Indian Journal of Anaesthesia 2007; 51 (5) : 415-419

Clinical Investigation

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

B.S.Sethi1 , Mary Samuel2, Deepak Sreevastava3 Summary
Clonidine ( -2-adrenergic agonist) has analgesic effect at spinal level mediated by postsynaptically situated -2adrenoreceptors 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 g.kg -1 with 12.5 mg 0.5% bupivacaine and the Control group received an identical volume of saline mixed with 12.5mg 0.5% bupivacaine. The maximum dose of clonidine used was 70 g. The mean time 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(mean 614 min). The number ofinjections of diclofenac in 24 hours was higher for Control group (mean 2.66) 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 doseof 1 g.kg -1 significantlyincreases the duration of spinal analgesia as compared to bupivacaine alone with clinically insignificant influence on haemodynamic parameters and level of sedation.

Key words

Intrathecal; Clonidine; Bupivacaine; Postoperative pain compared to bupivacaine alone in patients undergoing gynaecological surgery.

Introduction
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 effects1. 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 effects2. 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 post operative analgesia provided by low dose (1 g.kg 1 ) intrathecal clonidine admixed with bupivacaine as

Methods
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, SpO 2,noninvasive blood pressure recording device. Preloading was done with 15 ml.kg -1 of Ringers solution about 15 minutes before the intended time of intrathecal drug administration. Pa-

1. MD, Graded Specialist, 2. MD, DA, Associate Prof; 3. MD, DNB, Associate Prof., Military Hospital; Faizabad Armed Forces Medical College, Pune, Pin-411040. Correspondence to: B.S.Sethi, Military Hospital, Faizabad, Uttar Pradesh, India. Pin 224001. Email: brijindera_sethi@rediffmail.com Accepted for publication on: 17.08.07.

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Indian Journal of Anaesthesia, October 2007 tients 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 g.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, ECGand SpO2 were periodicallymonitored 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. Table 1 Bromage score
Grade I II III IV Criteria Free movement of legs and feet Just able to flex knees with free movement of feet Unable to flex knees, but with free movement of feet Unable to move legs or feet Age (yrs) (Mean S.D.) Weight (Kgs) (Mean S.D.) Height (cms) (Mean S.D.) Duration of surgery Mean (Range) Type of Surgery

recorded and rescue analgesia was pro vided 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 Pvalue <0.05 was taken as significant.

Results
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 Fig. 1 and 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 45 minutes after test drug administration until the end of 6 hours (P<0.001). Table 2 Patient characteristics
Control group N=30 44.47 ( 4.83) 56.53 ( 5.31) 156.27 ( 3.07) 89.77 (68-115) Clonidine group N=30 44.87 ( 4.38) 57.93 ( 4.75) 155.47 ( 2.54) 89.03 (67-118)

IV fluid was administered in the form of Ringers 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
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Total abdominal hysterectomy Vaginal hysterectomy Manchester repair Myomectomy ASA Status ASA I ASA Status ASA II

15 11 2 2 22 8

17 10 2 1 21 9

: Statisti cal ly not si gni fi cant Age(yrs) mean+ SD

B.S. Sethi et al. Low dose intrathecal clonidine as adjuvant to bupivacaine 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 218 min ( 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, 614 min (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 diclofenacrequired in 24 hourswas 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]. Table 3- Comparison of duration of surgery, analgesia and motor blockade
Control group Duration of surgery (min) Mean (range) Regression of sensory analgesia by two segments (min) (P<0.001) 89.77 (68-115) 136 (90-150) Clonidine group 89.03 (67-118) 218 (150-240)

Duration of motor blockade 161 (90-270) (min) (P<0.05) Analgesia time (min) (P<0.001) 223 (150-300)

205 (90-300) 614 (480-1140) 1.16 (1-2)

No. of Diclofenac injection 2.66 (2 3) in 24 hrs. [P <0.05] (Values are mean with range in parenthesis)

Table 4 Sedation score 0 1 2 3 No sedation Drowsiness Asleep but arousable Unarousable with loss of verbal contact

Table 5 Side effects

Nausea (P>0.05) Mouth dryness (P>0.05) Sedation [P<0.001] Respiratory rate (decrease from baseline) Desaturation Control group 1 5 0 Clonidine group 3 11 16

0 0

0 0

Discussion
Clonidine is a selective partial agonist for -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 recep-2 4, 5 tors in substantia gelatinosa of spinal cord . The rationale behind intrathecal administration of clonidine is to achieve a high drug concentration in the vicinity of -2 adrenoreceptors in the spinal cord and it works by blocking the conduction of C and Afibres, 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 evi417

Fi g. 1 Compari son of mean heart rate betw een Control & Cloni di ne group

F i g . 2 C o m p ar i s o n o f m e a n m ap b e t w e e n C l o ni di ne G r o up

C o nt r o l &

Indian Journal of Anaesthesia, October 2007 dence that less clonidine is needed intrathecally than epidurally to produce nearly same analgesic effect with fewer side effects6. Dobrydnjov et al in their study in orthopaedic patients, on postoperative pain relief following intrathecal bupivacaine combined with intrathecal or oral clonidine (150 g), 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 clonidine7. The data obtained from our study indicate that addition of 1 g.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 g. 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 (1g.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 50-200g of intrathecal clonidine produces dose dependent analgesia. Although the duration and quality of analgesia were more pronounced with 100g (60-180min) and 200g (75-210min) than with 50 g (25150 min), the high incidence of hypotension required caution with use of 200 g 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 L Niemi in which 3 g.kg-1 of clonidine was added to 15 mg of 0.5% bupivacaine administered intrathecally in patients undergoing knee arthroscopy9. 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 (613min) 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 1g.kg-1. Several other investigators have studied the effect of intrathecal clonidine. Negri et al looked at the interac418

tions and effects on the cardiovascular system of spinal anaesthesia with clonidine and bupivacaine in young humans and found the addition of 105 g clonidine to hyperbaric bupivacaine 1% was particularly useful in unilateral spinal anaesthesia, exerting minimal influence on haemodynamic parameters and guarantying a satisfactory postoperative analgesia10. 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 g) 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 150 g of clonidine, but heart rate was unaffected in their study performed on caesarean section patients soon after general anaesthesia6. Many previous studies have used intrathecal clonidine combined with opioids and local anaesthetics for labour analgesia and orthopaedic surgery12, 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, a typical side effect of clonidine16 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 g.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 1g.kg -1 of clonidine to intrathecal bupivacaine is safe and likely to be as effective as higher dosages minimizing the side effects.

B.S. Sethi et al. Low dose intrathecal clonidine as adjuvant to bupivacaine

References
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SHORT TERM COURSE

Department of Anaesthesiology announces short term (3 Months) course in Intraoperative transesophageal echocardiography for post MD Anaesthesiologists working in private or government institution setup startingfrom 1st March 2008. For detail: Dr.R.C.Rathod Prof. & Head of Anaesthesia Sree Chitra TirunalInstitute for Medical Sciences and Technology Trivandrum-695011 (Kerala) Ph: 0471-2524643, Fax: (91) 471-2446433 Email: rcrathod@sctimst.ac.in , rcrathod@gmail.com

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