Anesth Analg 1999;89:1487
© 1999 International Anesthesia Research Society
REGIONAL ANESTHESIA AND PAIN MANAGEMENT
Oral Clonidine Premedication Enhances Postoperative Analgesia by Epidural Morphine
Toru Goyagi, MD,
Makoto Tanaka, MD, and
Toshiaki Nishikawa, MD
Department of Anesthesiology, Akita University School of Medicine, Akita, Japan
Address correspondence and reprint requests to Makoto Tanaka, MD, Department of Anesthesiology, Akita University School of Medicine, Hondo 1-1-1, Akita City, Akita 010-8543, Japan. Address e-mail to mtanaka{at}med.med.akita-u.ac.jp
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Abstract
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This study was designed to evaluate the effects of oral clonidine premedication on postoperative analgesia by epidural morphine in a prospective, randomized, double-blinded design. Sixty consenting patients, scheduled for total abdominal hysterectomy, were randomly assigned to one of three groups (n = 20 each); the clonidine-morphine group received oral clonidine 5 µg/kg 90 min before arriving in the operating room and epidural morphine 2 mg before induction of general anesthesia, the clonidine-placebo group received oral clonidine 5 µg/kg and no epidural morphine, and the placebo-morphine group received no clonidine and epidural morphine 2 mg. An epidural catheter was placed at the L1-2 or L2-3 interspace, and 1.5% lidocaine was used for surgical anesthesia in all patients. General anesthesia was then induced with propofol, and maintained with a continuous infusion of propofol and 67% nitrous oxide in oxygen during surgery. Four patients were subsequently withdrawn from the study. After surgery, patient-controlled analgesia using IV morphine was used to assess analgesic requirement. Morphine consumptions determined every 6 h after surgery in the clonidine-morphine and placebo-morphine groups were significantly less than the clonidine-placebo group until 12 h after surgery, whereas those of the clonidine-morphine group were significantly less than the placebo-morphine group from 13 to 42 h after surgery. Visual analog (pain) scale (VAS) scores in the clonidine-morphine group were significantly lower than the placebo-morphine group at 48 h at rest, and at 1, 24, 36, and 48 h with movement. Similarly, VAS scores in the clonidine-morphine group were significantly lower than the clonidine-placebo group at 1 and 6 h both at rest and with movement, whereas VAS scores in the clonidine-placebo group were significantly lower than the placebo-morphine group at 24, 36, and 48 h at rest and with movement. The incidence of nausea and pruritus was similar between groups. We conclude that the combination of oral clonidine and epidural morphine produces more potent and longer lasting postoperative analgesia than either drug alone without increasing the incidence of adverse effects after major gynecologic surgeries.
Implications: A small dose of epidural morphine is often used for postoperative analgesia. We found that oral clonidine premedication 5 µg/kg improves the analgesic efficacy of epidural morphine without increasing the incidence of adverse side effects.
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Introduction
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Although 
2-adrenergic agonist, per se, has a modest antinociceptive activity (1–4), coadministrations of 2-adrenergic agonist with opioids produce enhanced antinociception compared with opioids alone in animal studies (5,6). In humans, however, analgesic interactions between 2-adrenergic agonist and opioids are conflicting. Oral administration of clonidine reduces postoperative analgesic requirement determined by IV morphine via patient-controlled analgesia (PCA) after knee surgery (7), but not after major abdominal surgery (8), whereas analgesia from intrathecally administered morphine is enhanced by oral clonidine premedication after total abdominal hysterectomy (9). On the other hand, oral followed by transdermal clonidine administration resulted in approximately 50% reduction of the postoperative PCA morphine requirement after abdominal surgery (10).
There is no report evaluating the effects of oral clonidine medication on postoperative analgesia from epidural morphine. Based on previous animal reports showing enhancement of the analgesic properties of opioids with 2-adrenoceptor agonists regardless of their administration route (5,6,11,12). This prospective, randomized, double-blinded study was designed to test the hypothesis that oral clonidine premedication enhances postoperative analgesia by epidural morphine.
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Methods
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This study was approved by the local ethics committee on human investigation, and informed consent was obtained from each patient. Sixty patients, ASA physical status I or II, aged 17–56 yr, undergoing total abdominal hysterectomy were selected. Patients were excluded if they did not have the intellectual capacity to understand the use of PCA or had a history of drug abuse.
All patients were randomly assigned to one of three groups (n = 20 each); the clonidine-morphine group received oral clonidine approximately 5 µg/kg and famotidine 20 mg orally as preanesthetic medication and epidural morphine 2 mg. The placebo-morphine group received a placebo tablet of identical appearance, famotidine 20 mg, and epidural morphine 2 mg. The clonidine-placebo group received oral clonidine approximately 5 µg/kg, famotidine 20 mg, and no epidural morphine. Preanesthetic medication was given 90 min before and epidural morphine was given immediately before induction of general anesthesia. Neither the patients, nurses, nor anesthesiologists caring for the patients were aware of the nature of the premedication and epidural morphine. After the patients arrived in the operating room, standard monitoring (such as electrocardiography), a noninvasive blood pressure cuff, and a pulse oximeter, were applied. An epidural catheter was placed at L1-2 or L2-3 interspace, and tested with 3 mL of 1.5% lidocaine containing 15 µg epinephrine followed by 12 mL of 1.5% lidocaine solution with or without morphine. The study solutions were prepared and coded by the hospital pharmacy. Upon completion of the study and all data collection, these codes were broken by the author. General anesthesia was induced with propofol 2 to 2.5 mg/kg, and a laryngeal mask airway was inserted in all patients. General anesthesia was then maintained with continuous infusion of propofol from 4 to 8 mg · kg-1 · h-1 plus 67% nitrous oxide in oxygen, whereas ventilation was mechanically controlled to maintain normocapnia. Lidocaine 1.5% (10 ml) was injected into the epidural space hourly, but no other analgesics were used. Hypotension during surgery (defined as systolic blood pressure <100 mm Hg or a decrease in systolic blood pressure by >20% of a resting value on the ward) was treated with ephedrine 5 mg IV, and a total dose of ephedrine was recorded. After surgery, IV morphine via PCA equipment was started in all patients (PCA bolus dose of 2 mg, lockout interval of 10 min, maximal 1 h dose of 12 mg). The intensity of postoperative pain scores was assessed using the visual analog scale (VAS), 0–10 cm at 1, 6, 12, 18, 24, 36, and 48 h after surgery at rest and with movement. The magnitudes of postoperative nausea and pruritus were assessed using a 4-point scale (0 = none, 1 = mild, 2 = moderate treatment effective, and 3 = severe treatment not effective) at the same time intervals. These assessments were performed by a nursing staff member blinded to the treatment of the patient. Since all patients had indwelling urinary catheters, urinary retention was not assessed.
A power analysis based on our pilot study involving 8 patients in each group demonstrated that more than 16 patients would provide a power greater than 0.8 (P = 0.05) for detection of a 40% difference in postoperative morphine consumption. Two-way analysis of variance was used for intergroup comparison of demographic data, duration of surgery, total dose of lidocaine, and cumulative morphine requirement. If a significant difference was detected, unpaired Student’s t-test, followed by Bonferroni correction, was used as a post hoc test. Nonparametric data, including VAS scores and severity of nausea and pruritus, were analyzed using repeated-measure analysis of variance and the Mann-Whitney U-test. Results are expressed as the means ± SD. VAS scores were expressed as median and 25th–75th percentiles, and the extended bars represent the 10th–90th percentiles. Statistical significance was inferred if P < 0.05.
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Results
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One and three patients in the clonidine-morphine and clonidine-placebo groups, respectively, were excluded because they required either additional lidocaine dose or narcotics intraoperatively. Thus, data obtained in the remaining 56 patients were used for subsequent analysis. Mean clonidine doses in the clonidine-morphine and clonidine-placebo groups were 5.2 ± 0.2 and 4.9 ± 0.6 µg/kg, respectively. There were no significant differences among the three groups in terms of age, weight, height, duration of surgery, duration of anesthesia, and total dose of lidocaine (Table 1).
Duration from the end of surgery until the first use of the PCA morphine was significantly shorter in the clonidine-placebo group (2.5 ± 3.4 h) than the clonidine-morphine and placebo-morphine groups (7.8 ± 8.1 and 8.4 ± 8.4 h, respectively, P < 0.05). Morphine consumption determined every 6 h after surgery in the clonidine-morphine and placebo-morphine groups was significantly less than the clonidine-placebo group up to 12 h. Morphine consumption in the clonidine-morphine group was significantly less than the placebo-morphine group from 13 to 42 h after surgery (Fig. 1).
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Figure 1. Morphine consumption (mean ± SD) determined every 6 h by a patient-controlled analgesia device for the first 48 h after surgery. *P < 0.05 versus the clonidine-placebo group.  P < 0.05 vs the placebo-morphine group.
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VAS scores at rest in the clonidine-morphine group were significantly less than those in the clonidine-placebo group at 1 and 6 h, and less than those in the placebo-morphine group at 48 h after surgery (Fig. 2). Similarly, VAS scores with movement in the clonidine-morphine group were significantly less than those in the clonidine-placebo group at 1 and 6 h, and less than those in the placebo-morphine group at 1, 24, 36, and 48 h after surgery (Fig. 3). VAS scores at rest and with movement in the clonidine-placebo group were significantly less than those in the placebo-morphine group at 24, 36, and 48 h after surgery (Figs. 2 and 3).
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Figure 2. Visual analog (pain) scale (VAS) scores at rest during 48 h after surgery. *P < 0.05 versus the clonidine-placebo group. P < 0.05 vs the placebo-morphine group. Box, solid line, and error bars represent 25th–75th percentiles, median, and 10th–90th percentiles, respectively.
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Figure 3. Visual analog (pain) scale (VAS) scores with movement during 48 h after surgery. *P < 0.05 versus the clonidine-placebo group. P < 0.05 vs the placebo-morphine group. Box, solid line, and extended bars represent 25th–75th percentiles, median, and 10th–90th percentiles, respectively.
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Median scores of postoperative nausea and pruritus were 0 (= none) in all groups throughout the study period, and no significant difference was detected among groups. Perioperative blood pressure and heart rate values were similar among the three groups with the exception that the heart rate of the clonidine-morphine group immediately before induction of anesthesia was significantly less than that of the placebo-morphine group (Table 2). Mean total doses of ephedrine used during surgery were also similar among three groups (11.6 ± 9.9, 9.4 ± 8.6, and 14.3 ± 11.7 mg in the clonidine-morphine, clonidine-placebo, and placebo-morphine groups, respectively). No patients developed respiratory depression (respiratory rate <10 breaths/min), bradycardia (heart rate <40 bpm), or other complications attributable to clonidine, morphine, or both.
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Discussion
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The major findings of our study are that oral clonidine premedication produced a morphine-sparing effect, prolonged the time to the first PCA morphine use, and enhanced analgesia from epidural morphine without increasing the incidence of adverse side effects after major gynecologic surgery. No clinical data have been available as to the analgesic interaction between preanesthetic oral clonidine and postoperative analgesia from epidural morphine. Under the circumstances of our study, epidural morphine reduced IV PCA morphine consumption with or without clonidine during the first 12 h (Fig. 1), and provided superior analgesia at rest and with movement in clonidine-treated patients during the first 6 h after surgery (Figs. 2 and 3), suggesting that epidural morphine played a major role in the early postoperative analgesia. On the other hand, these beneficial effects of clonidine (i.e., morphine-sparing effect and enhanced analgesia from epidural morphine) are more clearly demonstrated during the first postoperative day, suggesting that clonidine prolonged, rather than intensified, the analgesic potency of epidural morphine. We failed to demonstrate the difference in terms of the PCA morphine requirements between the placebo-morphine and clonidine-morphine groups up to 20 h after surgery. A possible explanation would be the small number of patients assigned in each group (i.e., that there was a Type II error, or that the relatively modest antinociceptive effect of clonidine was masked by the potent analgesic effect of epidural morphine during the early postoperative period).
Whereas a number of studies have demonstrated synergistic analgesic effects of parenteral clonidine and opioids (1–4,13–16), there are a few conflicting reports examining the effects of oral clonidine on postoperative analgesia and narcotic requirements (7,8). Our results compare favorably with those of Park et al. (7), who showed that oral clonidine before and after surgery reduced postoperative IV PCA morphine consumption in patients having knee surgery. In contrast, Benhamou et al. (8) failed to detect improved postoperative analgesia or reduced postoperative IV PCA morphine requirement in patients undergoing major abdominal surgery. Interestingly, our results demonstrate that patients in the clonidine-placebo group showed significantly lower VAS scores both at rest and with movement without increased morphine consumption or incidence of side effects on the first postoperative day, compared with those in the placebo-morphine group (Figs. 1 and 3). Since the observations of the Benhamou et al. study (8) were limited to the first 24 h after surgery, the late effects of clonidine, as seen in our study, may have been missed. In addition, these conflicting results may also be attributed to the difference in the types of surgeries.
It is not clear from our study where the analgesic interaction takes place between oral clonidine and epidural morphine. Pertovaara and Hämäläinen (6) reported that antinociception produced by a systemically administered 2-adrenergic agonist alone was mainly via spinal mechanisms in the rat. In spinally transected mice, systemic administration of clonidine produced a prolongation of the tail-flick latency, which was of the same degree as in spinally intact mice (11). These and other reports support the concept that systemically administered 2-adrenergic agonists produce a synergistic antinociception through direct spinal action (5,6,11,12). More importantly, the analgesic potentiation between various 2-adrenergic agonists and opioids seems independent of the route of administration (13). We demonstrated that oral clonidine premedication 5 µg/kg prolonged the duration of analgesia of intrathecal morphine (9). Based on these considerations, oral clonidine may have enhanced the postoperative analgesia from epidural morphine via direct spinal mechanism (17).
Blood pressure and heart rate values after surgery were not affected by clonidine premedication in our study, whereas Park et al. (7) and Benhamou et al. (8) showed significantly lower mean blood pressure and heart rate values, respectively, in clonidine-treated patients than placebo-treated patients after surgery. Most likely, the difference is explained by the fact that, in these previous reports, oral clonidine was repeatedly given after surgery, but was given only once before surgery in our study. On the other hand, epidural clonidine administered once before surgery resulted in similar blood pressure and heart rate postoperatively, compared with no clonidine after cesarean delivery and upper abdominal surgery (15,16).
Our results should be interpreted with some caution. First, plasma clonidine concentration was not determined. Oral clonidine is rapidly and almost completely absorbed after administration, and its peak plasma concentration is attained within 1–3 h after administration (18,19). The elimination half-life of clonidine is about 12 h, ranging from 6 to 24 h. Approximately 50% of the drug is metabolized in the liver to inactive metabolites, whereas the rest is excreted unchanged by the kidney (18,19). Thus, it is likely that oral clonidine administration before surgery affected postoperative analgesia from epidural morphine, presumably due to its long elimination half-life. Second, because no patients receiving clonidine or epidural morphine were assessed, the effects of clonidine, per se, are not clear. Third, our results may be applicable only in female patients. Dahan et al. (20) recently demonstrated that the way of µ-receptor-mediated respiratory depression is sex-dependent. However, no previous data supports a gender difference in analgesic efficacy by either epidural or IV morphine. Finally, the doses of epidural lidocaine and morphine were not individualized. Hence, various levels of analgesia and preemptive effects may have been produced. Indeed, four patients were subsequently excluded because of an inadequate level of analgesia during surgery.
In conclusion, oral clonidine 5 µg/kg administered before surgery reduced postoperative IV PCA morphine requirement and provided superior and longer lasting analgesia without increasing the incidence of side effects in patients receiving epidural morphine 2 mg. Clinically, clonidine prolonged, rather than intensified, analgesia from epidural morphine. The morphine-sparing effect and improved analgesia produced by clonidine were more evident during the first postoperative day than on the day of surgery.
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Footnotes
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Presented in part at the 73rd Annual Meeting of the International Anesthesia Research Society, Los Angeles, CA, March 15, 1999.
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Accepted for publication July 20, 1999.
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Abstract
Introduction
