Anesthesia: Essays and Researches  Login  | Users Online: 987 Home Print this page Email this page Small font sizeDefault font sizeIncrease font size
Home | About us | Editorial board | Ahead of print | Search | Current Issue | Archives | Submit article | Instructions | Copyright form | Subscribe | Advertise | Contacts

Table of Contents  
Year : 2018  |  Volume : 12  |  Issue : 2  |  Page : 402-406  

Comparison of intrathecal nalbuphine hydrochloride and clonidine hydrochloride as an adjuvant to hyperbaric bupivacaine in abdominal hysterectomy

1 Department of Anaesthesiology and Critical Care, Sawai Man Singh Medical College and Attached Group of Hospitals, Jaipur, Rajasthan, India
2 Department of Preventive and Social Medicine, Sawai Man Singh Medical College and Attached Group of Hospitals, Jaipur, Rajasthan, India

Date of Web Publication14-Jun-2018

Correspondence Address:
Dr. Dikshitha K Chetty
No. 16D Kalaivanar Colony, Medimix Avenue, Anna Nagar West Extension, Chennai - 600 101, Tamil Nadu
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aer.AER_5_18

Rights and Permissions

Background: Various adjuvants for prolongation of intraoperative and postoperative analgesia have been clinically studied in the literature. Aim: This study was done to evaluate and compare the effects of nalbuphine and clonidine as an adjuvant to bupivacaine in spinal anesthesia. Methods: In this prospective, randomized, placebo control, double-blind, and comparative study, a total of ninety patients of American Society of Anesthesiologists physical status Classes I and II undergoing abdominal hysterectomy under subarachnoid block were randomly divided into three groups. In addition to 15 mg of 0.5% hyperbaric bupivacaine administered, patients of groups BS, BN, and BC received 0.9% normal saline, 1.6 mg nalbuphine, and 30 μg clonidine, respectively. The total volume of drugs administered intrathecally was made up to 3.5 ml by addition of sterile isotonic normal saline in all. The onset time and duration of sensory and motor block, duration of analgesia, and total dose of postoperative analgesic requirement in the first 24 h were compared among groups. Hemodynamic changes and side effects were also recorded. Results: Addition of study adjuvants brought significantly faster onset of sensory and motor block. Patients in clonidine group showed significantly longer mean time two segment sensory block regression (P < 0.05) lowest seen in control group. The regression time of motor block to modified Bromage Grade I was significantly longer in clonidine group and comparable in the other groups. Adjuvants have significantly increased the mean duration of analgesia, highest in clonidine group (P < 0.05). Conclusion: Intrathecal clonidine is associated with prolonged motor and sensory block, better hemodynamic stability, and less postoperative analgesic requirement as compared to nalbuphine.

Keywords: Bupivacaine, clonidine, intrathecal, nalbuphine

How to cite this article:
Chetty DK, Ahmed F, Chatterjee R, Rathore M. Comparison of intrathecal nalbuphine hydrochloride and clonidine hydrochloride as an adjuvant to hyperbaric bupivacaine in abdominal hysterectomy. Anesth Essays Res 2018;12:402-6

How to cite this URL:
Chetty DK, Ahmed F, Chatterjee R, Rathore M. Comparison of intrathecal nalbuphine hydrochloride and clonidine hydrochloride as an adjuvant to hyperbaric bupivacaine in abdominal hysterectomy. Anesth Essays Res [serial online] 2018 [cited 2020 Apr 6];12:402-6. Available from:

   Introduction Top

Postoperative pain management remains a challenge despite exponential advances in the understanding of pain physiology and development of new pharmacological strategies including neuraxial drug administration. Regional anesthesia for lower abdominal hysterectomy is not only associated with shorter duration of analgesia but also associated with increase in the incidence of higher regional blockade and local anesthetic toxicity.[1] Circumvention of this concern by preemptive mixing of analgesic with local anesthetics for regional anesthesia provides a better alternative. Although various studies in the past have established the role of clonidine and nalbuphine as an adjuvant to local anesthetic, no study as far as we know have compared the efficacy between them. The primary objective of this research was to study the analgesic efficacy of these two adjuvants while secondary aim was to compare characteristics of spinal block, hemodynamic variations, and adverse effects.

   Methods Top

After approval by the Institutional Ethical Committee, ninety patients of American Society of Anesthesiologists (ASA) physical status Classes I and II, aged 30–60 years, scheduled for elective total abdominal hysterectomy under subarachnoid block, were included in this prospective, double-blinded, randomized interventional study conducted in a tertiary care center.

All patients underwent a thorough preanesthetic checkup, and patients with ASA physical status Class III and above, coagulation abnormalities, severe hypovolemia, increased intracranial pressure, local sepsis in spinal lumbar region, history of allergy to study drugs, preexisting neurological, cardiovascular, metabolic, hepatic, respiratory, and renal disease were excluded from the study.

After obtaining written informed consent, patients were randomly allocated to three groups (n = 30) by random computerized allotment. Control group received intrathecal bupivacaine 0.5% 3 ml (15 mg) with 0.5 ml normal saline (placebo). Study Group I received intrathecal bupivacaine 0.5% 3 ml (15 mg) with 1.6 mg nalbuphine hydrochloride. Study Group II received intrathecal bupivacaine 0.5% 3 ml (15 mg) plus 30 μg clonidine hydrochloride. Total volume of drugs administered intrathecally was made up to 3.5 ml in transparent looking similar syringes by addition of sterile isotonic normal saline in all three groups.

Following a fasting of 6 h before surgery, routine monitoring initiated and preoperative baseline readings of noninvasive blood pressure (NIBP), pulse rate (PR), and saturation were noted. All study patients were preloaded with Ringer's lactate 15 ml/kg over 10 min after peripheral intravenous (IV) access with 18-gauge IV cannula was obtained. Patients were placed in the left lateral position. Under all aseptic precautions, spinal anesthesia was administered at the L3–L4 interspace using 25G Quincke spinal needle. A volume of 3.5 ml of drug was injected over 30 s without barbotage. The intrathecal drug composition depended on the group to which a patient belonged. The patient was placed in supine position with a 15° Trendelenburg tilt immediately after spinal injection to achieve level of block of T5–T6. The investigator who observed the postspinal analgesic effects was different from the anesthetist giving spinal anesthesia.

Sensory level was monitored every minute till the maximum sensory level was achieved and then after 1 h at ½ h intervals using response to cold stimulation method bilaterally at the mid-clavicular line. Onset of sensory block was taken as the time taken to attain sensory level of T6 dermatome. Onset of motor block was taken as the time taken to achieve modified Bromage Grade II from the time of subarachnoid injection.

Regular monitoring of blood pressure, PR, saturation, and sedation score was done at 2, 5, 10, 15, 30, 60, 90, and 120 min intervals and postoperatively at 30 min interval until the administration of rescue analgesia. Postoperatively, PR, NIBP, and saturation were recorded at a regular interval of 30 min the first 4 h, once every 2 h for the next 8 h, and once every 4 h for the next 12 h.

Duration of surgery and two-segment regression time (time of regression of sensory block by two segments from the highest level attained) using response to cold stimulation method was noted. Time for motor block to regress to modified Bromage Grade I was noted.

Duration of analgesia (time from the intrathecal drug administration to the patients till the patients' visual analog scale [VAS] score >3) was noted. All the patients were elaborated about the VAS scoring system strip which consisted of a 10-cm horizontal paper strip with two endpoints labeled “No pain” and “Worst pain ever.” Patients were asked to mark on the strip at a point that corresponds to the level of pain intensity they felt when they complained pain. Injection diclofenac 75 mg intramuscularly was given as a rescue analgesic when patient experienced VAS >3.

Patients were monitored for the presence of nausea/vomiting, pruritus, sedation, and signs of respiratory depression (respiratory rate per min and SpO2). Nausea/vomiting was treated with injection ondansetron 4 mg IV. Pruritus was treated with injection promethazine 25 mg intramuscular (IM) which was repeated after 1 h if needed. Oxygen by Hudson mask was provided if SpO2 decreased to <94%. Injection naloxone (in dose of 0.1–0.2 mg IV bolus, to be repeated as needed every 3–4 min) was reserved for patients with a respiratory rate of <8 min −1. The study concluded at 24 h after intrathecal drug administration.

The sample size was calculated based on the expected difference of 135 min (±53.70) on comparison of mean duration of analgesia between the study groups as per the pilot study carried out at our tertiary care center. The sample size required was 9 in each group at α error 0.05 and with a power of 80%. This sample size was enhanced to 30 in each group to enable adequacy in the assessment of other study variables.

All the statistical analysis of data was done with statistical programming software – SPSS (Statistical Package for the Social Science) version 20.0.0 (SPSS Inc., Chicago, IL, USA). The continuous variables (quantitative data) such as age, weight, height, blood pressure, heart rate (HR), and time were presented as mean and standard deviation and analyzed by applying one-way ANOVA test and post hoc test Tukey for intergroup comparison. The categorical variables (qualitative data) such as ASA grade and sedation score were presented in frequency and percentage and were analyzed with Chi-square test (for nominal data). Mann–Whitney U-test was used for variables which did not show normal distribution. P < 0.05 was considered statistically significant in all the analysis.

   Results Top

Demographic profile (age, weight, height, ASA physical status, and duration of surgery) was statistically comparable among the three groups [Table 1].
Table 1: Demographic characteristics

Click here to view

The onset of sensory block and motor block was comparable in clonidine and nalbuphine group but significantly (P = 0.00) faster when compared to the control group. The two-segment regression time was significantly prolonged (P = 0.00) in both clonidine (165.5 ± 23.3) and nalbuphine groups (121.0 ± 21.3) compared to the control group (94.0 ± 24.4) and was significantly (P = 0.00) longer in clonidine group when compared to nalbuphine group. The duration of motor blockade was significantly (P = 0.00) longer in clonidine group (218.5 ± 52.7 min) than both nalbuphine (130.6 ± 20.9 min) and control (116.3 ± 16.4 min) group [Table 2] and [Table 3].
Table 2: Characteristics of spinal block

Click here to view
Table 3: Characteristics of spinal block (post hoc Tukey)

Click here to view

Time to first rescue analgesia was significantly (P = 0.00) prolonged in clonidine group (330.7 ± 47.7 min) in comparison to both control (131.0 ± 20.5 min) and nalbuphine (218.3 ± 35.1 min) group, where it was significantly (P = 0.00) longer than control group. The total dosage of analgesic given in 24 h was significantly different among the three groups. Total dosage of analgesic demand in study Group II was significantly lower than the other two groups [Table 4] and [Table 5].
Table 4: Postoperative analgesia

Click here to view
Table 5: Postoperative analgesia (post hoc Tukey)

Click here to view

Intraoperatively, HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were comparable among all the three groups. However, postoperatively, HR, SBP, DBP, and MAP were significantly lower in clonidine group in comparison to control and nalbuphine groups up to 4 h. However, after 4 h, the values were comparable among the three groups. Adverse effects such as hypotension, bradycardia, respiratory depression, nausea, vomiting, and pruritus were found, but the incidence of these adverse effects was not statistically significant among these three groups [Table 6].
Table 6: Characteristics of hemodynamics and adverse effects

Click here to view

   Discussion Top

Logarithmic growth in the administration of opioids followed the pioneering work by Yaksh and Rudy in 1976.[2] However, the high incidence of opioid-associated side effects has led to the development of various other adjuvants. Hence, the study for the use of alternative adjuvants such as opioid partial agonist [3] and α2 receptor agonist [4] continues.

Nalbuphine is a partial agonist–antagonist opioid with agonism at κ-receptor and antagonism at μ-receptor.[5] Activation of supraspinal and spinal κ-receptors produces analgesia without the undesirable side effects of μ-agonist. This inhibits the release of substance P and also causes postsynaptic inhibition of interneuron and ascending nociceptive spinothalamic tract.[6],[7] Analgesia produced by nalbuphine was equipotent to that of morphine on a milligram basis. The potency of opioid antagonism of nalbuphine hydrochloride was one-fourth of nalorphine and ten times of pentazocine. There is ample evidence that nalbuphine produces useful analgesia in humans when administered as a sole opioid agent or when given in combination with μ-agonist. There is no difference in the adequacy of analgesia produced by nalbuphine-patient-controlled analgesia (PCA), and morphine PCA treated posthysterectomy or postmyomectomy patients.[8] It also produces adequate analgesia after total hip replacement.[9] No reports including studies done on pregnant patients showed any neurological sequelae and adverse effects on the fetus.[3]

Clonidine is a mixed α1- and α2-adrenoceptor agonist with a predominant α2 action [10] α22α1 200:1 action. Descending medullospinal noradrenergic tract activation and central sympatholysis at presynaptic ganglionic site produces analgesia at spinal level while transduction produces analgesia supraspinally at locus coereleus.[11] Analgesic effect of clonidine is contributed by the inhibition of spinal substancePrelease and augmentation of acetylcholine release. The rationale behind analgesia produced by intrathecal clonidine is to achieve high concentration in the vicinity of α2-adrenoreceptors in the substantia gelatinosa.

It is known to increase both sensory and motor block of local anesthetics.[12],[13],[14],[15] This results in an increase in the potassium conductance blockade produced by local anesthetics. Walker et al.[16] have established the absence of neurotoxicity due to intrathecal clonidine.

The appropriate dose of intrathecal nalbuphine has been debatable and varied based on the type of patient population, the type of surgery, and several other noncomparable parameters.[3],[17],[18],[19] Based on various studies and characteristics of Indian female patient population, we have taken 1.6 mg nalbuphine as the dose of intrathecal adjuvant to hyperbaric bupivacaine.

Spinal clonidine doses from 15 to 450 μg have been used in diverse clinical scenarios. Based on studies done by Chopra and Talwar,[14] Khandelwal et al.,[20] and Dutta et al.,[21] we have chosen 30 μg of intrathecal clonidine versus 1.6 mg of intrathecal nalbuphine as an adjuvant to hyperbaric bupivacaine.

Demographic data (age, sex, weight, and height) and ASA physical status were comparable in this study.

Duration of analgesia increased to 218.3 ± 35.1 and 330.7 ± 47.7 min when bupivacaine was used in combination with nalbuphine and clonidine, respectively. These results coincide with Chopra and Talwar [14] and Khandelwal et al.[20] study patients who received 30 μg of clonidine in combination with bupivacaine. The total duration of analgesia in nalbuphine group was more when compared to Ahmed et al.[19] in which the total duration of analgesia was 199.8 ± 25.9 min. The present study demonstrated that clonidine produces a longer duration of postoperative analgesia when compared to nalbuphine.

The present study demonstrated that addition of clonidine prolongs the time for two-segment regression more when compared to nalbuphine. The time for two-segment regression (minutes) was increased from 94.0 ± 24.4 in patients receiving in hyperbaric bupivacaine alone to 121.0 ± 21.4 and 166.5 ± 23.3 min in patients of nalbuphine and clonidine group, respectively. This prolongation of two-segment regression by nalbuphine and clonidine as an adjuvant was supported by Tiwari et al.[17] and Dobrydnjov et al.,[22] respectively.

The present study adjuvants have produced significantly faster onset of sensory and motor block when compared to patients receiving bupivacaine only. However, it is comparable between nalbuphine and clonidine while Bansal et al.[23] demonstrated faster onset of sensory and motor block due to nalbuphine.

In the present study, the duration of motor block was 116.3 ± 16.4, 130.6 ± 20.9, and 218.5 ± 52.7 min in patients of bupivacaine alone, nalbuphine, and clonidine group, respectively. Our results demonstrate the increased duration of motor block due to clonidine while nalbuphine produces comparable duration of motor block when bupivacaine used alone as substantiated by a study done by Ahmed et al.[19]

IM diclofenac (75 mg) was given as rescue analgesic when patients experienced pain equivalent to VAS score >3. The mean dose of analgesic required in 24 h was significantly lower in clonidine group while patients of nalbuphine group required significantly lesser rescue analgesic when compared to those who received bupivacaine alone. We infer from the present study that addition of clonidine and nalbuphine intrathecally to hyperbaric bupivacaine significantly decreases the total dose of rescue analgesic given in 24 h postoperatively. The present study inference coincides with that established by Culebras et al.[3] and Chopra and Talwar.[14]

The present study demonstrated no clinically significant difference in the hemodynamic parameters and adverse effects (nausea, vomiting, and pruritus) among the three groups, supported by Bansal et al.[23] Low-dose clonidine is not associated with hemodynamic instability as evidenced by Dutta et al.[21] Opioid-related side effects were not encountered significantly in nalbuphine group due to its mu (μ)-antagonist property. Respiratory depression was not observed in any patient of this study. Degree of sedation produced in three groups was comparable. Single patient of nalbuphine group reported pruritis. Reduced incidence of opioid-related side effects in nalbuphine group is supported by Mukherjee et al.,[18] Mostafa et al.,[24] and Moustafa and Saleh.[25]

   Conclusion Top

Clonidine (30 mcg) when used as an adjuvant to 0.5% hyperbaric bupivacaine resulted in prolonged postoperative analgesia along with longer duration of motor blockade and two-segment regression as compared to nalbuphine (1.6 mg) and control group without significant adverse effects and hemodynamic alterations. Both clonidine and nalbuphine produce faster onset of motor and sensory blockade and are comparable. Intrathecally used nalbuphine also increases the duration of analgesia than control but its duration of motor blockade lesser than clonidine and comparable with control group. Postoperative analgesic demand in the first 24 h was the least in clonidine group.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Ramsay MA. Acute postoperative pain management. BUMC Proc 2000;13:244-7.  Back to cited text no. 1
Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of narcotics. Science 1976;192:1357-8.  Back to cited text no. 2
Culebras X, Gaggero G, Zatloukal J, Kern C, Marti RA. Advantages of intrathecal nalbuphine, compared with intrathecal morphine, after cesarean delivery: An evaluation of postoperative analgesia and adverse effects. Anesth Analg 2000;91:601-5.  Back to cited text no. 3
Sethi BS, Samuel M, Sreevastava D. Efficacy of analgesic effects of low dose intrathecal clonidine as adjuvant to bupivacaine. Indian J Anaesth 2007;51:415.  Back to cited text no. 4
De Souza EB, Schmidt WK, Kuhar MJ. Nalbuphine: An autoradiographic opioid receptor binding profile in the central nervous system of an agonist/antagonist analgesic. J Pharmacol Exp Ther 1988;244:391-402.  Back to cited text no. 5
Malamed SF. Neurophysiology in Hand Book of Local Anesthesia. 2nd ed. New Delhi, India: Jaypee Brothers; 1986. p. 20.  Back to cited text no. 6
Ready BL. Acute perioperative pain. In: Miller RD, editor. Anaesthesia. 5th ed. Philadelphia: Churchill Livingstone; 2000. p. 2323-50.  Back to cited text no. 7
Ho ST, Wang JJ, Liu HS, Hu OY, Tzeng JI, Liaw WJ, et al. Comparison of PCA nalbuphine and morphine in Chinese gynecologic patients. Acta Anaesthesiol Sin 1998;36:65-70.  Back to cited text no. 8
Fournier R, Van Gessel E, Macksay M, Gamulin Z. Onset and offset of intrathecal morphine versus nalbuphine for postoperative pain relief after total hip replacement. Acta Anaesthesiol Scand 2000;44:940-5.  Back to cited text no. 9
Delaunay L, Bonnet F, Liu N, Beydon L, Catoire P, Sessler DI, et al. Clonidine comparably decreases the thermoregulatory thresholds for vasoconstriction and shivering in humans. Anesthesiology 1993;79:470-4.  Back to cited text no. 10
Lee A, Rosin DL, Van Bockstaele EJ. Ultrastructural evidence for prominent postsynaptic localization of alpha2C-adrenergic receptors in catecholaminergic dendrites in the rat nucleus locus coeruleus. J Comp Neurol 1998;394:218-29.  Back to cited text no. 11
Thakur A, Bhardwaj M, Kaur K, Dureja J, Hooda S, Taxak S, et al. Intrathecal clonidine as an adjuvant to hyperbaric bupivacaine in patients undergoing inguinal herniorrhaphy: A randomized double-blinded study. J Anaesthesiol Clin Pharmacol 2013;29:66-70.  Back to cited text no. 12
[PUBMED]  [Full text]  
Singh A, Dwivedib S, Yadav K. Comparative evaluation of effects of different doses of intrathecal clonidine with bupivacaine on post-operative pain relief. Int J Biol Med Res 2013;4:2703-6.  Back to cited text no. 13
Chopra P, Talwar V. Low dose intrathecal clonidine and fentanyl added to hyperbaric bupivacaine prolongs analgesia in gynecological surgery. J Anaesthesiol Clin Pharmacol 2014;30:233-7.  Back to cited text no. 14
[PUBMED]  [Full text]  
Yoganarasimha N, Raghavendra T, Amitha S, Shridhar K, Radha M. A comparative study between intrathecal clonidine and neostigmine with intrathecal bupivacaine for lower abdominal surgeries. Indian J Anaesth 2014;58:43-7.  Back to cited text no. 15
[PUBMED]  [Full text]  
Walker SM, Grafe M, Yaksh TL. Intrathecal clonidine in the neonatal rat: Dose-dependent analgesia and evaluation of spinal apoptosis and toxicity. Anesth Analg 2012;115:450-60.  Back to cited text no. 16
Tiwari AK, Tomar GS, Agrawal J. Intrathecal bupivacaine in comparison with a combination of nalbuphine and bupivacaine for subarachnoid block: A randomized prospective double-blind clinical study. Am J Ther 2013;20:592-5.  Back to cited text no. 17
Mukherjee A, Pal A, Agrawal J, Mehrotra A, Dawar N. Intrathecal nalbuphine as an adjuvant to subarachnoid block: What is the most effective dose? Anesth Essays Res 2011;5:171-5.  Back to cited text no. 18
  [Full text]  
Ahmed F, Narula H, Khandelwal M, Dutta D. A comparative study of three different doses of nalbuphine as an adjuvant to intrathecal bupivacaine for postoperative analgesia in abdominal hysterectomy. Indian J Pain 2016;30:23-8.  Back to cited text no. 19
  [Full text]  
Khandelwal M, Dutta D, Bafna U, Chauhan S, Jetley P, Mitra S, et al. Comparison of intrathecal clonidine and magnesium sulphate used as an adjuvant with hyperbaric bupivacaine in lower abdominal surgery. Indian J Anaesth 2017;61:667-72.  Back to cited text no. 20
[PUBMED]  [Full text]  
Dutta D, Naskar C, Wahal R, Bhatia VK, Singh V. Intrathecal clonidine for perioperative pain relief in abdominal hysterectomy. Indian J Pain 2013;27:26-32.  Back to cited text no. 21
  [Full text]  
Dobrydnjov I, Axelsson K, Thörn SE, Matthiesen P, Klockhoff H, Holmström B, et al. Clonidine combined with small-dose bupivacaine during spinal anesthesia for inguinal herniorrhaphy: A randomized double-blinded study. Anesth Analg 2003;96:1496-503.  Back to cited text no. 22
Bansal M, Agarwal S, Gupta K, Gupta PK, Agarwal S, Pandey MN. Clinical efficacy of clonidine versus nalbuphine as intrathecal adjuvants to 0.5% hyperbaric bupivacaine for subarachnoid block during gynaecological procedures: A double blind study. Int J Res Med Sci 2017;5:2540-5.  Back to cited text no. 23
Mostafa MG, Mohamed MF, Farrag SH. Which has greater analgesic effects: Intrathecal nalbuphine or intrathecal tramadol? J Am Sci 2011;7:480-4.  Back to cited text no. 24
Moustafa MA, Saleh RS. Nalbuphine added to intrathecal morphine in total knee arthroplasty; effect on postoperative analgesic requirements and morphine related side effects. Alexandria J Med 2012;48:175-8.  Back to cited text no. 25


  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
    Article Tables

 Article Access Statistics
    PDF Downloaded105    
    Comments [Add]    

Recommend this journal