|Year : 2016 | Volume
| Issue : 3 | Page : 198-203
A prospective, double-blind dose-ranging study of intrathecal nalbuphine in the lower abdominal and lower limb surgeries
Sandip Roy Basunia, Suman Chattopadhyay, Aditi Das, Baishaki Laha, Debasish Bhar, Rita Pal
Department of Anaesthesiology, Midnapore Medical College, Midnapore, West Bengal, India
|Date of Web Publication||10-Jan-2017|
BC 103, Salt Lake, Kolkata - 700 064, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Nalbuphine is a synthetic opioid with mixed agonist-antagonist action, used as an adjuvant with intrathecal bupivacaine to prolong postoperative analgesia. However, only a few studies so far have quantified the optimal intrathecal nalbuphine dose. Our aim was to compare the relative effectiveness of three doses of intrathecal nalbuphine to determine the optimum dose which prolonged analgesia with minimal side effects. Settings and Design: This was a prospective, randomized, double-blind study. Subjects and Methods: Eighty American Society of Anesthesiologists I and II patients undergoing elective lower abdominal and lower limb surgeries under subarachnoid block were randomly allocated to four groups (A, B, C, and D of twenty patients each) to receive 0.5 ml normal saline or 0.8, 1.2, and 1.6 mg nalbuphine added to 0.5% hyperbaric bupivacaine 15 mg. The onset of sensory and motor blockade, two-segment regression time of sensory blockade, duration of motor blockade, duration of analgesia, visual analog scale pain score, and side effects were compared between these groups. Results: Two-segment regression time of sensory blockade and duration of effective analgesia were prolonged in both Group C (1.2 mg nalbuphine) and Group D (1.6 mg nalbuphine) compared to Groups A and B (P < 0.05), but the incidence of side effects was significantly higher in Group D (P < 0.05). Conclusion: Nalbuphine 1.2 mg is the optimum intrathecal dose which prolongs postoperative analgesia without increased side effects.
Keywords: Hyperbaric bupivacaine, intrathecal, nalbuphine, spinal anesthesia
|How to cite this article:|
Basunia SR, Chattopadhyay S, Das A, Laha B, Bhar D, Pal R. A prospective, double-blind dose-ranging study of intrathecal nalbuphine in the lower abdominal and lower limb surgeries. Indian J Pain 2016;30:198-203
|How to cite this URL:|
Basunia SR, Chattopadhyay S, Das A, Laha B, Bhar D, Pal R. A prospective, double-blind dose-ranging study of intrathecal nalbuphine in the lower abdominal and lower limb surgeries. Indian J Pain [serial online] 2016 [cited 2020 Jan 22];30:198-203. Available from: http://www.indianjpain.org/text.asp?2016/30/3/198/198060
| Introduction|| |
Subarachnoid block (SAB) is the most popular regional anesthetic technique for the lower abdominal and lower limb surgeries. However, local anesthetic drugs used alone for spinal anesthesia do not have the advantage of prolonged postoperative analgesia.  Various adjuvants, for example, opioids, midazolam, alpha-2 agonist, and ketamine, have been used along with the local anesthetics for prolongation of postoperative analgesia in neuraxial blockade, reduction of local anesthetic dose, and thereby side effects.  However, adverse effects such as pruritus, postoperative nausea and vomiting, urinary retention, and respiratory depression have been observed with the majority of these adjuvant drugs.  Hence, the search continues for a drug which is effective, cheap, and with minimal adverse effects.
Nalbuphine is a semi-synthetic opioid drug with mixed μ-antagonist and κ-agonist properties.  It provides reasonably potent analgesia to visceral nociception.  Previous studies have shown that epidural or intrathecal administration of nalbuphine produces a significant analgesia accompanied by minimal pruritus and respiratory depression. , However, only a few studies were done so far for determining the optimal dose of intrathecal nalbuphine.
While 0.8 mg of intrathecal nalbuphine is effective in a number of studies, , another study pointed out that 1.6 mg intrathecal nalbuphine has ceiling effects.  No studies till date have evaluated the "gray zone" in between 0.8 and 1.6 mg. Thus, this prospective, double-blinded, randomized, controlled study has been planned to compare the effectiveness of the previously studied groups (i.e., 0.8, 1.6 mg) along with an intermediate dose in between these doses (i.e., 1.2 mg) of intrathecal nalbuphine as an adjunct to 15 mg hyperbaric bupivacaine 0.5% in similar cohorts of patients undergoing elective lower abdominal and lower limb surgical procedures to find out the optimum dose intrathecal nalbuphine which prolongs postoperative analgesia with minimal side effects.
| Subjects and Methods|| |
After clearance from the Institutional Ethics Committee, we conducted a prospective, randomized, double-blinded study from September 2014 to August 2015 at a government-run district-level medical college in East India. Eighty consenting patients of the American Society of Anesthesiologists (ASA) Physical Status I and II, aged 18-50 years, scheduled for elective lower abdominal and lower limb surgeries with duration <2 h under SAB were included in the study.
Patients with a history of adverse response to either bupivacaine or nalbuphine; pregnant patients; patients receiving drugs such as phenothiazines, other tranquilizers, hypnotics, and other central nervous system depressants; alcohol addicts; patients suffering from peripheral or central neurological, cardiac, respiratory, hepatic, or renal disease; patients having body weight more than 100 kg; and patients having any contraindication for SAB were excluded from the study.
Patients were premedicated with tablet diazepam 10 mg and tablet ranitidine 150 mg orally the night before surgery and fasted for 6-8 h. The entire procedure of spinal anesthesia, 11-point visual analog scale  (VAS, no pain graded 0 to maximum pain graded 10 points), and study protocol were explained to the patient at preanesthetic checkup, and written consent was obtained.
Patients were randomly allocated by computer-generated random number and sealed opaque envelope technique into four groups of twenty patients each. They received either normal saline (NS) 0.5 ml (Group A, placebo) or nalbuphine 0.8 mg, 1.2 mg, and 1.6 mg (Groups B, C, and D, respectively) made up to 0.5 ml volume with NS, mixed with 15 mg of hyperbaric bupivacaine 0.5% (total volume 3.5 ml in all groups).
Ampoule-containing preservative-free nalbuphine hydrochloride 10 mg in 1 mL was used. The dose of intrathecal nalbuphine was measured using an insulin syringe. The baricities of the study drugs were comparable. The drugs were prepared and SAB performed by anesthesiologist who did not take further part in the study. Both patients and observers who recorded and analyzed the data were blinded to the study drug received. After securing intravenous access and attaching monitors, Ringer lactate solution 15 ml/kg was started. SAB was aseptically performed with 3.5 ml of the drug injected in L3-L4 space, using a 26-gauge Quincke spinal needle.
Hypotension was defined as a fall in systolic blood pressure (SBP) to <90 mmHg or more, and bradycardia was defined as a heart rate of 60 or less for the purpose of this study. Perioperative hypotension, bradycardia, and nausea/vomiting were treated with phenylephrine 100 mcg boluses, atropine 0.6 mg, and ondansetron 4 mg, respectively.
Following observations were made regarding onset of sensory blockade (time from intrathecal injection to loss of pinprick sensation at T10 dermatome), highest level of sensory block, duration of sensory blockade (two-segment regression time from highest level of sensory blockade), duration of effective analgesia (time from intrathecal injection to first analgesic requirement or VAS >3 whichever is earlier), onset of motor blockade (time from injection to Grade 4 motor block as per modified Bromage's criteria),  duration of motor blockade (time from onset to return to Bromage's Grade 1 motor blockade). Modified Bromage's criteria are as follows: Grade 1 - free movement of legs and feet, Grade 2 - just able to flex knees with free movement of feet, Grade 3 - unable to flex knees but with free movement of feet, and Grade 4 - unable to move legs or feet.
Intensity of pain was measured by VAS score at 0, 15, 30, 60 min after operation and then at every 30 min interval until the patient received a rescue analgesia (aqueous diclofenac 75 mg intramuscularly). Patients who did not develop sensory block up to T 10 or Grade 4 motor block were excluded from the study.
The changes in pulse rate, SBP and diastolic blood pressure (DBP), oxygen saturation (SpO 2 ), and respiratory rate were recorded just before operation (0 min) and then at every 5 min interval up to the end of operation. Any side effect in the form of postoperative hypotension, bradycardia, respiratory depression (SpO 2 <90%), or nausea and vomiting was recorded. Sedation was monitored every 2 hourly for the first 12 postoperative h with 1-6-point Ramsay sedation scoring,  any score above 4 was considered as excessive sedation, and the patient was put on moist oxygen through polymask at a rate of 4 L/min.
Sample size was calculated considering the duration of analgesia as the primary outcome measure. It was estimated that 17 patients would be required per group to detect a difference of 30 min in this parameter, with 80% power and 5% probability of Type I error. This calculation assumed a standard deviation of 30 min for the duration of analgesia. Rounding off, the recruitment target was kept at twenty patients per group or eighty overall. Categorical data were analyzed using Chi-square and Kruskal-Wallis test while continuous data were analyzed by one-way ANOVA and Student's unpaired t-test. A P < 0.05 was considered statistically significant. All data were analyzed by SPSS 17 software (2007) developed by SPSS Inc., Chicago, USA.
| Results|| |
This prospective, randomized, double-blinded cohort study was performed on eighty patients divided into four groups of twenty patients each to find the optimal dose of intrathecal nalbuphine which was effective and safe. These groups received intrathecally either NS 0.5 ml (Group A, placebo) or nalbuphine 0.8 mg, 1.2 mg, and 1.6 mg (Groups B, C, and D, respectively) made up to 0.5 ml volume with NS, mixed with 15 mg of hyperbaric bupivacaine 0.5% (total volume 3.5 ml in all groups). There was no case of failure or inadequate blockade after SAB. There was no intraoperative or postoperative patient drop out, and data of all eighty patients were analyzed [Figure 1].
[Table 1] shows that all the study Groups A, B, C, and D were comparable regarding demographic variables such as age, weight, height, and sex ratio (P > 0.05).
On intragroup comparison after SAB, patients receiving 1.6 mg intrathecal nalbuphine (Group D) had statistically significant hypotension (decrease in both SBP and DBP) and bradycardia in comparison to Groups A, B, and C [Table 2].
The onset time of sensory and motor blockade was significantly (P < 0.05) faster in Groups B, C, and D where nalbuphine was added intrathecally in comparison to Group A where NS was added to intrathecal nalbuphine. A T 10 level sensory blockade was achieved in all eighty patients, which allowed performance of below umbilical and lower limb surgeries. A few patients in all four groups achieved much higher sensory blockade. Maximum sensory block height till a level of T 6 was observed in two patients of each group. There was no statistically significant difference in the onset of either sensory or motor blockade among Groups B, C, and D.
The two-segment regression time of sensory blockade as well as duration of analgesia was prolonged in the nalbuphine Groups (B, C, and D) compared to Group A (NS). On intragroup comparison, Groups C and D (1.2 and 1.6 mg intrathecal nalbuphine) had a longer regression time of sensory blockade and a more prolonged analgesia compared to Group B (receiving 0.8 mg intrathecal nalbuphine). The two Groups C and D were comparable with respect to regression of sensory block and duration of analgesia.
Duration of motor blockade was significantly prolonged in all Groups B, C, and D as compared to Group A. There was no statistically significant difference in the duration of motor blockade among Groups B, C, and D even though there was a tendency for prolongation of motor blockade as the dose of intrathecal nalbuphine increased.
The duration of surgery was comparable in all groups (P > 0.05) and was well within the duration of sensory-motor blockade [Table 3].
|Table 3: Comparison of sensory-motor parameters, duration of analgesia, and surgical time|
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Number of patients having perioperative hypotension and bradycardia are depicted in [Table 4]. Perioperative hypotension and bradycardia were significantly higher in the group receiving 1.6 mg intrathecal nalbuphine (Group D) compared to other groups. The lowest recorded SBP, DBP, and heart rate were 80 mmHg, 50 mmHg, and 47 beats/min, respectively. All occurrences of hypotension were corrected within 10 min and bradycardia within 120 s with use of phenylephrine and atropine boluses as per the study protocol.
Most of the patients who received nalbuphine-bupivacaine combinations (Group B, C, and D) were sedated, calm, and easily arousable with verbal commands (Ramsay sedation score of 2). Patients in Group D also had higher incidences of excessive sedation (Ramsay score 4 and above) and nausea/vomiting compared to the other groups, but the values were not significant. We did not come across any case of respiratory depression in any patient, and all incidences of excessive sedation occurred within the first 4 postoperative h [Table 4].
| Discussion|| |
Intrathecal opioids (ITOs) used as an adjunct have certain advantages such as rapid onset of action, prolong postoperative analgesia, and allow early ambulation of patients because of their sympathetic and motor nerve-sparing activities. , However, the popularity of ITO was undermined by their side effects, such as respiratory depression, pruritus, and postoperative nausea and vomiting.  To overcome these side effects, opioids with partial agonist-antagonist action have been studied extensively. Nalbuphine is an opioid having agonist activity at kappa receptors and antagonistic activity at mu receptors. Nalbuphine when administered intrathecally binds to kappa receptors in the brain and spinal cord areas which are involved in nociception, producing analgesia and sedation without side effects associated with mu receptors. Till date, only a few studies have looked into optimal dose ranging of intrathecal nalbuphine, and in particular, no study till date has investigated the effects of 1.2 mg of intrathecal nalbuphine.
The onset time of sensory and motor blockade was significantly faster in all patients receiving ITO nalbuphine. Two-segment regression time of sensory blockade and duration of effective analgesia were prolonged only with 1.2 mg and 1.6 mg nalbuphine, but hypotension and bradycardia were more with 1.6 mg nalbuphine.
In the study results, we found that the duration of effective analgesia increased in Groups B, C, and D having intrathecal nalbuphine compared with the control Group A, proving the effectiveness of intrathecal nalbuphine as adjuvant to 0.5% hyperbaric bupivacaine in SAB. Our study results are in accordance with the previous studies of Lin,  Sapate et al.,  and Fournier et al. 
Regarding the studies comparing the different doses of nalbuphine, Culebras et al. studied intrathecal nalbuphine in doses of 0.2, 0.8, and 1.6 mg in ninety obstetric patients undergoing cesarean section and found 0.8 mg as the most effective dosage and after which it has ceiling effect.  Mukherjee et al.  also studied intrathecal nalbuphine in doses of 0.2, 0.4, and 0.8 mg in ASA 1 and 2 patients undergoing lower limb orthopedic surgeries and found 0.4 mg as the most effective dose and after it showed ceiling effect.
As pointed out, none of the previous studies had taken intermediate dose of 1.2 mg between 0.8 and 1.6 mg for intrathecal route. The dose 1.2 mg (Group C) was found to be more effective compared to Group B (0.8 mg) with minimal side effects compared to Group D (1.6 mg). In our study, nalbuphine exhibits analgesic ceiling effect at 1.2 mg dosage, above which it will not increase analgesic efficacy. Our results differ from the study by Culebras et al.  and Mukherjee et al.  as they have not studied the 1.2 mg group, and our study was conducted with a different demographic patient population in different surgery and with 15 mg 0.5% hyperbaric bupivacaine compared with 10 and 12.5 mg 0.5% hyperbaric bupivacaine in their studies, respectively.
The onset time of sensory and motor blockade was found to be statistically significant (P < 0.05) among all the four groups. Intrathecal nalbuphine seems to provide a significantly faster onset of pain relief compared to placebo probably because of its lipophilic properties. , Previous studies in rats demonstrated that visceral analgesia is mediated by both mu and kappa receptors and that intrathecal nalbuphine suppresses responses to visceral pain. ,
In our study, none of the patients had respiratory depression (respiratory rate below 10 bpm, SpO 2 <90%). Nalbuphine exhibits ceiling effect for respiratory depression. This is proved in studies done by Romagnoli and Keats  and Gal et al.  Since respiratory depression is predominantly mu receptor-mediated and nalbuphine is a mu receptor antagonist, respiratory depression effect is expected to be attenuated by nalbuphine.
In bupivacaine group, patients were wide awake whereas patients who received nalbuphine-bupivacaine combinations were sedated, calm, and easily arousable with verbal commands (Grade 2 sedation score). Similar results were seen in studies conducted by Culebras et al.,  Mostafa et al.,  and Tiwari et al.,  where there were minimal side effects with sedation score comparable between the groups.
Partial agonist-antagonist opioids have a ceiling effect to respiratory depression. Buprenorphine has a bell-shaped dose-response curve, where after a certain dosage there is no further increase in respiratory depression in contrast to pure μ agonists such as morphine where respiratory depression is dose dependent. A similar ceiling effect to respiratory depression is seen with nalbuphine and is a safety feature of this drug.  The partial agonist activity at μ receptors which is associated with analgesia and respiratory depression may be the cause of this ceiling effect. Similarly, dose-response curve of partial agonists has a maximal response which is below that obtainable by a full agonist.
Our study could be criticized on a number of accounts. A larger sample size in each group (preferably 30 or more) may have provided more detailed data on primary study outcome of prolongation of the duration as also the other effects/side effects of these doses of intrathecal nalbuphine. Measuring nalbuphine with an insulin syringe should also be meticulous as a slight mistake would alter the dosage. Moreover, we have studied only three of many feasible dosages of intrathecal nalbuphine. We also studied sedation for first 12 postoperative h only which could have been extended to either 18 or 24 h as in some other studies. We could have been more specific regarding our choice of surgical patients, choosing either lower abdominal or lower limb surgeries instead of choosing patients from both groups. Further studies are suggested to overcome these limitations of our study.
| Conclusion|| |
We conclude that 1.2 mg is the optimum intrathecal dose of nalbuphine to prolong postoperative analgesia in the lower abdominal and lower limb surgeries.
We would like to acknowledge Prof. (Dr.) Avijit Hazra of I.P.G.ME.R., Kolkata, and Dr. Abantika Bhattacharya of Midnapore Medical College and Hospital, West Bengal, India, for their kind help in biostatistics of this current study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]