Addition of epidural Clonidine enhances postoperative analgesia: A double-blind study in total knee- replacement surgeries.

BACKGROUND: This study was undertaken to evaluate the analgesic effect of the combination of epidural Clonidine with Bupivacaine versus epidural Bupivacaine alone in patients undergone knee replacement surgery.
MATERIALS AND METHODS: A randomized double-blind design was used, and 60 adult patients (40-60 years) of ASA grade I and II scheduled for post-operative pain relief in total knee replacement surgeries by epidural Clonidine were studied. Patients received either an epidural Clonidine (1μg/kg) with Bupivacaine (1.5mg/kg) group CL (n=30) or Bupivacaine alone group CT (n=30) for Knee replacement surgeries. The pain score, blood pressure, heart rate, respiratory rate were measured at fixed times during the first 24 h after operation. Onset and duration of sensory and motor blockade, duration of analgesia, and analgesic requirement were compared.
RESULTS: The onset of sensory anesthesia was faster (493.8±31.66 in sec.) and the duration was significantly longer in Clonidine group (334.2 min). Requirement of supplementary analgesia (Inj. diclofenac) was markedly decreased in Clonidine group as evident from the findings that in control group 18 patients required 3 supplemental analgesic doses in first 24 hours as compared to only 3 patients in Clonidine group. Epidural Clonidine produced a significant decrease (P less than 0.05) in heart rate and blood pressure, whereas the respiratory rate was not affected. We also observed for side effects in both the groups. Incidence of significant hypotension was higher, 8 patients (26%) in Clonidine group compared to 2 patient (6%) in control group. Incidence of dryness of mouth was higher, 12 patients (48%) in Clonidine group compared to 5 (18%) in control group.
CONCLUSION: The addition of Clonidine to Bupivacaine epiduraly prolongs motor and sensory block and analgesia, without an increased incidence of side effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Alpha2-adrenergic receptors are present both peripherally on nerve endings, in the spinal cord and in the brainstem. Alpha2 agonists probably exert their main analgesic activity in the spinal cord, presynaptically on thin afferents by reducing transmitter release. It also acts postsynaptically by interfering with NO-mechanisms and protein kinases as well as by stimulation of cholinergic interneuron. Use of Alpha2 agonists is hampered by side effects such as hypotension and sedation when given in doses that are analgesic as single agent.[1-4] Clonidine is the only alpha2 agonist that is commonly available. Number of studies has shown its effect on postoperative pain when given orally, intravenously, epiduraly, and intrathecally. In addition the prolongation of anaesthesia when added to peripheral local anesthetic blocks is, well known.[5-10] There is now increasing evidence that the spinal and epidural route is superior to systemic administration.[9-11] Epidural PCA versus Intravenous PCA showed better analgesia with a lower dose, less sedation and less depression of blood pressure following the epidural route by its actions on the spinal cord and reduction in NMDA mediated effects[10-12]

The present study was undertaken to evaluate and compare the onset and duration of sensory anesthesia, motor paralysis and duration of postoperative analgesia by using 0.5% Bupivacaine plain, with Clonidine (1μg/kg) epiduraly.

MATERIALS AND METHODS

After taking consent from ethical committee and informed consent from the patient of both the sex ASA grade I and II adult patients (40-60 years) undergoing total knee replacement surgery were selected. All selected patients were randomly allocated in to two equal groups in double blind study. All patients were thoroughly examined and investigated. Each selected patient was informed in general terms regarding the procedure of the study prior to analgesia and anesthesia as per hospital rules and regulations. We have selected only one type of surgery and the same operating surgeons’ team so that comparison is more effective.

We noted Baseline vitals and divided the Patients into two equal groups of thirty each: group CT (Control) and group CL (Clonidine).

Group CT - Inj. Bupivacaine plain 0.5% 1.5 mg/kg

Group CL- Inj. Bupivacaine plain 0.5% 1.5 mg/kg + Clonidine 1 μg/kg

Before procedure, vital data like temperature, pulse, blood pressure and respiration rate and SPO2 were noted. All the patients were monitored in the form of blood pressure, heart rate, respiratory rate and ECG and oxygen saturation (SPO2) at 1 min, 5min, 15 min, 30 min, 60 min, 90 min. Onset of sensory and motor blockade, quality of surgical anesthesia were evaluated as follows:

Motor function was assessed using a modified Bromage scale (zero, bilateral sustained straightening of leg; 1, unable to straighten leg; 2, just able to flex knees; 3, foot movement only) and sensory block was assessed using the pinprick method. Sedation was also evaluated by five-point scale (1, wide awake; 2, drowsy; 3, dozing; 4, mostly sleeping; 5, awakening only when aroused). Visual analogue scale was shown to the patient and the procedure of postoperative pain measurement was explained in detail.

Patients were instructed and trained on the use of 10 cm visual analogue scale (VAS): 0=No pain and 10=worst imaginable pain, the other side of the ruler is graduated over 100 mm and gives the investigator the numerical measure of pain. The other side effects such as itching, tremor, nausea-vomiting, motor block and hypotension were recorded. After surgery, patients were shifted to the recovery room and temperature, pulse rate, blood pressure, respiratory rate, SPO2 and visual analogue scale (VAS) were measured at 15 min, at 30 min, at 60 min, at 90 min then at 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, and then lastly at 24 hours. Time of regression of analgesia to pin prick below T12 dermatome was considered as duration of anesthesia. Supplemental analgesia was administered in form of injection Diclofenac sodium 75mg. I.M. when VAS is ≥5 and it was considered as duration of postoperative analgesia. The numbers of doses required in 24 hours were recorded. Duration, intensity and number of episodes of nausea, vomiting, bradycardia, hypotension, respiratory depression was noted.

STATISTICAL ANALYSIS

The data was analyzed using student ‘t’ test as applicable for comparison of different parameters in group CT and group CL.P value of <0.05 was considered as statistically significant and P value of <0.005 as highly significant.

RESULTS

The age, weight and were comparable in all the groups. Mean time for onset of sensory anesthesia in seconds was 493.8±31.66, 686.4±47.42 in Clonidine and control group respectively. Similarly, the mean time for onset of motor anesthesia in seconds was 615.6±31.99 and 808.0±54.39 in Clonidine and control group respectively. Therefore, Clonidine has faster sensory and motor onset than control group.

In present study, at 60 min intra operatively we observed more decrease in heart rate in the Clonidine group (74.33±8.90) compared to control group (81.96±6.41). And this difference is maintained in post operative period up to 5 hr [Table 1].

Table 1

Demographic data, onset of motor and sensory block

There was fall in blood pressure in all groups after epidural Anesthesia. However, it was greater in Clonidine group as compared to control group. In our study, preoperative mean arterial blood pressure in mmHg before premedication was 93.76±6.64 and 92.92±6.39 in Clonidine and control group respectively, which was not significant statistically. MAP changes at 30min intraoperative was 76.24±3.59 and 80.06±3.37 in group Clonidine and control group respectively and this fall in MAP was statistically highly significant between Clonidine and control group [Table 2].

Table 2

Change in pulse rate

There were no significant changes in Oxygen saturation and respiratory rate in any of the groups. There was not much difference in sedation score between both the groups

Duration of postoperative analgesia was very much prolonged in Clonidine group (334.2 min) as compared to control group (161.4 min). On intergroup comparison, the prolongation of the duration of postoperative analgesia was statistically significant between Clonidine group and control group [Table 3].

Table 3

Change in blood pressure (mean arterial pressure)

Requirement of supplementary analgesia (Inj. diclofenac) was markedly decreased in Clonidine group as evident from the findings that 16 patients in control group required 3 supplemental analgesic doses in first 24 hours as compared to only 3 patients in Clonidine group. Thus, Clonidine given epiduraly significantly reduced postoperative analgesic demand than control.

We also observed side effects in all three groups. Incidence of significant hypotension was higher, 8 patients (27%) in Clonidine group compared to 1 patients (3.3%) in control group. Incidence of dryness of mouth was higher, 12 patients (40%) in Clonidine group compared to 5 patients (17%) in control group. During postoperative period, 15(50%) patients were having sedation score of 2 in Clonidine group as compared to control group [Table 4].

DISCUSSION

Alpha-2 adrenergic agonists are known to have spinal and epidural antinociceptive effect via alpha-2 receptor sub types. Clonidine, a well-known alpha-2 adrenergic agonist, produces a synergistic antinociceptive effect with opioids. Several studies have been published in the last decades describing the anesthetic sparing effects and analgesic property of epidural clonidine.[1-3] Clonidine, a a-2 agonist agent, is causing analgesia with a non-Opioid mechanism as an alternative agent to Opioid.[13-15] It was stated that clonidine neither affects proprioception like local anesthetics nor causes respiratory depression, itching, nausea and vomiting like Opioids, but When given by epidural route with local anesthetics, it increase analgesia potency. However, it is also true that it causes side effects like hypotension, bradycardia and sedation[1315]

Additive effect of Clonidine to local anesthetics can be explained by various mechanisms. α-2 agonists form their antinociceptive effects probably by affecting descending noradrenergic tract in spinal cord that plays an important role in pain modulation by a non-opioid mechanism[15]. Noradrenergic ganglions in pons and medulla can not be activated by Opioid or noxious stimulus that causes nor epinephrine secretion at dorsal horn of spinal cord.[23] When molecular weight, lipid solubility and cerebrospinal fluid pharmacokinetics of clonidine are taken into consideration, start of its analgesic effect and duration of analgesia can be expected to be similar to Fentanyl but analgesic effect of Fentanyl starts faster and lasts longer.[1617]

All our patients were comparable with respect to demographic profiles and duration of surgery. A comparison of homodynamic effects of the drug shows statistically highly significant fall in MAP at 30 min. intraoperative. In present study, at 60 min intra operatively we observed decrease in heart rate in the Clonidine group compared to control group. On inter group comparison; this difference in pulse rate was statistically significant during whole intra operative period. Ikeda Yoshikazu, Nishikawa Kiyonobu et al.,[18] in their study in 2003, concluded that epidural administration of Clonidine induces hypotension and bradycardia secondary to decreased sympathetic nerve activity. Michael G. Rock Mann, Wulf Seeling, et al.,[19] in their study in 1995 concluded, that homodynamic alteration after epidural clonidine under conditions of stable filling pressures is caused mainly by a decrease in HR. It is not an effect of analgesia but of the intrinsic antihypertensive action of clonidine.

In the present study, duration of postoperative analgesia was very much prolonged in Clonidine group (334.2 min) as compared to control group (161.4 min). On intergroup comparison, the prolongation of the duration of postoperative analgesia was statistically significant between Clonidine group and control group. Robert K. Parker et al.,[20] in 2006 studied that Epidural Clonidine added to a Bupivacaine infusion increases analgesic duration in labor without adverse maternal or fetal effects. The mean duration prior to request for additional analgesia was significantly longer in the Clonidine group (269±160min), compared to the control group (164±64min).Youan--shiou-huang et al.,[21] done study of epidural Clonidine for postoperative pain total knee arthroplasty in Eighty ASA I-III patients, who underwent total knee arthroplasty, who received patient-controlled epidural analgesia (PCEA) with Clonidine. The analgesia effect was estimated by PCEA consumption volume and visual analog pain scale at rest and with movement at 1, 2, 4, 12, 24, 48, and 72 h after surgery. The Clonidine groups experienced less postoperative pain (P=0.002) in this study.

Giovanni cucchario et al., in 2006 compared the incidence of vomiting, and Pruritus as well as the analgesic profile and the sedation score. He studied three different combination of Bupivacaine, Clonidine, Fentanyl administered epiduraly, in patients undergoing Nuss procedure for pectus excavatum. He found no significant difference in sedation score (score=2) intraoperative as well as postoperatively among Bupivacaine- Clonidine and Bupivacaine- Fentanyl groups.[22] He also found that The number of patients who experienced vomiting in the study period was significantly less in the Clonidine group (27%) compared with the Fentanyl and Clonidine-Fentanyl groups (69% and 55%, respectively) (P=0.030). The number of patients who experienced pruritus was significantly less in the Clonidine (0%) group versus the Fentanyl (85%) and Clonidine-Fentanyl (54%) groups (P=0.01).

Similarly in our study 3 (10%) patients in Clonidine group experienced nausea as compared to 4 (14%) patients in control group, and 1 (3.3%) patient in Clonidine group compared to 2 (6.6%) patients in control group had vomiting.

CONCLUSION

In summary, Clonidine has interesting pain modulating effects, administration of Clonidine epiduraly with Bupivacaine significantly prolongs duration of sensory and motor blockade and duration of analgesia, but per operative hypotension may restrict the use of doses that are analgesic alone. However, there is increasing documentation of advantages of their use in analgesic combinations. For Clonidine, the epidural or intrathecally route seems most promising at present. In the near future, we can expect new alpha2 agonists to reach the clinic. We hope that these new agents are even more potent than our present drugs, and devoid of some of their side effects that limit a more widespread use.

Table 4

Duration of postoperative analgesia in minutes