|Year : 2014 | Volume
| Issue : 1 | Page : 18-23
A comparison of analgesic effect of different doses of intrathecal nalbuphine hydrochloride with bupivacaine and bupivacaine alone for lower abdominal and orthopedic surgeries
B Jyothi, Shruthi Gowda, Safiya I Shaikh
Department of Anesthesiology, Karnataka Institute of Medical Sciences, Hubli, Karnataka, India
|Date of Web Publication||15-Mar-2014|
Department of Anaesthesiology, Karnataka Institute of Medical Sciences, Hubli - 580 021, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Nalbuphine is a synthetic opioid with mixed agonist-antagonist action, when added as adjuvant to intrathecal bupivacaine acts on kappa receptors in the dorsal horn of the spinal cord producing analgesia. Aim: To evaluate the onset of sensory block, hemodynamic changes, duration and quality of analgesia, and adverse effects of different doses of nalbuphine with bupivacaine for spinal anesthesia. Materials and Methods: Randomized double blind study done on 100 patients undergoing lower abdominal and lower limb orthopedic surgeries under subarachnoid block. Patients were randomly allocated to four groups receiving either intrathecal 15 mg of bupivacaine + 0.5 mL normal saline alone or 15 mg of bupivacaine with either of nalbuphine 0.8, 1.6, and 2.5 mg + 0.5 mL normal saline. Results: The mean visual analogue scale score in group A is 4.08 ± 0.5 and in groups B, C, and D are 3.4 ± 0.4, 3.5 ± 0.5, and 3.5 ± 0.5, respectively. The duration of analgesia in group A is 190.4 ± 20.0 and in groups B, C, and D were 322.4 ± 31.1, 319 ± 39.8 and 317.8 ± 47.5. The quality of analgesia was good in 72%-76% and excellent in 16%-28% in groups B, C, and D and poor 28% to satisfactory 72% in group A. Conclusion: Addition of 0.8 mg of nalbuphine to 0.5% bupivacaine for subarachnoid block provides excellent analgesia with longer duration of action compared with 1.6 and 2.4 mg of nalbuphine.
Keywords: Bupivacaine hydrochloride, nalbuphine hydrochloride, subarachnoid block
|How to cite this article:|
Jyothi B, Gowda S, Shaikh SI. A comparison of analgesic effect of different doses of intrathecal nalbuphine hydrochloride with bupivacaine and bupivacaine alone for lower abdominal and orthopedic surgeries. Indian J Pain 2014;28:18-23
|How to cite this URL:|
Jyothi B, Gowda S, Shaikh SI. A comparison of analgesic effect of different doses of intrathecal nalbuphine hydrochloride with bupivacaine and bupivacaine alone for lower abdominal and orthopedic surgeries. Indian J Pain [serial online] 2014 [cited 2019 Nov 17];28:18-23. Available from: http://www.indianjpain.org/text.asp?2014/28/1/18/128881
| Introduction|| |
The surgical stress response peaks during the postoperative period and has major effects on almost all body systems. A pain-free and stress-free postoperative period definitely helps in early mobilization and recovery, thereby reducing morbidity and mortality. Intrathecal opioid is widely used in treating intraoperative, postoperative, traumatic, obstetric, and chronic cancer pain. The technique of intrathecal opioid administration along with local anesthetics has been studied extensively and found to provide superior quality of analgesia in a variety of surgical procedures. , The rationale for the combination of opioids and local anesthetics is that these two types of drugs eliminate pain by acting at two different sites. Local anesthetics act at the nerve axon and the opioid at the receptor site in the spinal cord. 
Nalbuphine is a μ receptor antagonist and ĸ receptor agonist. , Nalbuphine when added as adjunct to intrathecal local anesthetics has the potential to provide good intraoperative and postoperative analgesia with decreased incidence and severity of μ receptor side effects. , In contrast to other centrally acting opioid analgesics, nalbuphine has minimal respiratory depressant effect and low potential abuse; it can be used as an alternative to other opiates.
| Materials and Methods|| |
Following ethical committee approval, a double-blind randomized controlled clinical study was conducted on 100 adult patients admitted for lower abdominal and orthopedic procedures under subarachnoid block.
- American Society of Anaesthesiologists (ASA) I and II patients
- Age group of 18-60 years
- Patient with written valid consent
- Patient undergoing elective lower abdominal and orthopedic surgery
- Infection at the site.
- Bleeding disorder.
- Allergic reaction to any anesthetic drug.
- ASA III and IV grade.
- Patients on tranquilizers, hypnotics, sedatives, and other psychotropic drugs.
Patients were randomly allocated into four groups. Each group consists of 25 patients. They received either of drug solution as below [Table 1].
Preanesthetic evaluation was done to all patients under inclusion criteria.
Premedicated with tab diazepam 10 mg and tab ranitidine 150 mg orally night before surgery. Basic laboratory investigations were done. Patient's height and weight was noted. The entire procedure of spinal anesthesia was explained to the patient. Patients were explained about visual analogue scale (VAS) and were taught how to express the degree of pain on the scale. The patient and the anesthetist were blinded in the study. Ampoule containing preservative free nalbuphine hydrochloride 10 mg/20 mg in 1 mL (Glenmark Pharmaceuticals Limited) was used. The dose of intrathecal nalbuphine was measured using insulin syringe.
In the operating room, routine monitors like Non invasive blood pressure, pulseoximetry, Electrocardiogram were connected. Before administration of Subarachnoid block, vital parameters were recorded. Patients received intraavenoouus prehydration with 10 mL/kg Ringer lactate. Under aseptic precaution, lumbar puncture performed in the L3-4 interspace with 25 G Quincke's spinal needle in the sitting position. The patient received either one of the drug solution as in [Table 3] and made to lie supine. Vitals monitored every 15 min intraoperatively and postoperatively for 2 h, later at 4 th , 8 th , 12 th , 16 th , and 24 th h.
The following parameters were noted and used for comparison between the groups:
- Time of onset of sensory block (i.e., time taken from intrathecal injection of drug to time to complete loss of sensation to pin pricks)
- Hypotension, bradycardia, and respiratory depression.
- Duration of effective analgesia [i.e., time of onset of sensory block to the first request of analgesia (VAS > 3)]
- Quality of analgesia.
- Incidence of side effects like nausea, vomiting, urinary retention, and itching.
- Sedation were monitored for 24 h by Campbell scoring
- Wide awake
- Sedated but easily arousable
- Drowsy, difficult to arouse
Pain was assessed by VAS at the time of 1 st pain medication. Patient was given a scale marked from 0 to 10 and were asked to mark on a scale the degree of pain he or she experienced ranging from no pain at 0 to maximum pain at 10 point. At the time of rescue analgesia, quality of analgesia was assessed by asking the patient to give a global assessment of overall effectiveness of the analgesic treatment. When VAS > 3, rescue analgesia with inj. diclofenac sodium given and study ended.
The statistical analysis was done using Statistical Package for Social Science evaluation (SPSS) version 16. Results are expressed as mean, standard deviation, and range values. Frequencies expressed as number and percentage. One-way analysis of variance used for multiple group comparison and categorical data analyzed by chi-square test. P value of 0.05 or less is considered for statistical analysis.
| Results|| |
The effects of intrathecal 0.5% hyperbaric bupivacaine with nalbuphine hydrochloride at three different doses (0.8, 1.6, and 2.4 mg) was studied and compared with 0.5% hyperbaric bupivacaine alone in 100 patients belonging to ASA grade I and II who underwent lower limb orthopedic and lower abdominal procedures including general surgeries and gynecological surgeries.
The four groups of patients A, B, C, and D included in the study did not differ significantly with respect to age, sex, body weight, height, type, and duration of surgery as shown in [Table 3].
The results regarding the characteristics of sensory block are summarized in [Table 4].
The mean time of onset of sensory blockade between the groups is comparable with the P value >0.05 which is statistically not significant. Two segment regression of sensory blockade is significantly prolonged by addition of intrathecal nalbuphine as seen with Groups B, C, and D when compared with group A with bupivacaine alone. The duration of analgesia was significantly prolonged with the addition of nalbuphine as compared with bupivacaine alone as shown in [Figure 1]. The mean VAS score in group A is higher 4.08 ± 0.5 when compared with the VAS score in groups B, C, and D 3.4 ± 0.4, 3.5 ± 0.5, and 3.5 ± 0.5, respectively. Statistical analysis shows that there is significant difference between Groups B, C, and D when compared with Group A. The quality of analgesia is good with nalbuphine groups compared with bupivacaine alone as shown in [Table 2] and [Figure 2]. In study patients, there were no serious complications like nausea, vomiting, urinary retention, shivering, pruritis, hypotension, or respiratory depression as shown in [Table 5] and [Figure 3].
| Discussion|| |
We conducted this study to compare the efficacy and adverse effects of different doses of nalbuphine as an adjunct to intrathecal bupivacaine and bupivacaine alone in lower abdominal and orthopedic surgeries.
Nalbuphine, a mixed agonist-antagonist drug, binds both to μ and kappa receptors, but its action on these receptor is divergent. When nalbuphine binds to μ receptor, it serves only to competitively displace other μ agonists from the receptor without itself displaying any agonist activity similar to those of naloxone. However, when it binds to kappa receptor, it has agonist activating effect. This pattern of binding and effects defines nalbuphine as a mixed agonist-antagonist.
Nalbuphine, administered intrathecally, binds to kappa receptors in the brain and spinal cord areas which are involved in nociception, producing analgesia and sedation without μ side effects.
Large number of animal studies has been under taken to prove that intrathecal nalbuphine was not neurotoxic. Rawal et al., showed, in a sheep model using histopathological methods that intrathecal nalbuphine, even at large doses 15-24 mg were not associated with histopathological changes of the spinal cord.
In our study, the mean onset time of sensory blockade was comparable among the groups but two segment regression of sensory block was prolonged with addition of nalbuphine to intrathecal bupivacaine and this result correlates with that of Tiwari et al.,  who also found that addition of nalbuphine with bupivacaine prolonged sensory blockade when compared to bupivacaine alone.
Nalbuphine also provided hemodynamic stability. Similar findings are seen in the study conducted by Culebras et al.,  Tiwari et al.,  Mostafa et al.,  where there was no gross hemodynamic changes throughout their study. From our study, we can conclude that use of nalbuphine hydrochloride along with bupivacaine causes no gross hemodynamic disturbances even with increasing the dosage from 0.8 to 2.4 mg.
In our study, none of patient had respiratory depression (respiratory rate below 10 bpm, SPO2 <90%). Nalbuphine exhibits ceiling effect for respiratory depression. This is proved in studies done by Romagnoli and Keats,  Thomas et al.  Since respiratory depression is predominantly μ receptor-mediated and nalbuphine is a μ receptor antagonist, respiratory depression effect is expected to be attenuated by nalbuphine.. Increasing the dosage from 0.8 to 2.4 mg did not cause any respiratory complications. This result correlates that of the studies done by Culebras et al.,  Tiwari et al.,  and Mustaffa et al.  Culebras et al., who conducted double-blind study in cesarean section with three different doses of nalbuphine 0.2,0.8, and 1.6 mg with 0.5% hyperbaric bupivacaine and compared with intrathecal morphine 0.2 mg with bupivacaine reported no differences were found with respect to maternal oxygen desaturation, Apgar scores, or neonatal umbilical blood gas values. There were no cases of newborn respiratory depression.
Patients who received bupivacaine with nalbuphine had significantly longer duration for first request of analgesia when compared with patients who received bupivacaine alone. Since nalbuphine is a mixed agonist-antagonist, studies by Pugh and Drummond GB,  Thomas et al.,  have proved that it exhibits a ceiling effect to analgesia that is increasing doses of drug produce increasing analgesia only up to a certain point. Beyond that point, further increase in dose does not result in increased intensity of analgesia. In our study, nalbuphine exhibits analgesic ceiling effect at 0.8 mg dosage, above which will not increase analgesic efficacy. This analgesic ceiling effect can be a significant limitation of nalbuphine usage. In our study, addition of nalbuphine significantly prolonged duration of analgesia which correlates to results of studies done by Lin,  Culebras et al.,  Tiwari et al.,  Mostaffa et al.  where nalbuphine found to provide good intraoperative analgesia and prolonged postoperative analgesia in their studies. Increasing nalbuphine dosage from 0.8 to 1.6 mg and 2.4 mg, did not increase analgesic efficacy as nalbuphine attains analgesic ceiling effect at 0.8 mg dosage. This result correlates with that of Culebras et al.
Patient who received bupivacaine alone had significantly higher pain scores earlier than patients who received nalbuphine-bupivacaine combinations as assessed by VAS. Studies done by Tiwari et al.,  Mostaffa et al.,  also reported that nalbuphine prolonged duration of analgesia with reduced VAS pain score.
Study conducted by Lin  found that nalbuphine 0.4 mg with intrathecal tetracaine improved quality of introperative analgesia. Culebras et al., also found that intrathecal nalbuphine 0.8-1.6 mg improved the quality of intraoperative analgesia during cesarean deliveries with good visceral analgesia. Our study also showed good to excellent analgesia with nalbuphine as an adjunct to intrathecal bupivacaine.
In bupivacaine group, patients were wide awake where as 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., Mostaffa et al.,  Tiwari et al.,  where there were minimal side effects with sedation score comparable between the groups.
Adverse effects like nausea, vomiting, urinary retention, and shivering were statistically insignificant.
With all the above observations we conclude that addition of nalbuphine to bupivacaine provides prolonged analgesia, superior pain relief and better sedation with minimal side effects compared to bupivacaine alone in spinal anesthesia. Since nalbuphine reaches ceiling effect at lower intrathecal dosage, the increased drug dosage is not required and this increases the safety margin.
| Conclusion|| |
On the basis of this study, we concluded that nalbuphine hydrochloride (0.8, 1.6, and 2.4 mg) prolongs duration of sensory blockade, provides excellent quality, and longer duration of postoperative analgesia with good sedation and minimal side effects when added intrathecally to 0.5% hyperbaric bupivacaine in lower abdominal and orthopedic surgeries. Among nalbuphine-bupivacaine group, 0.8 mg of nalbuphine provides excellent analgesia with longer duration of action without any side effects.
| References|| |
|1.||Bhattacharya R, Dutta B. Postoperative analgesia with local anesthetic and opioid combination using double space CSE technique. Indian J Anaesth 2007;51:409-14. |
|2.||Chakraborty S, Chakrabarti J, Bhattacharya D. Intrathecal tramadol added to bupivacaine as spinal anesthetic increases analgesic effect of the spinal blockade after major gynecological surgeries. Indian J Pharmacol 2008;40:4180-2. |
|3.||Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of narcotics. Science 1976;192:1357-8. |
|4.||Chen JC, Smith ER, Cahill M, Cohen R, Fishman JB. The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine. Life Sci 1993;52:389-96. |
|5.||Pick CG, Paul D, Pasternak GW. Nalbuphine, a mixed kappa 1and kappa 3 analgesic in mice. J Pharmacol Exp Ther 1992;262:1044-50. |
|6.||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. |
|7.||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. |
|8.||Rawal N, Nuutinen L, Lovering SL, Gobuty AH, Hargardine J, Lehmkuhl L, et al. Behavioral and histopathologic effects following intrathecal administration of butorphanol, sufentanil, and nalbuphine in sheep. Anesthesiology 1991;75:1025-34. |
|9.||Tiwari AK, Tomar GS, Agrawal J. Intrathecal bupivacaine in comparision with a combination of nalbuphine and bupivacaine for subarachnoid block: A randomized prospective double blind clinical study. Am J Ther 2013;20:592-5. |
|10.||Mostafa M G, Mohamad MF, Farrag WS. Which has greater analgesic effect; Intrathecal nalbuphine or intrathecal tramadol. J Am Sci 2011;7:480-4. |
|11.||Romagnoli A, Keats AS. Ceiling effect for respiratory depression by nalbuphine. Clin Pharmacol Ther 1980;27:478-85. |
|12.||Gal TJ, DiFazio CA, Moscicki J. Analgesic and respiratory depressant activity of nalbuphine: A comparison with morphine. Anesthesiology 1982;57:367-74. |
|13.||Pugh GC, Drummond GB. A dose-response study with nalbuphine hydrochloride for pain in patients after upper abdominal surgery. Br J Anaesth 1987;59:1356-63. |
|14.||Lin ML. The analgesic effect of subarachnoid administration of tetracaine combined with low dose of morphine or nalbuphine for spinal anaesthesia. Ma Tsui Hsueh Tsa Chi 1992;30:101-5. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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