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CLINICAL INVESTIGATION
Year : 2007  |  Volume : 51  |  Issue : 5  |  Page : 415 Table of Contents     

Efficacy of Analgesic Effects of Low Dose Intrathecal Clonidine as Adjuvant to Bupivacaine


1 MD, Graded Specialist, Military Hospital, Faizabad Armed Forces Medical College, Pune, Pin-411040, India
2 MD, DA, Associate Prof., Military Hospital, Faizabad Armed Forces Medical College, Pune, Pin-411040, India
3 MD, DNB, Associate Prof., Military Hospital, Faizabad Armed Forces Medical College, Pune, Pin-411040, India

Date of Acceptance17-Aug-2007
Date of Web Publication20-Mar-2010

Correspondence Address:
B S Sethi
Military Hospital, Faizabad, Uttar Pradesh, India. Pin 224001
India
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Source of Support: None, Conflict of Interest: None


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Clonidine (α-2-adrenergic agonist) has analgesic effect at spinal level mediated by postsynaptically situated α-2-adrenoreceptors in dorsal horn of spinal cord. Previous studies have used this drug intrathecally in higher dosages.
Sixty adult patients belonging to ASA grade I and II, scheduled for gynaecological surgery under spinal anaesthesia were randomly divided into two groups. Clonidine group received clonidine 1 μg.kg -1 with 12.5 mg 0.5% bupivacaine and the Control group received an identical volume of saline mixed with 12.5mg0.5% bupivacaine.
The maximum dose of clonidine used was70 μg. The meantime from injection to regression of the level of sensory analgesia by two segments was longer in the Clonidine group than in Control group (P<0.001). The duration of motor blockade was longer in Clonidine group than in Control group (P<0.05). There was also a significant difference in the duration of analgesia between the two groups (P<0.001). The rescue analgesia was required earlier in the Control group(mean 223 min) compared to the Clonidine group(mean614 min). The number of injections of diclofenacin24 hours was higher for Control group (mean2.66) than Clonidine group (mean 1.16) (P <0.05). The patients in the Clonidine group had a significant fall in mean arterial pressure and heart rate and were more sedated than those in Control group, however, no therapeutic interventions needed. We concluded that addition of clonidine to bupivacaine in the dose of 1μg.kg -1 significantly increases the duration of spinal analgesia as compared to bupivacaine alone with clinically insignificant influence on haemodynamic parameters and level of sedation.

Keywords: Intrathecal; Clonidine; Bupivacaine; Postoperative pain


How to cite this article:
Sethi B S, Samuel M, Sreevastava D. Efficacy of Analgesic Effects of Low Dose Intrathecal Clonidine as Adjuvant to Bupivacaine. Indian J Anaesth 2007;51:415

How to cite this URL:
Sethi B S, Samuel M, Sreevastava D. Efficacy of Analgesic Effects of Low Dose Intrathecal Clonidine as Adjuvant to Bupivacaine. Indian J Anaesth [serial online] 2007 [cited 2019 May 19];51:415. Available from: http://www.ijaweb.org/text.asp?2007/51/5/415/61173


   Introduction Top


Central neuraxial opioids, intrathecal as well as epidural, offer the perceived benefit of selective analge­sia without sensory or motor blockade. However, side effects such as potentially catastrophic delayed respira­tory depression have prompted further research to de­velop non opioid analgesics with less worrisome side effects [1] . Intrathecal clonidine is being extensively evalu­ated as an alternative to neuraxial opioids for control of pain and has proven to be a potent analgesic, free of at least some of the opioid related side effects [2] . It has been used as a sole agent as well as admixed with opioids and local anaesthetics in labour analgesia and orthopaedic surgery. However there is still dearth of studies using intrathecal clonidine for postoperative analgesia in lower abdominal surgeries with apparently higher algogenic potential. Besides, the previous studies have described use of intrathecal clonidine in higher dosages.

This study was undertaken to assess the degree of postoperative analgesia provided by low dose(1 µg.kg­-1 ) intrathecal clonidine admixed with bupivacaine as compared to bupivacaine alone in patients undergoing gynaecological surgery.


   Methods Top


The study was approved by hospital ethical com­mittee and informed consent from all the participants was obtained. It was designed in the form of a prospec­tive, randomized and double blinded study. Sixty patients scheduled to undergo lower abdominal surgery were randomly divided into two groups of thirty each. All the patients were in ASA I and II grades and in the age group of 20 - 50 years.

All patients were advised to fast after 2200 hrs and administered diazepam orally (10 mg) night before surgery and at 0600 hrs on the morning of surgery. In­side the operation theatre, basal pulse rate and blood pressure (mean) were obtained. A wide bore intrave­nous line was established and the patients were con­nected to monitors such as ECG, SpO2, noninvasive blood pressure recording device. Preloading was done with 15 ml.kg -1 of Ringer's solution about 15 minutes before the intended time of intrathecal drug administration. Pa­tients were positioned in the left lateral decubitus posi­tion and after adequate aseptic precaution; lumbar punc­ture was performed at L3/L4 intervertebral space using midline approach with a 25 gauge Quincke spinal needle. After ensuring a free flow of CSF, patients in the Clonidine group received a single dose of 12.5 mg of 0.5% bupivacaine (heavy) + 1 µg.kg -1 of preservative free clonidine. The patients in the Control group were given 12.5 mg of 0.5% bupivacaine (heavy) mixed with an identical volume of saline. The drug combinations were prepared by the first author however various observations were made by a second anaesthesiologist who was involved after the procedure had been performed.

The cephalad spread of analgesia and the degree of motor blockade of the lower limbs was recorded every 05 minutes. The level of sensory blockade was assessed using a 25 gauge short bevel needle and recorded as anal­gesia to loss of sensation to pin prick. Motor blockade was determined according to the modified Bromage scale [Table 1]. The parameters such as heart rate, non-inva­sive blood pressure, ECG and SpO 2 were periodically moni­tored and recorded at 05 minutes interval. A note was also made of blood loss, urine output, IV fluid input. Pa­tients were observed for any discomfort, nausea, vomit­ing, shivering, pain, bradycardia and any other side effect and the need for additional medications was recorded.

IV fluid was administered in the form of Ringer's lactate, in calculated doses depending on the weight of the patient and further adjusted as per blood loss during surgery. A fall of mean arterial pressure (MAP) to less than 70 mm of Hg was treated with rapid infusion of 500 ml of RL and 3 mg aliquots of injection mephentermine intravenously if there was no response to fluid adminis­tration. Bradycardia (heart rate less than 60/minute) was treated with intravenous atropine sulphate.

All patients were observed in the post anaesthesia recovery room and then in the ward. Severity of pain was measured using a 10 cm visual analogue scale at hourly interval for next 24 hours by the nursing staff that was unaware of the group the patient belonged to. The pain free post operative interval was observed and recorded and rescue analgesia was provided by diclofenac sodium 75 mg intramuscularly. The frequency of rescue analgesia required in each case was recorded.

The various data obtained, which included the haemodynamic parameters, respiratory rate, SpO 2 , du­ration of analgesia were calculated and compared with baseline values within each group as well as with corresponding times among the groups, using paired t-test and students t-test respectively. A 'P' value <0.05 was taken as significant.


   Results Top


A total of 60 patients were studied. Both the groups were similar in respect of age, weight, ASA status and types of surgeries [Table 2]. The variations in the haemodynamic parameters (heart rate and mean arte­rial pressure) have been shown in [Figure 1] and [Figure 2]. The decrease in mean heart rate from 45 minutes until the end of 6 hours was greater in Clonidine group than in the Control group (P<0.001). In addition, the decrease from baseline value within the Clonidine group was also statistically significant at 45 minutes to end of 6 hours (P<0.001). The MAP also showed a similar trend and there was a statistically significant lower mean arterial pressure in the Clonidine group compared to the Control group from 45minutes after test drug administration until the end of 6 hours (P<0.001).

There was no significant change in respiratory rate and SpO 2 from the baseline in both the groups (P>0.05) and supplemental oxygen or any other form of airway management was not needed. The mean time from in­jection to regression of the level of sensory analgesia by two segments was 218min ( range 150 - 240 min ) in the Clonidine group which was significantly longer than the duration of 136 min (range 90-150 min) in the Control group (P<0.001). Complete motor blockade of the lower extremities was noted in all the patients and the duration of motor blockade was 205 min (range 90-300min) in Clonidine group as compared to only 161 min (range 90­270 min) in Control group (P<0.05).

There was a significant difference (P<0.001) in the mean duration of analgesia between the two groups, the recordings being, 614min (480- 1140min) in the Clonidine group as against 223 min (150- 300 min) in the Control group [Table 3]. Similarly, the number of injections of diclofenac required in 24 hours was also significantly higher for Control group (mean - 2.66) than the Clonidine group (mean - 1.16) [P<0.05]. Incidence of sedation as assessed by sedation score [Table 4], was higher in the Clonidine group than in the Control group 3-6 hours after injection which was statistically significant(P<0.001). The differ­ence in number of patients having dryness of mouth or nausea in the two groups was not significant [Table 5].


   Discussion Top


Clonidine is a selective partial agonist for á-2 adrenoreceptors. It is known to increase both sensory and motor block of local anaesthetics [3] . The analgesic effect following its intrathecal administration is mediated spinally through activation of post synaptic á-2 recep­tors in substantia gelatinosa of spinal cord [4],[5] . The ratio­nale behind intrathecal administration of clonidine is to achieve a high drug concentration in the vicinity of á-2 adrenoreceptors in the spinal cord and it works by block­ing the conduction of C and Aδ fibres, increases potassium conductance in isolated neurons in vitro and inten­sifies conduction block of local anaesthetics. Clonidine is now an acceptable adjuvant to local anaesthetics for epidural route; nevertheless clinical trials provide evidence that less clonidine is needed intrathecally than epidurally to produce nearly same analgesic effect with fewer side effects [6] . Dobrydnjov et al in their study in orthopaedic patients, on postoperative pain relief follow­ing intrathecal bupivacaine combined with intrathecal or oral clonidine (150 µg), found that addition of intrathecal clonidine prolonged analgesia and decreased morphine consumption postoperatively more than oral clonidine. Hypotension was less pronounced after intrathecal than oral clonidine [7] .

The data obtained from our study indicate that ad­dition of 1 µg.kg -1 of clonidine to 0.5% bupivacaine sig­nificantly prolongs the analgesia and thus reduces the postoperative analgesic requirement. The maximum dose of clonidine used in our patients was 70 µg. Even though a statistically significant decrease in mean arterial pres­sure (MAP) and heart rate was noted in the Clonidine group compared to the Control group, none of the pa­tients required any therapeutic intervention for either. Despite the small sample size, it implies that the intrath­ecal dose studied (1µg.kg -1 ) may not produce excessive haemodynamic effects in healthy patients between 20 and 50 years of age.

Chiari et al in a dose response study using intrath­ecal clonidine as sole analgesic during first stage of labour found that 50-200µg of intrathecal clonidine produces dose dependent analgesia. Although the duration and quality of analgesia were more pronounced with 100µg (60-180min) and 200µg (75-210 min) than with 50µg (25­-150 min), the high incidence of hypotension required caution with use of 200 µg for labor analgesia [8] . In our study much longer analgesia times (480-1140 min) were obtained with minimal haemodynamic alterations. Our findings are in consonance with the study by LNiemi in which 3 µg.kg -1 of clonidine was added to 15mg of 0.5% bupivacaine administered intrathecally in patients under­going knee arthroscopy [9] . However it is pertinent to men­tion that Niemi used thrice the amount of clonidine as compared to our study. Despite that, the mean time to administration of first analgesic from test drug adminis­tration was similar to our study (613 min) and 3 patients required intervention for hypotension and 1 patient for bradycardia. Our study thus implies that it is possible to achieve equally good analgesia without side effects when clonidine is used in dosages as low as 1µg.kg -1 .

Several other investigators have studied the effect of intrathecal clonidine. Negri et al looked at the interac­tions and effects on the cardiovascular system of spinal anaesthesia with clonidine and bupivacaine in young hu­mans and found the addition of 105 µg clonidine to hyperbaric bupivacaine 1% was particularly useful in uni­lateral spinal anaesthesia, exerting minimal influence on haemodynamic parameters and guarantying a satisfac­tory postoperative analgesia [10] . Racle et al in their study using isobaric bupivacaine spinal anaesthesia with epinephrine and clonidine for hip surgery in elderly found that intrathecal clonidine (150 µg) for patients aged 75 years or more resulted in a decrease in systolic blood pressure of only 15% from resting values [11] . Filos et al reported significant decrease in arterial blood pressure after administration of 150µg of clonidine, but heart rate was unaffected in their study performed on caesarean section patients soon after general anaesthesia [6] .

Many previous studies have used intrathecal clonidine combined with opioids and local anaesthetics for labour analgesia and orthopaedic surgery [12],[13],[14] . However the combination with opioids would seem less attractive for obvious reasons. Using intrathecal clonidine in place of opioids avoids problems of respiratory de­pression, pruritus, urinary retention and abuse liability. Sedation is a well known side effect of clonidine and notwithstanding the fact that patients who received clonidine were more sedated than those in the control group, no significant respiratory depression was seen in our study. This again underlines the safety of low dose intrathecal clonidine. In fact, Grubb, et al in their study on video assisted thoracic surgery for lobectomy or pleurectomy found that exclusive use of narcotics for pain relief may result in respiratory depression which may require prolonged intubation whereas intrathecal clonidine may provide adjunct analgesia without addi­tional respiratory depression [15] . Dryness of mouth, atypi­cal side effect of clonidine [16] was also reported by more patients in the Clonidine group but was not worrisome.

In conclusion, our study has demonstrated that addi­tion of clonidine to bupivacaine in the dose of 1 µg.kg -1 significantly increases the duration of analgesia following its placement in subarachnoid space as compared to bupivacaine alone. These doses have an effect on seda­tion level, heart rate and mean arterial pressure which does not however, require any therapeutic intervention. The results of our study show that addition of 1µg.kg -1 of clonidine to intrathecal bupivacaine is safe and likely to be as effective as higher dosages minimizing the side effects.

 
   References Top

1.Gustafsson LL, Schildt B, Jackobson K. Adverse effects of extradural and intrathecal opiates: Report of a nationwide sur­vey in Sweden. Br J Anaesth 1982; 54: 479-86.  Back to cited text no. 1      
2.Eisenach JC. Overview : First international symposium on a­2 adrenergic mechanisms of spinal anaesthesia. Reg Anaesth 1993; 18 (4S) : i-vi.  Back to cited text no. 2      
3.ChiariA, EisenachJC, Spinal anaesthesia:Mechanisms, agents, methods, and safety. Reg Anesth Pain Med 1998; 23: 357-62.  Back to cited text no. 3      
4.Reddy SVR, Yaksh TL, Spinal noradrenergic terminal system mediates antinociception. Brain Res 1980; 189 : 391-401.  Back to cited text no. 4      
5.Brandt SA, Livingston A. Receptor changes in spinal cord of sheep associated withexposure to chronic pain. Pain 1990; 42:323-9.  Back to cited text no. 5  [PUBMED]    
6.Filos KS, Goudas LC, Patroni O, Polyzou V. Intrathecal clonidine as a sole analgesic for pain relief after caesarean sec­tion. Anesthesiology 1992; 77: 267-74.   Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Dobrydnjov I, Axelsson K, Samarutel J, Holmstrom B. Post­ operative pain relief followingintrathecal or oral clonidine. Acta Anaesthesiol Scand 2002; 46: 806-14.   Back to cited text no. 7      
8.ChiariA, Lorber C, Eisenach JC, et al. Analgesic and hemody­ namic effects of intrathecal clonidine as thesole analgesic agent during first stage of labor. Anesthesiology 1999; 91: 388-96.  Back to cited text no. 8      
9.L Niemi. Effects of intrathecal clonidine on duration of bupivacaine spinal anaesthesia, haemodynamics and postoperative analgesia in patients undergoing knee arthroscopy. Acta Anaesthesiol Scand 1994; 38: 724-8.  Back to cited text no. 9      
10.DeNegri P, Salvatore R, Visconti C, DeVivo P, Mastronardi P. Spinal anesthesia with clonidine and bupivacaine in young hu­mans: interactions and effects on cardiovascular system. Minerva Anesthesiology 1997; 63: 119-25.  Back to cited text no. 10      
11.Racle JP, Benkhadra A, Poy JY, Gleizal B. Prolongation of isobaric bupivacaine spinal anaesthesia with epinephrine and clonidine for hip surgery in elderly. Anesth Analg 1987; 66: 442-6.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Gautier PE, De Kock M, Luc F, Steenberge AV, Hody JL. In­trathecal clonidine combined with sufentanil for labour analge­sia. Anesthesiology 1998; 88:651-6.  Back to cited text no. 12      
13.Mercier FJ, Dounas M, Bouaziz H, et al. The effect of adding a minidose of clonidine to intrathecal sufentanil for labour anal­gesia. Anesthesiology 1998; 89: 594-601.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Sites BD, Christopher R, Biggs R, Beach ML, Wiley C. In­trathecal clonidine added to a bupivacaine-morphine spinal improves postoperative analgesia following total knee arthro­plasty. Anesthesiology 2002; 96: A918.  Back to cited text no. 14      
15.Grubb WR, Kushins LG, Langenfeld JE, Barbella J, Pollak P. ASA meeting abstracts 2000.  Back to cited text no. 15      
16.Gordh T Jr. Epidural clonidine for treatment of postoperative pain afterthoracotomy. Adoubleblind placebo-controlled study. Acta Anaesthesiol Scand 1988; 32: 702:9.  Back to cited text no. 16  [PUBMED]    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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