|Year : 2016 | Volume
| Issue : 1 | Page : 23-28
A comparative study of three different doses of nalbuphine as an adjuvant to intrathecal bupivacaine for postoperative analgesia in abdominal hysterectomy
Fareed Ahmed, Hunny Narula, Mamta Khandelwal, Debojyoti Dutta
Department of Anesthesiology, SMS Medical College, Jaipur, Rajasthan, India
|Date of Web Publication||7-Jan-2016|
Dr. Mamta Khandelwal
Flat No. 201, B-80, Sona Enclave, Rajendra Marg, Bapu Nagar, Jaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
Background: Spinal anesthesia is still the most commonly used technique for lower abdominal surgeries as it is very economical and easy to administer. Its main disadvantage remains the short duration of action. Hence, different additives have been used. Nalbuphine is an agonist-antagonist opioid that binds to μ-receptors, as well as to κ-and δ-receptors. The aim of this randomized, double-blind study was to evaluate the potentiating effect of intrathecal nalbuphine with bupivacaine for postoperative analgesia in three different doses. Materials and Methods: A total of 100 patients were randomized into four groups. Group A: Patients received 15 mg of 0.5% hyperbaric bupivacaine, group B: Patients received 15 mg of 0.5% hyperbaric bupivacaine plus 0.8 mg of nalbuphine, group C: Patients received 15 mg of hyperbaric bupivacaine plus 1.6 mg of nalbuphine, and group D: Patient received 15 mg of hyperbaric bupivacaine plus 2.4 mg of nalbuphine intrathecally. Results: The onset of sensory and motor block and duration of motor block were comparable in all groups. Two-segment regression was statistically significant when group A was compared to groups B, C, and D. The total durations of analgesia were 133.8 + 28.3 min, 199.8 + 25.9 min, and 166.8 + 27.8 min in groups B, C, and D, respectively. Conclusion: Our study showed that the combination of intrathecal bupivacaine with nalbuphine significantly prolonged postoperative analgesia as compared to the control group, and a 1.6 mg dose of nalbuphine administered intrathecally showed the best results among all other study groups.
Keywords: Abdominal hysterectomy, intrathecal, nalbuphine
|How to cite this article:|
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
|How to cite this URL:|
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 [serial online] 2016 [cited 2020 Aug 5];30:23-8. Available from: http://www.indianjpain.org/text.asp?2016/30/1/23/173457
| Introduction|| |
Pain is frequently the result of nociception - an activity in the nervous system that results from the stimulation of nociceptors.  The transmission of nociceptive stimuli from the periphery to the central nervous system (CNS) results in neuroendocrine stress response resulting in increased sympathetic tone, increased catecholamine levels, and catabolic hormone secretion. Shallow respiration and inadequate cough due to pain can result in postoperative pulmonary complications. A control of these pathophysiologic processes by administering adequate postoperative analgesia along with intraoperative anesthesia may lead to improvement in morbidity and patient satisfaction. ,
Adjuvants are drugs that increase the efficacy or potency of other drugs when given concurrently. They increase the speed of the onset of neural blockade (reduce latency), improve the quality, and prolong the duration of neural blockade. Examples of neuraxial adjuvant include opioids (morphine, fentanyl, nalbuphine, and buprenorphine), sodium bicarbonate (NaHCO3), vasoconstrictors (epinephrine), alpha-2 adrenoceptor agonists (clonidine and dexmedetomidine), cholinergic agonists, N-methyl-d-aspartate (NMDA) antagonists (ketamine) and γ-aminobutyric acid (GABA) receptor agonists (midazolam). 
Nalbuphine is an agonist-antagonist opioid that is structurally related to oxymorphone and naloxone.  Intrathecal opioids are transported supraspinally by bulk cerebrospinal fluid (CSF) flow where they modulate descending inhibitory pain pathways, and a small amount of opioid diffuses into the epidural space with subsequent systemic absorption resulting in centrally mediated analgesia.
As per our knowledge, there have been no literature available comparing 0.8 mg, 1.6 mg, and 2.4 mg doses of nalbuphine as an intrathecal adjuvant to local anesthetic agents. The aim of our study was to evaluate the potentiating effect of intrathecal nalbuphine with bupivacaine for postoperative analgesia in three different doses.
| Materials and Methods|| |
This prospective, randomized, double-blind study was done at a tertiary care center after the approval of local institutional ethical committee and obtaining written informed consent from all patients before participation.
One hundred patients of the American Society of Anesthesiologists (ASA) physical status grade I and II, aged 30-60 years, scheduled for elective total abdominal hysterectomy under subarachnoid block were included in the study. After taking written informed consent patients were randomized to four groups (N = 25) by chit-in-box method.
All the patients were thoroughly examined preoperatively which included history, general physical examination, and checking the vital parameters of the patients such as blood pressure, pulse, respiratory rate and systemic examination, and ASA grading. The patients with a contraindication to spinal anesthesia or major neurological, cardiovascular, metabolic, respiratory, renal disease, or coagulation abnormalities were excluded.
The visual analogue scale (VAS) scoring system was explained to all the patients. The VAS consisted of a 10-cm horizontal paper strip with two endpoints labeled "No pain" and "Worst pain ever". When the patient complained of pain in ward or recovery room, he or she was asked to mark the strip at a point that corresponds to the level of pain intensity, she presently felt.
All the patients were fasted for at least 6 h before the procedure. All the routine monitors were attached and the preoperative baseline readings of noninvasive blood pressure (NIBP), pulse arte (PR), and saturation were noted. After securing an intravenous (IV) access using an 18-Gauge IV cannula all patients irrespective of the group they belonged to were preloaded with Ringer's lactate 15 mL/kg over 10 min. Under all aseptic precautions, spinal anesthesia was performed in the operating room at the L 3 -L 4 interspace, with the patient in the left lateral position using a 25-Gauge (B D Spinal Needle). A volume of 3.5 mL of drug was injected over 30 s. The composition of intrathecal drugs depended upon the group to which the patient belonged. The drug combination was prepared by one anesthesiologist and was given by another anesthesiologist who was blinded to the drug used in the study. Both the patients and the observer were blinded to the study drug or the group.
In group A: The patients received a dose of 15 mg of 0.5% hyperbaric bupivacaine, in group B: The patients received a dose of 15 mg of 0.5% hyperbaric bupivacaine plus 0.8 mg of nalbuphine, in group C: The patients received a dose of 15 mg of 0.5% hyperbaric bupivacaine plus 1.6 mg of nalbuphine, and in group D: The patients received a dose of 15 mg of 0.5% hyperbaric bupivacaine plus 2.4 mg of nalbuphine intrathecally. In all groups, normal saline was added to make total volume of 3.5 mL.
The patient was placed in supine position with a head down tilt immediately after spinal injection to achieve highest level of block up to T5 or T6. An indwelling urinary catheter was inserted before the start of the operation. Intraoperative fluid management was done according to the blood loss and hemodynamic parameters.
Intraoperatively regular checkup of blood pressure, pulse rate, saturation, and respiratory rate were done at 2-min, 5-min, 10-min, 15-min, 30-min, 60-min, 120-min interval. The level of sensory block was tested by pinprick bilaterally at midclavicular line that was done every minute till the maximum sensory level is achieved and then after 1 h 30-min interval. The onset of sensory block was taken as the time taken to attain sensory level of T6 dermatome.
The time of the onset of motor block was assessed using the Bromage scale [Table 1]. The onset of motor block was taken as the time taken to achieve Bromage grade III block from the time of subarachnoid injection.
Episodes of intraoperative hypotension were managed with colloids and if required with incremental doses of ephedrine (5 mg) intravenously. Bradycardia was treated with 0.6 mg of atropine intravenously. Intraoperative nausea was treated with ondansetron injection (4 mg) and any pruritus was treated using antihistamines.
Immediately after the operation, the patients were shifted to the recovery room. In postoperative period, PR, NIBP, and saturation were recorded at regular interval of 30 min. Two-segment regression time (time of regression of sensory block by two segments from the highest level attained) and duration of motor block (measured from anesthetic injection until the time to reach a Bromage score of I) was recorded in all patients.
The VAS score was serially assessed at 30-min interval starting from 60 min to 270 min or till the patient complains of pain (VAS score <3). The duration of effective analgesia was measured as time from the intrathecal drug administration to the patient's VAS score <3 either in the recovery room or in the ward, and was recorded in minutes. The patient's VAS score<3 and administration of rescue analgesia constituted the end point of the study. Intravenous diclofenac (75 mg) was given as a rescue analgesic. The patient was kept under observation for a total period of 24 h for a routine postoperative monitoring and to observe the following side effects: Bradycardia (PR <60 bpm), hypotension (MAP <70 mmHg), nausea and vomiting, pruritus, and respiratory depression.
The sample size was calculated to be 22 subjects in each groups based on two-segment regression time, minimum difference in means being 7.1, and standard deviation 6.95 as per study assuming α error 0.05 and power 80% so for study purpose 25 subjects were taken in each group.
The statistical analysis was performed using Statistical Package for the Social Sciences (SPSS), version 15.0, for Windows statistical software package (SPSS Inc., Chicago, IL, USA). Categorical data, i.e., ASA grade, type of surgery, and the incidence of adverse events (hypotension, bradycardia, respiratory depression, pruritus, and nausea and vomiting) are presented as numbers (percent) and were compared among groups using Chi-square test. P value <0.05 was considered statistically significant. The groups were compared for demographic data (age and weight), duration of surgery, time for two segment regression, VAS score, and total duration of motor block and analgesia by analysis of variance (ANOVA) and t-test. The probability was considered significant if it was less than 0.05. Data were represented as mean and standard deviation. Intergroup comparison was done by using post hoc Tukey's honest significant difference (HSD) test.
| Results|| |
hundred patients were enrolled in this study. All the groups were comparable with respect to age, gender, weight, ASA status, type of surgery, and duration of surgery. There were no statistically significant differences in the demographic data among all the groups (P > 0.05) [Table 2].
The onset of sensory and motor block was found to be similar in all the four groups. There was no statistically significant difference among groups (P > 0.05). The onset of sensory block were 7.5 ± 1.2 min, 7.2 ± 1.5 min, 7.4 ± 1.3 min, and 7.1 ± 1.1 min in groups A, B, C, and D, respectively [Table 3].
The times of the onset of motor block were 8.5 ± 1.0 min, 8.4 ± 1.4 min, 8.5 ± 1.1 min, and 8.2 ± 1.1 min in groups A, B, C, and D, respectively.
There was no statistically significant difference found in duration of motor block among groups (P > 0.05). The duration of motor block was 116.6 ± 11.0 min, 123.8 ± 16.8 min, 123.2 ± 13.6 min, and 125.6 ± 10.5 min in groups A, B, C, and D, respectively.
The statistically significant difference in duration of two-segment regression was seen when group A was compared with other three groups (B, C, and D) The mean durations of two-segment regression was 82.4 ± 23.1 min, 98.7 ± 21.4 min, 132.7 ± 21.1 min, and 117.2 ± 23.9 min in group A, B, C, and D, respectively. In inter-group comparison, we observed a significant result on comparison of groups A and C, groups A and D, and groups B and D. In groups A and B and in groups C and D, the result was found insignificant [Table 4].
The total duration of analgesia were 117.8 ± 23.3 min, 133.8 ± 28.3 min, 199.8 ± 25.9 min, and 166.8 ± 27.8 min in groups A, B, C, and group D, respectively. Statistically significant difference in duration of postoperative analgesia was found when group A was compared with the other three groups (B, C, and D) [Table 3]. On intergroup comparison between groups A and B, it was found insignificant and for rest of the groups significant results were obtained [Table 5].
Degree of sedation, incidence of adverse effects, and hemodynamic variability were not statistically significant among all the study groups [Table 6] and [Table 7].
|Table 7: Characteristics of hemodynamic and incidence of side effects (intraoperative and early postoperative period) |
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| Discussion|| |
Intrathecal opioids used as adjuncts are capable of producing analgesia of prolonged duration and allow early ambulation of patients because of their sympathetic and motor nerve sparing activities. 
We conducted our study with 100 female patients using intrathecal nalbuphine in three different doses. Our results reemphasized the well-known fact that intrathecal nalbuphine is an effective neuraxial adjunct. In our study, when we used nalbuphine in 1.6 mg dose the duration of effective analgesia (time from induction to VAS score <3) is significantly increased with reduced VAS pain score, when compared to control (P value <0.05) without any significant increase in associated adverse effects (P value >0.05). We found that 0.8 mg dose did increase the analgesia duration as compared to control (P value <0.05), but less than the increase in 1.6 mg group and also the VAS scores noted were higher [Table 8]. In case of 2.4 mg dose, there was no further increase in analgesia duration, exhibiting ceiling effect but there was a definitive increase in the incidence of side effects (although statistically they were insignificant with P > 0.05). The side effects in all the three groups were comparable with the control group. The ceiling effect of nalbuphine, which prevents it from providing sufﬁcient analgesia to cover the most severe discomfort, also prevents increasing sedation and respiratory depression as the dose is increased, potentially providing an increased safety margin in comparison to μ-agonists.
In 2000, Culebras et al. suggested that intrathecal nalbuphine (0.8 mg) provides good intraoperative and early postoperative analgesia without side effects The additional increase to 1.6 mg did not increase the efficacy. 
In 2011, Mukherjee et al. compared 0.2 mg, 0.4 mg, and 0.8 mg doses of nalbuphine. They concluded that nalbuphine is a useful adjunct in Sub-arachnoid Block (SAB) in a dose of 0.4 mg. 
The results of our study differ from the study of Culebras et al.  and by Mukherjee et al.  In our study using 1.6 mg dose of nalbuphine along with bupivacaine showed significantly (P = 0.00) increased duration of analgesia compared to the control group. This may be attributable to the different study population (nonpregnant) and different types of surgery (abdominal) requiring sensory level of at least T5-T6.
In 2010, Farrag et al. in their study concluded that the intrathecal administration of 50 mg tramadol and intrathecal nalbuphine (2 mg) had similar postoperative analgesia without producing significant side effects. Sedation score was equal for both the groups and the number of rescue analgesia was small in the nalbuphine group. 
Moustafa et al. in 2012 studied that intrathecal addition of nalbuphine (1mg) to morphine (0.2 mg) decreases the opioid related side effects without affecting the postoperative analgesia. 
If the patient has a history of μ-agonist-induced pruritus, nausea/emesis, or other μ-side effects, or a preexisting respiratory impairment, then nalbuphine might be particularly considered. Apart from its potent analgesic property, its other characteristics such as antagonizing morphine-induced pruritus and its potent anti-shivering effect has been explored.  There are safety issues regarding the intrathecal use of nalbuphine and insufficient data to guarantee safe intrathecal use in human patients. There was an animal study by Rawal et al.  that examined the effects of nalbuphine in a dose of 0.75 mg/kg and reported no behavioral or systematic histopathologic abnormalities. We are not aware of any reports of neurotoxicity of intrathecal nalbuphine since then and also none of our patients showed any neurological sequelae. Some of the previous studies were even conducted with intrathecal nalbuphine in pregnant patients, but no neurotoxicity was reported in them as well as without any adverse effect on the fetus. 
So, we conclude that intrathecal nalbuphine is an effective adjuvant to 0.5% hyperbaric bupivacaine in a 1.6 mg dose in patients undergoing total abdominal hysterectomy under subarachnoid block. It increases the duration of postoperative analgesia with the side effects well tolerated by the patients. Using 2.4 mg dose does not offer any added advantage regarding the duration of analgesia.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]