|Year : 2014 | Volume
| Issue : 1 | Page : 23-27
Prolongation of post-operative spinal analgesia: A randomized prospective comparison of two doses of oral clonidine
Anita Kumari1, Sukhminder Jit Singh Bajwa2, Jasbir Kaur Bains3, Kanwarjit Singh3
1 Department of Anaesthesiology and Intensive Care, Sri Guru Ramdas Medical college, Amritsar, Punjab, India
2 Department of Anaesthesiology and Intensive Care, Gian Sagar Medical College and Hospital, Banur, Punjab, India
3 Department of Anaesthesiology and Intensive Care, Government Medical College and Hospital, Patiala, Punjab, India
|Date of Web Publication||15-Apr-2014|
Sukhminder Jit Singh Bajwa
House No. 27 A, Ratan Nagar, Tripuri, Patiala 147 001, Punjab
Source of Support: None, Conflict of Interest: None
Background and Aims: Efforts to prolong analgesia with various intrathecal and oral adjuvants have been tried with varying success. The present study was aimed to explore and to compare the potential beneficial effects of prolongation of spinal analgesia with two different doses of oral clonidine. Materials and Methods: A randomized double-blind study was carried out among 60 (American Society of Anesthesiologists)-I and II patients with aged range from 25 to 65 years undergoing lower abdominal surgery. They were divided randomly into three groups of 20 each. Group 1 patients were administered placebo whereas Group 2 and 3 received oral clonidine tablets (0.15 and 0.30 mg respectively) 1-h prior to surgery. Subarachnoid block was administered as per standard protocol. Time to onset of analgesia at T-10, time to achieve maximum sensory level, dermatomal regression and time to rescue analgesia were observed. Side-effects such as hypotension, bradycardia, nausea and vomiting were noted. Statistical analysis was performed using ANOVA with post-hoc Students unpaired t-test and Chi-square test and value of P < 0.05 was considered to be significant. Results: The demographic profile and initial block characteristics were comparable among the three groups (P > 0.05). Two segment regression was 78.3 ± 10.44 min, 150.2 ± 23.07 min and 149.3 ± 18.33 min in Groups 1-3 respectively. Time to rescue analgesia was significantly prolonged in Groups 2 and 3 compared with Group 1 (P < 0.05). Incidence of hypotension was higher in Group 2 (P < 0.05). Conclusion: Optimal dose of oral clonidine that produces clinically useful prolongation of spinal anesthesia using bupivacaine appears to be 0.15 mg when compared with 0.3 mg when overall efficacy is being compared.
Keywords: Alpha-2 agonists, clonidine, lower abdominal surgery, spinal anesthesia
|How to cite this article:|
Kumari A, Bajwa SS, Bains JK, Singh K. Prolongation of post-operative spinal analgesia: A randomized prospective comparison of two doses of oral clonidine
. Int J Health Allied Sci 2014;3:23-7
|How to cite this URL:|
Kumari A, Bajwa SS, Bains JK, Singh K. Prolongation of post-operative spinal analgesia: A randomized prospective comparison of two doses of oral clonidine
. Int J Health Allied Sci [serial online] 2014 [cited 2019 Sep 20];3:23-7. Available from: http://www.ijhas.in/text.asp?2014/3/1/23/130604
| Introduction|| |
Neuraxial anesthesia, spinal and epidural, is one of the most common and popular anesthetic technique for surgeries pertaining infra-umbilical surgeries. One of the main inherent limitations of spinal anesthesia is the inability to provide effective analgesia for a prolonged period in spite of availability of long acting local anesthetic drugs such as bupivacaine and levo-bupivacaine. In a quest to prolong the duration of analgesia and to provide a long duration of post-operative pain relief, a continuous need is felt among anesthesia fraternity to look for suitable drugs and adjuvants. Various drugs such as morphine, fentanyl, sufentanil, neostigmine, ketamine, have been used intrathecally for this purpose. ,,,,
Pharmacologically, clonidine is a centrally acting alpha 2 selective agonist with alpha 2:alpha 1 ratio of 200:1. , It can be used as a premedicant.  The sedative properties of clonidine further help in decreasing the requirements of hypnotics.  Besides performing the role of a premedicant, oral clonidine can augment the analgesic effect of local anesthetics in subarachnoid block. Intrathecal clonidine is also a popular method but will not serve as a premedicant and as such a different premedication is required. Therefore oral, clonidine can serve as premedicant as well as an adjuvant, which can provide a prolonged duration of pain relief post-operatively. However, there is no specifically proven dose of oral clonidine which can enhance the post-operative analgesic effects of local anesthetic.
Taking into consideration the various beneficial properties of clonidine, the present study was designed to evaluate and to compare the effectiveness and safety of oral clonidine 0.15 mg and 0.3 mg for possible prolongation of duration of spinal anesthesia and also to observe its effects on perioperative hemodynamic variables in patients undergoing elective lower abdominal surgery.
| Materials and Methods|| |
After institutional ethical committee clearance and written informed consent, 60 adult patients of either sex in the age group of 25-65 years belonging to American Society of Anesthesiologists physical status 1 and 2 undergoing elective lower abdominal surgery for inguinal hernia, hemorrhoidectomy, varicose veins, uretheroplasty and others were enrolled for the present study. Patients who refused spinal anesthesia and patients with neurological deficits or diseases, bleeding disorders, cardiac diseases, obvious skeletal deformities, on adrenergic beta blockers and antihypertensive medication were excluded from the study.
Pre-anesthetic assessment was carried out 1 day before surgery. Routine biochemical investigations and electrocardiography (ECG) were done. All patients were kept fasting for 6 h prior to surgery and were randomly allocated into three groups of 20 each. Randomization was done by coded envelope method and double blinding was ensured as the person performing the procedure and carrying out the observations was blinded to the drug used. Group 1 patients received sweetener tablets while Groups 2 and 3 patients were administered tab. Clonidine 0.15 mg and 0.30 mg respectively 1 h prior to anesthesia.
In the operation theater, intravenous access was secured with a wide gauged cannula and patients were pre-loaded with 8-10 ml/kg of lactated ringer solution. Gadgets for routine monitoring were attached which included continuous ECG, heart rate (HR), non-invasive blood pressure and oxygen saturation (SpO 2 ). Baseline reading of all vital parameters was observed and recorded. Under all aseptic precautions, subarachnoid block was performed using 26G spinal needle at L2-3/L3-4 intervertebral space in the lateral decubitus position. After achieving clear and free flow of cerebrospinal fluid, 3 ml of hyperbaric 0.5% bupivacaine was injected slowly. The dermatomal level of sensory anesthesia was evaluated by pin prick method. The level of pinprick analgesia were studied every 5 min for 30 min after injection and then at 15 min intervals until regression. Blood pressure (BP) and HR were monitored continuously and were recorded initially at every 2 min interval for the first 10 min and every 10 min thereafter until the end of surgery. Effectiveness of analgesia was assessed as the onset of analgesia, level of analgesia and time to achieve the maximum level of analgesia (when the level does not change 5 min apart). Duration of analgesia was taken from time for achieving maximum level to regression of analgesia to 2 segments, 4 segments and up to L1 segment. Time for the first appearance of post-operative pain and rescue analgesia were also noted. Sedation was assessed using six point Ramsay sedation scale (1-anxious or agitated, 2-co-operative, oriented and tranquil, 3-responding to verbal commands, 4-brisk response to light glabellar tap, 5-sluggish response to light glabellar tap and 6-no response).
Side-effects such as hypotension, bradycardia, respiratory depression, nausea and vomiting were also observed and recorded and treated symptomatically. Injection mephenteramine (6 mg) was given whenever there was >25% fall in mean systolic blood pressure (SBP) from baseline and injection atropine 0.3 mg was given when HR decreased to <60 beats/min.
At the end of study decoding of groups was done. All the observations were compiled and statistical analysis was performed with SPSS version 15 for windows. The data was analyzed using ANOVA for the parametric data with post-hoc Student's unpaired t-test and Chi-square-test for non-parametric data. The sample size of 18 was calculated on the basis of a 30-min difference in the time required to administer rescue analgesia during the post-operative period, accepting a one-tailed α-error of 5% and a β-error of 5%. All the values were expressed as mean ± standard deviation range or number (%). The results were considered as statistically significant if P < 0.05 and highly significant when P < 0.001.
| Results|| |
A total of 60 patients were enrolled in the present study. The demographic profile of the patients was comparable which provided an unbiased platform for statistical analysis. Various demographic variables such as age, gender, weight, height and duration of surgery were comparable in all the three groups and statistically non-significant (P > 0.05) [Table 1].
Oral clonidine premedication did not result in any significant changes in initial block characteristics. The initial onset of analgesia at T-10 dermatomal level, maximum level of sensory analgesia level achieved and the time required to achieve the maximum sensory analgesic level was comparable in all the three groups and non-significant on statistical comparison (P > 0.05) [Table 2].
However, the neuraxial anesthetic characteristics showed significant changes in the peri-operative period as well as during post-operative period. The dermatomal segmental regression (2 and 4 segments as well as up to L-1) showed statistically significant variation in Group 2 and 3 when compared with Group 1 (P < 0.05). Similarly, the number of patients requiring rescue analgesia in the immediate post-operative period was statistically highly significant in Group 1 when compared with Group 2 and 3 (P < 0.001) [Table 3].
Incidence of hypotension and bradycardia was higher in Group 3 when compared to Group 1 and 2 which was statistically significant on comparison (P < 0.05) [Figure 1] and [Figure 2], [Table 4]. Nausea and vomiting as well sedation characteristics were comparable in all the three groups and were non-significant on statistical analysis (P > 0.05) [Table 4].
|Figure 1: Intra-operative mean systolic blood pressure of all age groups at different time interval|
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|Figure 2: Intra-operative heart rate of all the groups at different time interval|
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| Discussion|| |
Spinal anesthesia is probably the most widely used regional anesthetic technique in the surgical patients. Its disadvantages are the risk of extensive block, fixed duration of anesthesia, hypotension, inability to extend the block once it is fixed and risk of post dural puncture headache. Many drugs are being used singly or in combination to increase the duration of spinal anesthesia, but now alpha 2 adrenergic agonist are assuming greater importance as anesthetic adjuvants. Traditionally they have been used as antihypertensive drugs. The primary effect of the drug is sympatholytic but its new role as sedative, anxiolytic and analgesic is being investigated throughout the globe. ,,, Hence these properties are responsible for a new enthusiasm for the use of this drug in anesthesia. Recent work in animals and human suggests they have properties that are considered advantageous for premedication. , Clonidine when administered orally, intramuscularly, epidurally or intrathecally produce an analgesic effect with duration of 4-6 h ,,,,, and has potent hypnotic and hypotensive effects also. ,
This study shows that clonidine when administered orally 1 h prior to spinal anesthesia produced a clinically useful prolongation of sensory block. Effectiveness of analgesia (i.e. onset, maximum level achieved and time to achieve the maximum level of analgesia) was same in all the three groups but the duration of analgesia was significantly prolonged in Group 2 and 3 when clonidine was administered orally in a dose of 0.15 and 0.3 mg as compared to Group 1. Ota et al.  also found similar results. The duration of analgesia with groups receiving clonidine was same, thus indicating that by increasing its dose does not prolong the duration of analgesia rather aggravate the side-effects. A dose response relationship seems to exist with plateau effect at a dose of 0.15 mg. Similar results were seen in other studies. ,, The exact mechanism of the analgesic action of alpha-2 agonists have not been fully understood probably presynaptic activation of the alpha-2 adrenoceptor in locus coeruleus inhibits the release of norepinephrine thus terminating the propagation of pain signals responsible for analgesic properties of clonidine.  This could be responsible for prolongation of post-operative analgesia in our study.
Clonidine caused significant fall in HR and reduction in mean SBP in patients receiving 0.3 mg oral clonidine compared with 0.15 mg. The underlying mechanism involves central activation of alpha-2 adrenoceptors, which causes both reduction in peripheral sympathetic tone and an increase in vagally induced reflex bradycardia, peripheral stimulation of presynaptic alpha adrenoceptors, which leads to diminished release of nor epinephrine from nerve endings toward the vasculature and to a reduction in peripheral sympathetic tone to the heart.  Ota et al. also observed that oral clonidine when used as pre medication in a dose of 4-5 μg/kg for spinal anesthesia, tended to enhance bradycardia. , Our present study supports this finding and suggests that oral clonidine dose ≤0.15 mg does not cause significant hemodynamic responses such as hypotension and bradycardia during spinal anesthesia.
There was no requirement of sedation in patients receiving clonidine compared with placebo, but no respiratory depression was seen in any patient, similar to studies conducted by Wright and Benahamou. , Nausea and vomiting was seen only in those cases who had a concomitant fall in BP more than 25% from baseline as clonidine does not induce nausea and vomiting of its own rather it has antiemetic properties.  The time for appearance of post-operative pain and the time to require post-operative analgesics were longer in the groups, which had received clonidine than in the groups, which had received placebo. This shows that oral clonidine when used as premedicant not only prolongs the duration of spinal anesthesia, but also reduces the early post-operative analgesic requirements.
| Conclusion|| |
To conclude, clonidine in the dose of 0.15 mg and 0.3 mg increases the duration of spinal anesthesia in comparison to placebo, but 0.3 mg caused more hemodynamic changes compared with 0.15 mg. Hence the study conclude that the optimal dose of oral clonidine, which produces clinically useful prolongation of spinal anesthesia using bupivacaine, appears to be 0.15 mg when compared with 0.3 mg when overall efficacy was being compared.
| References|| |
|1.||Gehling MH, Luesebrink T, Kulka PJ, Tryba M. The effective duration of analgesia after intrathecal morphine in patients without additional opioid analgesia: A randomized double-blind multicentre study on orthopaedic patients. Eur J Anaesthesiol 2009;26:683-8. |
|2.||Duman A, Apiliogullari S, Duman I. Effects of intrathecal fentanyl on quality of spinal anesthesia in children undergoing inguinal hernia repair. Paediatr Anaesth 2010;20:530-6. |
|3.||Kumar S, Bajwa SJ. Neuraxial opioids in geriatrics: A dose reduction study of local anesthetic with addition of sufentanil in lower limb surgery for elderly patients. Saudi J Anaesth 2011;5:142-9. |
|4.||Ahmed F, Garg A, Chawla V, Khandelwal M. Transdermal nitroglycerine enhances postoperative analgesia of intrathecal neostigmine following abdominal hysterectomies. Indian J Anaesth 2010;54:24-8. |
|5.||Nafiu OO, Kolawole IK, Salam RA, Elegbe EO. Comparison of caudal ketamine with or without bupivacaine in pediatric subumbilical surgery. J Natl Med Assoc 2007;99:670-3. |
|6.||Bajwa SJ, Bajwa SK, Kaur J, Singh A, Singh A, Parmar SS. Prevention of hypotension and prolongation of postoperative analgesia in emergency cesarean sections: A randomized study with intrathecal clonidine. Int J Crit Illn Inj Sci 2012;2:63-9. |
|7.||Bajwa SJ, Bajwa SK, Kaur J, Singh G, Arora V, Gupta S, et al. Dexmedetomidine and clonidine in epidural anaesthesia: A comparative evaluation. Indian J Anaesth 2011;55:116-21. |
|8.||Ota K, Namiki A, Ujike Y, Takahashi I. Prolongation of tetracaine spinal anesthesia by oral clonidine. Anesth Analg 1992;75:262-4. |
|9.||Mikawa K, Maekawa N, Nishina K, Takao Y, Yaku H, Obara H. Efficacy of oral clonidine premedication in children. Anesthesiology 1993;79:926-31. |
|10.||Carabine UA, Wright PM, Moore J. Preanaesthetic medication with clonidine: A dose-response study. Br J Anaesth 1991;67:79-83. |
|11.||Bajwa SJ, Kaur J, Bajwa SK, Bakshi G, Singh K, Panda A. Caudal ropivacaine-clonidine: A better post-operative analgesic approach. Indian J Anaesth 2010;54:226-30. |
|12.||Mohamed SA, Abdel-Ghaffar HS. Effect of the addition of clonidine to locally administered bupivacaine on acute and chronic postmastectomy pain. J Clin Anesth 2013;25:20-7. |
|13.||Apostolos K, Georgios K, Omiros C, Christos T. Comparison between ropivacaine 1.5 mg ml(-1) plus fentanyl 2 mg ml(-1) and ropivacaine 1.5 mg ml(-1) plus clonidine 1 mg ml(-1) as analgesic solution after anterior cruciate ligament reconstruction: A randomized clinical trial. Middle East J Anesthesiol 2011;21:341-5. |
|14.||Trevor S, Upadya M, Sinha C, Kaur M. A comparison of midazolam and clonidine as an oral premedication in pediatric patients. Saudi J Anaesth 2012;6:8-11. |
|15.||Hossmann V, Maling TJ, Hamilton CA, Reid JL, Dollery CT. Sedative and cardiovascular effects of clonidine and nitrazepam. Clin Pharmacol Ther 1980;28:167-76. |
|16.||Engelman E, Marsala C. Bayesian enhanced meta-analysis of post-operative analgesic efficacy of additives for caudal analgesia in children. Acta Anaesthesiol Scand 2012;56:817-32. |
|17.||Bajwa SJ, Bajwa SK, Kaur J. Comparison of epidural ropivacaine and ropivacaine clonidine combination for elective cesarean sections. Saudi J Anaesth 2010;4:47-54. |
|18.||Liu SS, Bae JJ, Bieltz M, Wukovits B, Ma Y. A prospective survey of patient-controlled epidural analgesia with bupivacaine and clonidine after total hip replacement: A pre- and postchange comparison with bupivacaine and hydromorphone in 1,000 patients. Anesth Analg 2011;113:1213-7. |
|19.||Yazbeck-Karam VG, Siddik-Sayyid SM, Abi Nader EL, Barakat DE, Karam HS, Cherfane GM, et al. Supplementation of retrobulbar block with clonidine in vitreoretinal surgery: Effect on postoperative pain. J Clin Anesth 2011;23:393-7. |
|20.||Bajwa SJ, Bajwa SK, Kaur J, Singh A, Bakshi G, Singh K, et al. Admixture of clonidine and fentanyl to ropivacaine in epidural anesthesia for lower abdominal surgery. Anesth Essays Res 2010;4:9-14. |
|21.||Ota K, Namiki A, Iwasaki H, Takahashi I. Dosing interval for prolongation of tetracaine spinal anesthesia by oral clonidine in humans. Anesth Analg 1994;79:1117-20. |
|22.||Benahamou D, veillette Y, Narchi P. Ventilatory effects of pre medication with clonidine Anesth Analg 1991;73:799-803. |
|23.||Bajwa SJ, Kaur J, Singh A, Parmar S, Singh G, Kulshrestha A, et al. Attenuation of pressor response and dose sparing of opioids and anaesthetics with pre-operative dexmedetomidine. Indian J Anaesth 2012;56:123-8. |
|24.||Ravel DL, Mehta MK. Oral clonidine premedication for attenuation of haemodynamic response to laryngoscopy and intubation. Indian J Anaesth 2002;46:124-9. |
|25.||Mikawa K, Nishina K, Maekawa N, Asano M, Obara H. Oral clonidine premedication reduces vomiting in children after strabismus surgery. Can J Anaesth 1995;42:977-81. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]