mg of hyperbaric bupivacaine. In a double-blinded and random manner, patients were then assigned to receive one of four intrathecal treatments. Group 1 received sterile preservative-free saline, Group 2 received 250 µg of preservative-free morphine (Astramorph; AstraZeneca, Wilmington, DE), Group 3 received 250 µg of preservative-free morphine and 25 µg of preservative-free clonidine (Duraclon; Roxane Laboratories, Columbus, OH), and Group 4 received 250 µg of preservative-free morphine and 75 µg of preservative-free clonidine. The syringes containing the study drug were prepared in the pharmacy and hand delivered to the anesthesia team with a label indicating "Intrathecal Study Drug" and the patient’s name. The total volume in each syringe was 2 mL. The study drug was added to 2 mL of 0.75% bupivacaine with 10% dextrose. Therefore, the total volume of the intrathecal injection was 4 mL. All spinals were performed in the sitting or lateral position using the L3-4 or L4-5 interspace. Intraoperatively, patients received any medications thought necessary by the anesthesia team. Intraoperative data included case length, minimal blood pressure, minimal heart rate, minimal oxygen saturation, total IV fluids, any medications given, sensory level after spinal, and the occurrence of nausea, vomiting, itching, or dry mouth.
In the postanesthesia care unit, all patients were given a morphine PCA set at a demand rate of 1 mg every 6 min. Subsequent adjustments in the PCA settings were not constrained by the study protocol. While in the postanesthesia care unit, patients could receive supplemental IV morphine to achieve satisfactory analgesia. At 1, 2, 4, 6, 12, and 24 h, data were collected by the study nurses. These included minimal interval systolic blood pressure, heart rate, and oxygen saturation. Morphine consumption and any ancillary medications were also recorded. In addition, patients were asked on a subjective scale if they had any nausea, vomiting, itching, or dry mouth. The scale was 1 = no, 2 = mild, 3 = moderate, and 4 = severe. At each data collecting time, the patients were asked to fill out a visual analog scale (VAS) for average pain. The scale was 0–10 cm. All patients were given ketorolac on a scheduled basis. Patients <55 yr of age were given 30 mg IV every 6 h, and patients >55 yr were given 15 mg IV every 6 h.
Patients were randomized into the four treatment groups. Randomization was performed by a computer driven random number generator, and the code was kept in the pharmacy. Bilateral TKAs were randomized separately. Univariate analysis was accomplished by using standard nonparametric tests for proportions and Student’s t-test for continuous variables. Because each patient had multiple measurements over time, we used generalized linear models to adjust for covariates in which observations are correlated.
Although we randomized four groups, our primary comparison was between the combined clonidine groups and the morphine-alone group. A P value of 0.05 was taken to indicate statistical significance.
Our primary comparison was total IV morphine use at 24 h. Based on prior data, we estimated the standard deviation of 24-h morphine use to be 12 mg. A sample size of 20 patients per group provides a power of 0.85 for comparing the intrathecal morphine group with the combined intrathecal clonidine groups assuming a mean difference of approximately 10 mg of IV morphine. We also had power of 0.85 to detect a difference of 1 standard deviation between the morphine-alone group and the large-dose clonidine group.
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Results |
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The groups had similar demographics (Table 1).
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Our primary end point for this study was 24-h morphine consumption. For statistical analysis, we combined the two clonidine groups (Groups 3 and 4) for comparisons with Group 2 (morphine alone). As indicated in Table 2, the combined administration of intrathecal clonidine and morphine decreased the 24-h IV morphine consumption by 13 mg (P = 0.028) as compared with intrathecal morphine alone. This corresponded to a decrease in the VAS score by 1.3 cm (13%) at 24 h (P = 0.047). VAS scores were also significantly lower (P < 0.05) at 4 and 6 h. Table 2 also depicts the individual clonidine groups in comparison with the morphine-alone group. Both clonidine groups used statistically less cumulative morphine at hours 6 and 12. However, only the larger-dose clonidine group had statistically lower VAS scores (hours 4, 6, and 24). Figures 1 and 2 depict the IV morphine use and VAS scores over the 24 h.
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Table 3 lists the incidence of side effects in the various treatment groups. There was an increased incidence of nausea in the groups that had intrathecal morphine. The incidence of hypotension was 50% in the clonidine groups as compared with the placebo (33%) and the morphine-alone group (30%). There were no bradycardiac events in any of the treatment groups at any time as defined by 70% or less than baseline. There was a statistically significant increased use of IV fluids and neosynephrine in both clonidine groups in comparison with the placebo (Group 1) and morphine alone (Group 2). Four of the 20 patients in each of the clonidine groups used neosynephrine postoperatively for hypotension. There was no neosynephrine use in the placebo or morphine-alone group. Group 3 (M + C25) used a mean and standard error of 3251 ± 133 mL and Group 4 (M + C75) used 3377 ± 138. Group 1 (placebo) and Group 2 (M) used 2217 ± 170 and 2299 ± 140, respectively.
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Discussion |
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The neuraxial effects of clonidine have been extensively described. Specifically, it is well accepted that clonidine potentiates the sensory and motor block of intrathecal local anesthetics by 30%–50% (13). Intrathecal clonidine has been used to enhance postoperative analgesia in cesarean deliveries, repair of femoral fractures, and ambulatory knee arthroscopy (10,14,15) . The exact mechanism of action of spinally administered clonidine is unknown, but is presumed to involve inhibition of afferent nerve cell firing at the level of the dorsal horn. This may result from activation of descending noradrenergic pathways that release acetylcholine to produce analgesia (9).
Our study is the first to demonstrate improved postoperative analgesia when intrathecal clonidine and morphine are coadministered as compared with intrathecal morphine alone. One prior study by Grace et al. (16) failed to show that the combined administration was beneficial in hip replacement surgery. However, they used a relatively large dose of morphine (500 µg) which could have masked the effects of clonidine and contributed to the frequent rate of reported side effects. Consistent with our results are those of Siddall et al. (17) who demonstrated improved analgesia from the combined intrathecal administration of clonidine and morphine in the treatment of pain after spinal cord injury.
We hypothesized that the potential synergy of clonidine and morphine, which has been demonstrated in animal models (18), would allow us to use relatively small doses of both drugs, therefore minimizing potential side effects. The determination of "small dose" was accomplished by historical controls that used 0.5–1 mg of intrathecal morphine and 1–3 µg per kg of intrathecal clonidine (9,12) . Although the incidence of emesis was less than reported by Grace et al. (16), we experienced significant relative hypotension in the clonidine groups (Table 2). The hypotension resolved between hours 6–12, which is similar to the clonidine-induced hypotension found by Klimscha et al. (13). Consistent with this increased incidence of relative hypotension, there was an increased fluid administration and neosynephrine use in the clonidine groups. Although there was a trend toward an increased incidence of hypotension in the clonidine groups compared with the morphine-alone group, it was not statistically significant. This is likely a reflection of our conservative definition of hypotension (70% of baseline) and our sample numbers.
An unexpected result was that Group 3 (25 µg of clonidine) had the same incidence of hypotension as did the 75-µg group (Group 4). Because the analgesic profile also appeared similar, further study should be directed to defining a dose-response curve for intrathecal clonidine. The mechanism of hypotension is likely central sympatholysis (9), and, therefore, smaller doses may have less of an effect.
Interestingly, of the 8 patients who received 
4 mg of supplemental morphine over 24 hours, 7 received intrathecal clonidine with 5 receiving the 75-µg dose of clonidine. The significance of these findings is unclear, and a larger study population is required to help identify any analgesic differences between the two groups of clonidine.
Figure 2 reveals the VAS scores for the four groups over time. It is interesting to note that the graphs converge at 12 h. This likely reflects the finding that Groups 1 and 2 used significantly more IV morphine than the clonidine groups and arrived at a similar state of comfort. At 24 hours, however, the clonidine groups combined (Groups 3 and 4) compared with the intrathecal morphine-alone group (Group 2) had significantly less pain as indicated by scoring 13% (1.3 cm) less on the VAS scale (Table 2). This corresponded to a reduction of 13 mg of IV morphine use in the combined clonidine groups (Table 2). This could possibly be explained by better preemptive analgesia or simply longer duration of neuraxial analgesia. It is difficult to explain why the VAS scores at 24 hours were higher in the morphine group (Group 2) as compared with the placebo (Group 1). One argument would be that the analgesia from the intrathecal morphine began to wane between hours 6–12. This is supported by the fact that the steepest portion of the curve in Figure 1 is between hours 6–12. This is in contrast to the placebo group which had a more even use of morphine during each time interval (Table 4). It is possible that when the effects of intrathecal morphine began to resolve, the patients in Group 2 had a more difficult time reaching a similar state of comfort compared with the placebo group who had been receiving IV morphine consistently.
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In retrospect, it would have been helpful to measure the patient’s satisfaction with their analgesia. The question of whether a 13% decrease in VAS scores and using less IV morphine equates to happier patients remains unanswered. In addition, only the 75-µg clonidine dose (Group 4) demonstrated a statistically significant reduction in the mean VAS score at 24 hours when compared with the morphine-alone group (Group 2). Because the placebo group had a similar VAS score at 24 hours in comparison to the 75-µg clonidine group, a validated patient satisfaction scale would add support for the use of intrathecal clonidine for postoperative analgesia.
In conclusion, compared with intrathecal morphine, the combined administration of clonidine and morphine reduces postoperative IV morphine use and improves the VAS score at 24 hours. There was an increase in relative hypotension which did necessitate intervention. There seemed to be little difference between 25 µg and 75 µg of clonidine in terms of pain control and adverse side effects. Future study should be directed toward generating a dose-response curve for clonidine <25 µg, morphine <250 µg, and to measuring patient satisfaction.
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Footnotes |
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Presented in part at the 2003 annual meeting of the American Society of Anesthesiologists, Orlando, FL.
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References |
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- Bonica J. Postoperative pain. In: Bonica J, ed. The management of pain. 2nd ed. Philadelphia: Lea & Febiger, 1990: 461–80.
- Shoji H, Solomonow M, Yoshino S, et al. Factors affecting postoperative flexion in total knee arthroplasty. Orthopedics 1990; 13: 643–9.[Web of Science][Medline]
- Horlocker T, Hebl J, Kinney M, Cabanela M. Opioid-free analgesia following total knee arthroplasty: a multimodal approach using continuous lumbar plexus (psoas compartment) block, acetaminophen, and ketorolac. Reg Anesth Pain Med 2002; 27: 105–8.[Web of Science][Medline]
- Singelyn FJ, Deyaert M, Joris D, et al. Effects of intravenous patient-controlled analgesia with morphine, continuous epidural analgesia, and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg 1998; 87: 88–92.
[Abstract/Free Full Text] - Allen HW, Liu SS, Ware PD, et al. Peripheral nerve blocks improve analgesia after total knee replacement surgery. Anesth Analg 1998; 87: 93–7.
[Abstract/Free Full Text] - Eisenach J, Detweiler D, Hood DD. Hemodynamic and analgesic actions of epidurally administered clonidine. Anesthesiology 1993; 78: 277–87.[Web of Science][Medline]
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- Eisenach J, De kock M, Klimscha W. alpha2-Adrengeric agonists for regional anesthesia: a clinical review of clonidine (1984–1995). Anesthesiology 1996; 85: 655–74.[Web of Science][Medline]
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- De Kock M, Gautier P, Fanard L, et al. Intrathecal ropivacaine and clonidine for ambulatory knee arthroscopy: a dose-response study. Anesthesiology 2001; 94: 574–8.[Web of Science][Medline]
- Grace D, Bunting H, Milligan KR, Fee JP. Postoperative analgesia after co-administration of clonidine and morphine by the intrathecal route in patients undergoing hip replacement. Anesth Analg 1995; 80: 86–91.[Abstract]
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