This randomized and placebo controlled study was performed at a Tertiary Medical College Hospital in Chennai. Forty patients were chosen for the study and by simple random sampling they were divided as 20 patients for each group. Patients who were posted for orthopaedic lower limb surgeries in the age group of 18 years to 65 years belonging to ASA physical status I & II were chosen for the study. After getting approval by the institutional ethical committee and after obtaining written informed consent from each patient, the study was conducted.

All patients were assessed preoperatively before enrolling for the study. No premedication was given. On arrival in the operating room, baseline cardio respiratory parameters viz., Heart Rate (HR), Systolic blood pressure (SBP), Diastolic blood pressure (DBP), Mean arterial pressure (MAP) and Respiratory rate (RR) were recorded. A good intravenous access was established using 18G IV cannula. Preloading was done with ringer’s lactate solution at 10 ml/kg.

Patients were allocated randomly into two equal groups (20 in each group). Group P (placebo) received 1 ml of normal saline with the first dose of epidural 0.5% bupivacaine. Group C (clonidine) received 50μg of fixed dose of clonidine diluted with normal saline to 1 ml epidurally along with the first dose of bupivacaine.

With the patient in sitting posture, after informing the procedure to the patient & under strict aseptic precautions, epidural space was identified at L3-L4 interspace using 16G Tuohy needle by loss of resistance technique. Epidural catheter was threaded in a cephalad direction & 4 cm of catheter length was kept inside the epidural space. A test dose of 3 cc of 1.5 % lignocaine with adrenaline (5μg/ml) was given. After confirming negative result for test dose, epidural catheter was fixed and secured with tapes. A standard anaesthetic technique was followed in all patients.

Epidural 1^st dose - 14 ml of 0.5% bupivacaine + 1ml of placebo or 50 μg of injection clonidine diluted with normal saline to 1 ml.

Epidural 2^nd dose - 6ml of 0.5% bupivacaine (90 min after 1^st dose)

Patients with duration of surgery between 2-2:30 hours requiring standard 2 doses of epidural local anaesthetics were only taken up for study. Time of incision was noted. Heart rate (HR), Systolic blood pressure (SBP), Diastolic blood pressure (DBP), Mean arterial pressure (MAP) and Respiratory rate (RR) were continuously monitored intraoperatively and noted every 10 min. Ramsay sedation scale (RSS) was also noted every 30 min.

All patients were given oxygen supplementation (4-5 L/min) through Hudson’s face mask. No intravenous opioid analgesics were supplemented during the study. Intravenous fluid management was done based on Mean arterial blood pressure and surgical blood loss.

The epidural catheter was retained in position. Postoperatively the patient was transferred to the Post Anaesthetic Care Unit (PACU) where PR, SBP, DBP, SPO₂ & RR monitored continuously and recorded every hour. The intensity of pain was measured by using the verbal pain rating scale.

Grade 0 - No complaint of pain

Grade 1 - Patient complaints of pain but tolerable (mild pain)

Grade 2 - Patient complaining of severe pain and demands relief (Moderate pain)

Grade 3 - Patient restless and screaming with pain (Severe pain)

When the patient complained of pain, the pain intensity was assessed based on verbal rating scale & if pain score reaches 1, epidural top up of 6ml of 0.125% bupivacaine was given to the patient.

The time of first rescue analgesia (TFA) was calculated from the time of injection of study drug in the epidural space to the time when the verbal rating pain score reached 1 in the postoperative period. Number of epidural top-ups (6 ml of 0.125% bupivacaine) required by each patient for a period of 48 hours was noted in both the groups. Patients were observed for any side effects like hypotension, bradycardia, respiratory, depression and shivering.

Patients in both the groups were similar in terms of age, sex, height, weight distribution [Table/Fig-1] and type of surgery. All the data were expressed as mean ± standard deviation (SD). Qualitative variables were compared with ‘Chi-square test’ and quantitative variables were compared with the ‘student t-test’. The level of statistical significance was set at p < 0.05. There was no significant difference in the duration of surgery (hour) between the two groups [Table/Fig-2].

During the intraoperative monitoring, there were no significant changes in heart rate [Table/Fig-3] and respiratory rate [Table/Fig-4] among the two groups. Difference in Systolic blood pressure monitoring between two groups were found to be significant only during 60,70,110,120,130,150 minutes [Table/Fig-5]. Difference in Intraoperative Diastolic Blood Pressure monitoring between the two groups were found to be significant only during 60, 70 and 110 minutes [Table/Fig-6]. Difference in Intraoperative Mean Arterial Pressure monitoring between the two groups were found to be significant only during 60, 70 and 110 minutes [Table/Fig-7].

According to Chi- square test, Difference in Ramsay Sedation Scale (RSS) between the two groups was significant at 30 min (p-0.003), 60 min (p<0.001) and 90 min (P<0.001). Difference in RSS between the two groups was not significant at 120 min and 150 min respectively [Table/Fig-8].

The postoperative pain score (verbal rating scale) was found to be significantly low at 4, 12, 18 and 24 hours in Group C when compared to Group P. Significantly low pain scores were observed at 4, 12, 18 and 24 hours intervals in patients belonging to Group C (p < 0.001 at 4,12 and 24 hours intervals and p -0.004 at 18 hours interval) than Group P [Table/Fig-9]. The study demonstrated that pain relief was significantly better (p < 0.05) in patients who received epidural bupivacaine with clonidine than the patients who received epidural bupivacaine with placebo. The mean time of first rescue analgesia (hours) was found to be (6.05±0.65 hours) in Group C as compared to (3.27±0.53 hours) observed in Group P which was statistically significant (P-0.001) [Table/Fig-10].

The no of postoperative epidural top ups for next 48 hours were significantly low (4 or 5 doses) in group C compared to (6 or 7 doses) in Group P [Table/Fig-11].

A number of clinical trials have been conducted to prove the efficacy of anti- nociceptive effect of α2 agonists using different techniques and different types of drugs with conflicting results. The use of epidural techniques also offers the advantage of effective prolonged postoperative analgesia as compared to nerve blocks and local infiltrations.

The dose-dependent antinociceptive effects of clonidine were demonstrated in 1981. These effects are partly mediated by spinal cord muscarinic and nicotinic receptors and the release of acetylcholine and by the activation of inhibitory noradrenergic pathways. In experimental studies, animal models and clinical trials, subarachnoid opioids, local anaesthetics and α2 adrenergic agonists show synergistic or additive interactions. Intrathecal or epidural clonidine is not neurotoxic [3].

In this randomized and placebo controlled study, we have evaluated the analgesic efficacy of bupivacaine with clonidine mixture given through lumbar epidural route in patients undergoing orthopaedic lower limb surgeries.

In this study, we found that bupivacaine and clonidine administered epidurally, reduced the amount of analgesic that patients required postoperatively suggesting that clonidine may enhance the analgesic effect of bupivacaine. This study correlates with the meta-analysis done by Armand et al., which concluded that epidural clonidine clearly produced an analgesic effect and reduced the need for other analgesics [4].

The level of sedation intraoperatively was monitored using Ramsay Sedation Scale. The patients in Group C were well sedated and comfortable than in Group P [Table/Fig-8]. This study correlates with the study conducted by Vieira AM et al., and Parker RK et al., in which they concluded that the association of clonidine and local anaesthetic (ropivacaine [5,6], bupivacaine [7–9]) had produced longer analgesia and sedation [10].

Pain intensity was assessed using the verbal rating scale (VRS) postoperatively. Significant lower VRS scores after 2,4,6,8,12,18,24,36,48 hours [Table/Fig-9], in group C has demonstrated the clinical advantage of administering mixture of bupivacaine and clonidine through lumbar epidural route for effective postoperative analgesia [8,11–17].

Duration of analgesia was significantly more in group C patients receiving bupivacaine and clonidine mixture (6.05±0.64 h) as compared to Group P (3.26±0.53 h). The demand for supplementary epidural top-ups over 48 hours postoperatively was significantly low in group C than Group P [Table/Fig-10]. This correlates with the study of Armand et al., [4].

In this study the dosage of clonidine was fixed at 50 μg for all patients in Group C. Because of the low dose of clonidine used, when compared to Thimmappa M et al., and Gupta S et al., the incidence of side effects were very low [6,8]. Two patients of placebo Group (10% of Group P) and two patients of clonidine group (10% of Group C) had episodes of hypotension with a MAP< 70 mm Hg during intraoperative period [Table/Fig-4,5 and 6] who were managed with a single dose of ephedrine 6 mg iv and crystalloids, and this may be as a result of epidural bupivacaine as such. Postoperatively none of the patients had episode of hypotension. No incidence of any bradycardia [Table/Fig-3] was noted in both the group during intraoperative and postoperative period.

Single dose administration of clonidine and bupivacaine mixture given through lumbar epidural route provides effective postoperative analgesia in patients undergoing elective orthopaedic lower limb surgeries, without any hemodynamic instability. Epidural clonidine significantly reduces the postoperative analgesic consumption and also provides good sedation.