|Year : 2013 | Volume
| Issue : 2 | Page : 67-74
Epidural clonidine for postoperative pain after lower abdominal surgery: A dose - response study
Jyothi Jain, Anjum Khan Joad, Vinita Jain
Department of Anaesthesia & Palliative Care, Bhagwan Mahaveer Cancer Hospital & Research Centre, Jawahar Lal Nehru Marg, Jaipur, Rajasthan, India
|Date of Web Publication||4-Oct-2013|
Anjum Khan Joad
Department of Anaesthesia & Palliative Care, Bhagwan Mahaveer Cancer Hospital & Research Centre, Jawahar Lal Nehru Marg, Jaipur - 302 017, Rajasthan
Source of Support: None, Conflict of Interest: None
Background: Patient controlled epidural analgesia with local anesthetic and opioid is an effective technique for postoperative analgesia after abdominal surgery. Clonidine has a synergistic effect on epidural local anesthetics. The purpose of this study was to determine the optimal epidural clonidine dose to be added to a solution of bupivacaine and morphine for patient controlled epidural analgesia to deliver an optimal balance of analgesia and side effects. Methods: Sixty patients were randomly assigned to three study groups (C0, C1, C2) of 20 patients each. Before the induction of general anesthesia, epidural anesthesia was induced using 10 mL of 1% lidocaine and epinephrine (1:200,000) and was maintained with a continuous infusion of the lidocaine - epinephrine solution until the completion of surgery. After surgery, groups CO, C1, and C2 received patient controlled epidural analgesia (PCEA) with morphine (0.1 mg/mL) in 0.1% bupivacaine. Group C1 and C2 also received epidural clonidine (1 and 2 mcg/mL, respectively). Pain was assessed at rest, cough, and on movement at 1, 2, 4, 8, 12 h after surgery and on day 1, 2, and 3. Differences in the mean postoperative Numerical Rating Scale (NRS) score and analgesic consumption were assessed by one-way analysis of variance and multiple comparisons. Result: Patients in all the groups experienced adequate pain relief during the 72-h period after surgery. There was no statistically significant difference between the mean NRS scores and CRS scores for pain at rest, cough, or during mobilization between the three groups. The cumulative volumes of analgesic solution were C0, 131 ± 21.285 mL; C1, 89.9 ± 18.44 mL; and C2, 80.1 ± 21.32 mL. There was no significant difference in the PCEA analgesic consumption between group C1 and C2 (P = 0.128). Groups C1 and C2 required lower volume of analgesic solution (P < 0.001) than group C0. Also, the number of rescue doses consumed by clonidine group were less (P < 0.001). Conclusion: The optimal epidural clonidine concentration in a morphine (0.1 mg/mL) and bupivacaine (0.1%) solution after lower abdominal surgery is 1.0 μg/ml. The combination of bupivacaine (0.1 %), morphine (0.1%), and clonidine (both 1 and 2 μg/mL) resulted in excellent pain relief in the 72 hour period after surgery and was not accompanied by significant hypotension, sedation, sensory blockade, or motor blockade.
Keywords: Bupivacaine, clonidine, morphine, patient controlled epidural analgesia
|How to cite this article:|
Jain J, Joad AK, Jain V. Epidural clonidine for postoperative pain after lower abdominal surgery: A dose - response study. Indian J Pain 2013;27:67-74
|How to cite this URL:|
Jain J, Joad AK, Jain V. Epidural clonidine for postoperative pain after lower abdominal surgery: A dose - response study. Indian J Pain [serial online] 2013 [cited 2020 Sep 20];27:67-74. Available from: http://www.indianjpain.org/text.asp?2013/27/2/67/119334
| Introduction|| |
The ideal epidural analgesic technique for major surgery would provide effective pain relief with minimal side effects and high levels of patient satisfaction. It would also obtund central sensitization and pain-induced organ dysfunction, leading to an improved outcome. The primary measure of efficacy of any analgesic regimen is pain relief. However, pain is a complex, subjective experience, which has proved difficult to measure in a reproducible way. Early studies of postoperative analgesia relied on the measurement of pain scores at rest and surrogate measures, such as respiratory spirometry.  Reliance on measuring pain scores at rest resulted in failure to identify those techniques that allowed patients to move and cough effectively, that is, techniques that provided dynamic pain relief.  A more realistic approach is to measure pain on movement or coughing and to aim for a patient who can move, take deep breaths, and cough effectively and who scores 3 or less out of 10 on a visual analog scale (VAS) or Numerical Rating Scale (NRS) measured on movement.  Total dynamic pain relief, that is, complete absence of pain on moving and coughing after major abdominal surgery, can be achieved by the use of large doses of opioid and local anesthetic drugs, which may be associated with undesirable side effects. The side effects of epidural morphine include nausea and vomiting, somnolence, pruritus, urinary retention, and respiratory depression. ,
The goal of postoperative analgesia is to achieve dynamic pain relief at the same time minimizing the adverse effects. The combination of epidural local anesthetic and opioid is one of the strategies used to achieve postoperative analgesia after abdominal surgery. Patient controlled epidural analgesia (PCEA) is a rational and effective method of postoperative analgesia for achieving patient's desired level of analgesia by operating a programmed pump.
Various combinations of local anesthetics, opioids, and adjuvant drugs have been used for epidural analgesia. Clonidine, an α2-adrenergic agonist added to a solution of bupivacaine and morphine has analgesic properties.  It also has a synergistic effect on local anesthetics and has been effectively used for postoperative analgesia. It has been used epidurally in different doses 18.75 mcg/h, 10, 15, and 20 mcg/h (Peach) and De Koch (6 mcg/kg/h). 
The purpose of this study was to determine the optimal epidural clonidine dose to be added to a solution of 0.1% bupivacaine and 0.1 mg/mL morphine for postoperative pain management after lower abdominal surgery to provide an optimal balance of analgesia and side effects.
It was hypothesized that epidural clonidine enhances the analgesic effect of morphine and bupivacaine, thereby decreasing the dose requirement. The lower dose requirement of opioids and local anesthetics would decrease the incidence of side effects compared with epidural morphine alone. The safety of epidural clonidine when used with morphine and bupivacaine via PCEA was also evaluated.
| Materials and Methods|| |
The institute's Ethics Committee approved the study protocol. Sixty patients aged between 18 and 65 years, ASA(American Society of anesthesiologists) physical status I-II, posted for lower abdominal surgery were included in the study. All patients gave informed consent.
Exclusion criteria were as follows:
Patients were randomly assigned to one of the three study groups (C0, C1, C2) of 20 patients each. Randomization was done by sealed envelope technique. All study personnel and participants were blinded.
- History of allergic reaction and contraindications to any of the analgesic drugs.
- Contraindications to epidural catheter placement.
- Chronic use of opioids, nonsteroidal anti-inflammatory drugs or corticosteroids.
- Inability to understand PCEA, the NRS, or the study protocol.
All patients were subjected to fasting for over 8 h and premedicated with oral diazepam 0.1 mg/kg 1 h before surgery. On arrival in the operating room, standard anesthesia monitoring was attached, including noninvasive blood pressure, continuous electrocardiogram, and pulse oximetry. Baseline values were recorded.
Before the induction of general anesthesia, lumbar epidural catheter was inserted at a T12-L2 interspace. Epidural anesthesia was induced using 10 mL of 1% lidocaine and epinephrine (1:200,000) and was maintained from 30 min thereafter by continuous infusion of the lidocaine - epinephrine solution at a rate of 6-10 mL/h until completion of surgery. Level of T6 was established and confirmed with loss of sensation to pinprick before induction of anesthesia. General anesthesia was administered using injection propofol (2 mg/kg), fentanyl (2 mcg/kg), and endotracheal intubation was facilitated with vecuronium (0.1 mg/kg). Anesthesia was maintained with isoflurane in 40%-50% nitrous oxide.
After surgery, group C0 received PCEA with morphine (0.1 mg/mL) in 0.1% bupivacaine, whereas group C1 and C2 received clonidine in addition to morphine (0.1 mg/mL) and 0.1% bupivacaine in doses 1 and 2 mcg/mL, respectively. 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 lock out time of 15 min. There was no 4-h limitation. A basal infusion was not used. All observations and interventions were made by an acute pain service resident who was blinded to the treatments. The period of observation was 72 h. Side effects associated with morphine administration (pruritus, drowsiness, dizziness, nausea and vomiting, respiratory desperation) were recorded at 1, 2, 4, 8, 12 h after surgery and at 9.00 am on 1st, 2nd, and 3rd postoperative days.
NRS-11 and four-point Categorical Rating Scale (CRS) were used to assess pain intensity at rest, cough, and on movement from lying down to sitting position at 1, 2, 4, 8, 12 h after surgery and at 9.00 am on day 1, 2, and 3 after surgery.
The amount of PCEA analgesic solution consumed postoperatively was also measured. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and sedation scores were recorded at 1, 2, 4, 8, and 12 h after surgery and at 9.00 am on 1st, 2nd, and 3rd postoperative days.
Sedation was assessed using the following scale. 
Sensory blockade was assessed by pinprick and alcohol sponge. Lower limb motor blockade was graded according to the Bromage scale  (Modified Bromage scale): 0 = no motor block; 1 = able to move knees; 2 = able to move feet only; and 3 = unable to move feet or knees.
- Awake and alert.
- Awake but drowsy, responsive to verbal stimulus.
- Drowsy but arousable, responsive to physical stimulus.
- Unarousable, not responsive to physical stimulus.
All patients received only PCEA and rescue fentanyl. If the patient complained of pain, up to one to two additional boluses PCEA doses were administered along with intravenous fentanyl 20 mcg administered every 10 min until the patient was pain free (not exceeding 1 mcg/kg).
Postoperative nausea and vomiting (PONV) were assessed with a four-point scale  : 0 = no nausea; 1 = slight nausea; 2 = moderate nausea; and 3 = severe nausea with vomiting.
After 72 h, patients were asked to score their level of satisfaction with regard to pain relief for the initial postoperative period (three days) on a four-point scale  : 1 = totally dissatisfied; 2 = moderately dissatisfied; 3 = reasonably satisfied; and 4 = totally satisfied with pain relief.
All patients were asked the kind of pain treatment they would choose in the future for a similar operation.
A power analysis was performed using the volume of analgesic solution consumed during PCEA as the primary variable and retrospective data from a surgical population at our institution. A sample size of at least 20 patients per group was necessary for a group difference of 15 mL in the mean volume of analgesic used during PCEA and a one-tailed type I error rate of 0.05 to be detected with a power of 80%. Descriptive data were summarized as means (SD) or as percentages. Differences in the mean postoperative NRS score, volume of analgesic consumed epidurally, and rescue fentanyl dose consumed postoperatively were assessed by one-way analysis of variance and multiple comparisons. The incidence of PONV and sedation score were analyzed by Chi-square test. A Cox regression analysis was used to compare the day when flatus was first passed. All the analyses were done using software and Primer for biostatistics software.
| Results|| |
Demographic variables did not differ significantly among the three groups [Table 1], [Table 2] and [Table 3]. None of the patients were excluded from the study. Twenty patients in C0, 19 patients in C1, and 17 patients in C2 required rescue fentanyl after 12 h postoperatively. Number of patients in clonidine groups requiring rescue analgesia were significantly less as compared with non clonidine group and the difference was statistically significant (P < 0.001) at 2, 4, 8, and 12 h. Also, mean doses of rescue analgesia consumed by clonidine groups were significantly less and the difference was statistically significant (P < 0.001).
Patients in all the three groups experienced adequate pain relief during the 72 h period after surgery. There was no statistically significant difference between the mean NRS scores and CRS scores for pain at rest, cough, or during mobilization from the supine to sitting at any time between the three groups as shown in [Table 4], [Table 5] and [Table 6].
The cumulative volumes of analgesic solution consumed by the different groups during the study period were C0, 131 ± 21.285 mL; C1, 89.9 ± 18.44 mL; and C2, 80.1 ± 21.32 mL. There was no significant difference in the PCEA analgesic consumption between groups C1 and C2. (P = 0.128). Groups C1 and C2 required lower volume of analgesic solution. P < 0.001) than Group C0. Also the number of rescue doses consumed by clonidine group were less (P < 0.001).
Hemodynamic data are shown in [Table 7], [Table 8] and [Table 9]. HR recorded was lower in the clonidine groups than in the control group, the difference being statistically significant (P < 0.05) except at 12 h (P = 0.202) [Table 7].
Although SBP and DBP were lower in the clonidine groups than in control group, the difference was not statistically significant (P > 0.05) except for SBP at 4 h (P = 0.0190). However, the fall in blood pressure was not significant clinically. The fall in SBP was less than 20% of baseline and HR was more than 50 beats/min for all patients at all sampling intervals during the postoperative period. [Table 8] and [Table 9].
However, patients receiving clonidine were more sedated when compared with control and the difference was statistically significant at 8 h, 12 h, postoperative day 1, 2, and 3. post operative day (POD). None of the patients had a score greater than 3 after 2 h postoperatively.
None of the patients in any of the three groups suffered from prolonged sensory blockade. One patient in group C1 suffered from motor blockade (Modified Bromage Scale 2) for the initial 2 h postoperatively, which was attributed to intraoperative epidural supplementation.
Pruritus was observed only in groups C0 and C1. One patient in each group experienced pruritus on 2nd and 3rd postoperative day. Overall incidence of pruritus was 3.33%. It was treated with intravenous ondansetron 4 mg with good relief.
Eight patients (40%) in C0, three (15%) patients each in C1 and C2 groups suffered from nausea, including one patient in C1 group, who suffered from severe nausea (score 2). The overall incidence of nausea and vomiting was less in clonidine groups as compared with control group but the difference was not statistically significant (P = 0.097). All patients who had nausea or vomiting were treated with intravenous ondansetron 4 mg.
All patients had an indwelling bladder catheter for 3 days, therefore urinary retention as a side effect could not be evaluated.
According to Cox regression analysis, the time taken to first pass flatus between three groups was not statistically significant (P = 0.838).
All patients were either satisfied or reasonably satisfied by the degree of pain relief obtained. Overall, 35 patients (58.3%) were reasonably satisfied and 25 patients (41.7%) were fully satisfied. Overall satisfaction concerning the pain management regimen was good to excellent in all three groups. There was no statistically significant difference between all three groups (P = 0.0740).
All patients said that they would choose the same kind of pain treatment for a similar type of surgery in the future.
| Discussion|| |
The aim of postoperative analgesia is to provide subjective comfort with minimum side effects. Adequate analgesia helps to blunt autonomic and somatic reflex responses to pain and allows early ambulation and restoration of function.
A review article by Moraca et al. on the potential and proven benefits and complications of epidural anesthesia/analgesia suggested improved postoperative outcome and attenuation of the physiological stress response to surgery.  Meta-analysis of retrospective and prospective studies has demonstrated an improvement in surgical outcome through beneficial effects on perioperative pulmonary function, blunting the surgical stress response, and improved analgesia. In the same study, they found significant reduction in preoperative cardiac morbidity (~30%), pulmonary infections (~40%), pulmonary embolism (~50%), ileus (~2%), acute renal failure (~30%), and blood loss (~30%). Potential complications related to epidural anesthesia/analgesia range from transient paresthesia (<10%) to potentially devastating epidural hematomas (0.0006%). 
The addition of other adjuvant drugs, such as clonidine or ketamine, to solutions of analgesics may, through additive and synergistic mechanisms result in better analgesia.  This effect may reduce the dosage of opioids and thus decrease the incidence of dose-related side effects. 
Clonidine induces dose-dependent spinal cord antinociception, mainly through stimulation of α2-adrenoceptors in the dorsal horn, mimicking the activation of descending inhibitory pathways. 
Epidural administration of clonidine in combination with opioids or local anesthetics has been used in single bolus doses of 75-80 mcg or continuous infusion rates of 20-50 mcg/h. However, these higher dosages of clonidine are commonly associated with hypotension, bradycardia, and sedation. 
The main finding of our randomized study was that the optimal epidural clonidine concentration in a morphine (0.1 mg/mL) and bupivacaine (0.1%) solution after lower abdominal surgery is 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. There was no statistically significant difference between the mean NRS scores at rest, cough, or during mobilization from the supine to sitting at any time between the three groups. Similar findings were seen in a study of postoperative analgesia after total knee replacement surgery by Huang et al. 
The cumulative volumes of analgesic solutions consumed by the different groups during the study period were C0, 131 ± 21.28 mL; C1, 89.9 ± 18.84 mL; and C2, 80 ± 21.32 mL. Groups C1 and C2 required a significantly lower volume of analgesic solution (P < 0.001) than group C0. However, the volume of analgesic solution used by groups C1 and C2 during postoperative PCEA (P = 0.128) did not differ significantly. Also the numbers of rescue doses consumed by the clonidine groups were significantly less (P < 0.001).In our study, the NRS was used for pain assessment as many patients were not able to score pain on VAS. Verbally administered NRS has been substituted for the VAS in acute pain measurement. 
In our study, arterial pressure and HR were slightly lower in the clonidine group than in the control group. Similar modest hemodynamic changes have been described consistently in many previous studies utilizing clonidine for postoperative analgesia. , After neuraxial 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. showed that 160 mcg clonidine decreases arterial blood pressure by merely 18% and reduces HR only by 5%-20%, and concluded that epidural clonidine does not induce hemodynamic instability.  Another study by Huang et al also found that the lack of an obvious deleterious effect on SBP and HR, which might have been due to small doses of clonidine (mean, 49.6, 96.2, and 157.6 μg for groups C1, C2 and C4 respectively) delivered by PCEA during the first 3 days after surgery. 
Mogensen et al demonstrated that thoracic epidural analgesia after hysterectomy is improved by administration of 18.75 mcg/h clonidine in a mixture of bupivacaine (5 mg/h) and morphine (0.1 mg/h). 
Peach et al. reported that clonidine (20 mcg/h) in a mixture of bupivacaine (6.25 mg/h) and fentanyl (10 mcg/h) improves postoperative thoracic epidural analgesia after abdominal gynecological surgery. However, hemodynamic changes, that is, dose-dependent decrease in blood pressure and pulse rate and an increase in vasopressor requirement were also observed in the study.  Forster and Rosenberg 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 lower abdominal surgery and did not cause clinically significant hemodynamic perturbations. 
In our study none of the patients suffered from prolonged sensory blockade. One patient in Group C1 suffered from motor blockade (Modified Bromage Scale) for initial 2 h postoperatively, which was attributed to intraoperative epidural supplementation.
The effects of clonidine on the prolongation of nerve blockade are dose dependent. , In a study by Huang et al., after total knee replacement, 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. 
Postoperative nausea and vomiting (PONV) still remains a common and undesirable side effect of anesthesia. Eight patients (40%) in C0 and three patients (15%) each in C1 and C2 suffered from PONV. Although the incidence of nausea and vomiting were less in clonidine groups, the difference was not statistically significant as compared with the nonclonidine group. Also, decreased PONV (P = 0.097) in the clonidine group may be due to lower dose of opioids received. There are recent reports that α2-adrenergic agonists might be useful in the treatment of nausea and vomiting. , About 14 (23.3%) of our patients suffered from PONV, which is less than the incidence in other reports using epidural opioid analgesia (on average 42%). 
Sedation is frequently associated with the use of clonidine and is often observed when clonidine is used in conjunction with opioids. ,, In our study, sedation scores were higher in clonidine group as compared with control group and the difference was statistically significant at 8 h, 12 h, postoperative day 1, 2, and 3. However, none of the patients in any of the groups had sedation scores more than 3. In other words, patients were mildly sedated. Probably the dose of clonidine used was low and therefore did not contribute to sedation.
Pruritus after neuraxial administration of opioids is a well-known adverse effect with a reported range of incidence as wide as 0%-100%.  Pruritus in groups C0 and C1 were observed in one patient (5%) each postoperatively, on day 2 and day 3. Overall incidence of pruritus in our patients was 3.3%. This contrasts with the findings of Arms and Shaw who reported an incidence of pruritus ranging from 27% to 40% after epidural morphine. ,,
Patient satisfaction is rapidly evolving as an important consideration in the field of postoperative pain management. JCAHO and The National Committee for Quality Assurance (NCQA) have introduced standards that list patient satisfaction as one of several performance yardsticks.  Postoperative pain management was satisfactory, which is evident by the fact that overall satisfaction concerning the pain management regimen was good to excellent in all the three groups. This may also be due to frequent monitoring, patient involvement in self-care, and their control over pain. There was no statistically significant difference between satisfaction levels in all the three groups (P = 0.0740).
When multidrug regimes are employed to address acute postoperative pain, it makes physiologic, pharmacologic, and economic sense to use the minimum effective analgesic concentration of all the drugs. Our study demonstrated that when administered through PCEA, a solution of bupivacaine 1.0 mcg/mL, morphine 0.1 mg/mL, and clonidine 1.0 mcg/mL provided optimal dynamic analgesia after lower abdominal surgery without significant adverse effects.
The limitation in this study was that it was powered to prove the decrease in analgesic requirement. With this sample size the decrease in opioid-related side effects due to reduced PCEA analgesic consumption could not be proved.
| Conclusion|| |
There is a synergism between epidural clonidine (1 mcg/mL) and epidural morphine and bupivacaine, that is, lower doses of analgesics are needed to achieve dynamic pain relief. At the same time, this dose of clonidine does not increase morbidity.
| Acknowledgments|| |
The authors thank Dr. Manisha Hemrajani, Ms. Laxmi Shekhawat, and Mr. Anil Prajapati for their help.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]