Attenuation of postoperative pain, especially with certain types of analgesic regimens, may decrease perioperative morbidity and mortality [1]. Acute pain results in potentially life-threatening problems [2]. Epidural anesthesia with local anesthetics, reduces physiologic responses to surgery and also provides superior pain relief [3]. Various adjuvants like opioids, epinephrine, clonidine, ketamine, neostigmine, adenosine, midazolam, magnesium, verapamil, ketorolac, etc. have been tried with local anesthetics in the epidural space, to enhance analgesia while minimizing side effects [4]. Clonidine being a partial α2 adrenergic agonist has antihypertensive effects and can potentiate effects of local anesthetics. It acts by opioids-independent mechanism, stimulates α2 adrenoreceptors reducing central neural transmission in spinal neurons, and inhibits the release of substance-P. It acts presynaptically interfering with nitric oxide mechanisms and protein kinases as well as by stimulation of cholinergic interneuron [5]. Anaesthesia was prolonged when clonidine was added to local anaesthetics for peripheral nerve blocks [6-12]. The analgesic effect of clonidine is more potent after neuraxial administration which points to a spinal site of action, thus favouring neuraxial (intrathecal or epidural) administration [13-16]. Epidural or intrathecal administration of clonidine potentiates the anesthetic action and reduces the dose requirement of volatile or injectable general or regional anesthetic agents with correspondingly fewer side effects [17-20].

62 patients undergoing elective lower abdominal, gynaecological and lower limb surgeries under epidural anesthesia at Kasturba Medical College Hospital, Mangaluru were enrolled in the study. Ethics committee approval and written informed consent from patients aged between 18 to 60 years, height more than 150 cm of ASA physical status 1 or 2 were obtained. Patients with absolute or relative contraindications for epidural, ASA grade 3 or 4, with an adverse reaction to local anesthetics, on alpha-adrenergic receptor blockers, calcium channel blockers, ACE inhibitors, with body weight > 120 kg and height < 150 cm were excluded. Patients were randomized and allocated into 2 groups of 31 individuals each by sealed envelope method.

Group І: 0.5% bupivacaine + 0.9% normal saline, 1 ml.

Group ІІ: 0.5% bupivacaine + Inj. Clonidine 2μg/kg (1 ml).

The volume of bupivacaine injected depended on the type of surgery and level of block required (1.5 ml/segment).

A pre-anesthetic evaluation was done for all patients on the day prior to surgery regarding history, general physical examination and relevant investigations. Baseline vital signs were recorded. Pre-operative preparation included a period of overnight fasting. Patients were introduced to the Visual Analogue Scale (VAS) and were taught how to use it. Zero end of the scale was taken as no pain and 10 as maximum possible pain imaginable. Patients asking for pharmacological premedication were excluded from the study. This was done to assess the effect of study drug i.e., clonidine, on sedation levels. After patients were transferred to the operating room, an Intravenous (IV) access was secured in the non-dominant upper limb using an 18G IV cannula. 10-15 ml/kg of IV crystalloid solution was given over 15 minutes just before administering epidural anesthesia. Minimum mandatory monitors like a pulse oximeter, non-invasive blood pressure and electrocardiogram were used and baseline oxygen saturation (SpO₂), Blood Pressure (BP) and pulse were noted. The patients were positioned in the lateral decubitus/ sitting position. Under absolute asepsis, L2-L3 interspace was punctured with an 18G Tuohy needle after infiltration of the skin and interspinous space with 2% plain lignocaine. Epidural space was identified with loss of resistance technique with saline. An 18G epidural catheter was then passed through the Tuohy needle and was left 4-5 cm into the epidural space in cephalad direction. A test dose of 3cc of 2% lignocaine with adrenaline 1:200,000 was given. BP, Pulse Rate (PR), Electrocardiograph (ECG) and SpO₂ were monitored intraoperatively. PR, BP and SpO₂ were measured at an interval of every 5 min up to 30 min, then at 15 min interval upto 60 min and thereafter at 30 min interval till the end of surgery. After confirming that there was no catheter misplacement, the control group(1) received 0.5% bupivacaine and 1 ml of 0.9% normal saline whereas the clonidine group (2) received 0.5% bupivacaine and 1ml of 2ug/kg of clonidine. During surgery, crystalloid intravenous fluids were administered at a rate of 150 ml/hr. Depending on perioperative blood loss and hemodynamic instability, additional IV fluids (crystalloids, colloids and blood) were administered.

(1) Respiratory rate lower than 8 breaths/ min.

(2) Oxygen saturation lower than 90%.

(3) Systolic blood pressure less than 90 mmHg.

(4) Inadequate analgesia (Patients with VAS more than 6 i.e severe to worst possible pain).

SPSS 11.5 software was used to perform statistical analysis. The student’s unpaired T-test was used for the analysis of mean age, height and weight distribution, time of onset of sensory and motor block, duration of motor block and analgesia. A chi-square test was used for the analysis of intraoperative side effects. P-value < 0.05 was considered statistically significant.

The age, weight and height were comparable in both the groups with no significant statistical differences (Table 1).

In this study, MAP in mm Hg preoperatively was 98.06 ± 7.12 and 97.77 ± 5.33 in control and clonidine group, respectively, which was not statistically significant.

Changes in Mean Arterial blood Pressure (MAP) at 60 mins after administration of the epidural drug was 83 ± 10.63 and 75.03 ± 9.06 in control and clonidine group, respectively. This fall in mean arterial blood pressure was statistically significant in the clonidine group (p-value= 0.002) (Table 2).

A decrease in pulse rate was statistically significant (p-value = 0.026) after 30 mins of drug administration in the clonidine group (71.94 ± 11.89) as compared to the control group (74.03 ± 9.74) (Table 3).

No significant difference in the onset of sensory and motor block in either of the groups. The clonidine group had a significant prolongation of the motor block (p-value < 0.001). Duration of motor blockade (in mins) was 108 ± 11.15 and 229 ± 44.27 in the control and clonidine group respectively (Table 4).

The analgesic duration was significantly prolonged in the clonidine group (p-value < 0.001) Duration of analgesia (in mins) was 136 ± 11.74 and 380 ± 63.01 in control & clonidine groups, respectively (Table 5).

Three patients had nausea and two patients had vomited in the control group. However, no significant difference was observed in the incidence of nausea and vomiting in either group. The control group had 19.4% of patients exhibiting shivering which was statistically significant (Fig. 1).

The clonidine group had patients with a sedation score of 3 and above, which was statistically significant (Fig. 2).

Synergistic antinociceptive effect with opioids is known to occur with clonidine, an α2 adrenergic agonist. Clonidine, an α2 agonist, produces analgesia with a non- opioid mechanism [24]. Clonidine does not affect proprioception like local anesthetics. Respiratory depression, itching, nausea and vomiting, which occur with opioids, are not seen with clonidine [24]. The potency of clonidine as an analgesic increased when given epidurally. Side effects like hypotension, bradycardia and sedation can occur. α2 agonists affect the descending noradrenergic tract in the spinal cord that helps in pain modulation via a non-opioid mechanism. All the patients in this study were comparable with respect to demographic profiles. In our study, there was a significant fall in mean arterial pressure at an interval of 60 min (p-value = 0.002) after the epidural injection of the drug in the clonidine group (75.03 ± 9.06) as compared to control group (83.00 ± 10.63). Ikeda et al. in their study in 2003, concluded that epidural administration of clonidine causes hypotension and bradycardia due to sympathetic blockade [25]. Rockemann et al. in their research in 1995, concluded that hemodynamic alteration after epidural clonidine was caused mainly by a fall in heart rate [26]. In our study, decrease in pulse rate was statistically significant (p-value = 0.026) after 30 minutes of drug administration in the clonidine group (71.94 ± 11.89) as compared to the control group (74.03 ± 9.74).

Intrinsic antihypertensive action of clonidine was known to cause this and not the effect of analgesia. In this study, the duration of analgesia was very much prolonged in the clonidine group (380.84 ± 63.01) as compared to the control group (136.06 ± 11.74). Parker et al. in 2007 studied increased analgesic duration on the addition of clonidine to bupivacaine continuous epidural infusion [27]. Huang et al. 2007 conducted a study on patients undergoing total knee arthroplasty, who received clonidine for patient-controlled epidural analgesia [28]. Less postoperative pain was seen in clonidine groups. Giovanni Cucchiaro in 2006 compared the incidence of vomiting and pruritus as well as the analgesic profile and sedation score of three different combinations of bupivacaine, fentanyl, and clonidine administered epidurally in patients undergoing Nuss procedure [29]. He found no significant difference in the sedation score. He also found that the number of patients who experienced vomiting was significantly less in the clonidine group. The number of patients who experienced pruritus was significantly less in the clonidine group versus the other groups. In our study, the clonidine group had a sedation score of 3 and above as compared to patients in the control group which was statistically significant.

No patients in the clonidine group experienced nausea and vomiting, whereas 9.7% of patients experienced nausea, 6.5% of patients experienced vomiting in the control group in our study.

There was an increase in the duration of analgesia following the addition of clonidine to bupivacaine 2 ug/kg in comparison to bupivacaine alone when instilled in the epidural space. The duration of motor block was increased with no effect on the onset of sensory and motor block.