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| ORIGINAL ARTICLE |
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| Year : 2017 | Volume
: 45
| Issue : 2 | Page : 57-63 |
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Different low doses of levobupivacaine 0.5% with nalbuphine in spinal anesthesia for transurethral resection of prostate surgery
Osama M Rehab MSc , Salah I Al Shreif, Yasser M Amr, Rehab S El Kalla
Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Tanta University, Tanta, Egypt
| Date of Submission | 07-Feb-2017 |
| Date of Acceptance | 09-May-2017 |
| Date of Web Publication | 13-Oct-2017 |
Correspondence Address:
Osama M Rehab
Reyad Ghoraba Street, Tanta, El-Gharbia, 31511
Egypt
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/tmj.tmj_9_17
Background
Subarachnoid block is a widely used technique for transurethral resection of the prostate (TURP) surgery in elderly, especially in those with respiratory and cardiac problems.
Aim
The aim of this study was to evaluate the efficacy of different low doses of levobupivacaine 0.5% when they are combined with nalbuphine in spinal anesthesia for TURP surgery, their efficiency for postoperative analgesia, and its side effects.
Patients and methods
A total of 90 patients older than 60 years of age and American Society of Anesthesiologists physical status I–III who underwent TURP under spinal anesthesia were enrolled. Patients were randomly divided into two groups: group I received intrathecal injection of 5 mg levobupivacaine 0.5% and 1 mg nalbuphine in 1 ml normal saline as total volume of 3 ml and group II received intrathecal injection of 7.5 mg levobupivacaine 0.5% and 1 mg nalbuphine in 0.5 ml normal saline as total volume of 3 ml. Patients were assessed for sensory and motor block characteristics, postoperative visual analog pain scale, and side effects.
Results
Patients in group II had earlier onset of sensory block at T10, longer duration of sensory and motor block and two-segment regression times, higher level of maximum sensory block, higher Bromage score at the end of surgery, and lower visual analog pain scale in the early postoperative period.
Conclusion
Levobupivacaine 0.5% of 5 and 7.5 mg with the addition of 1 mg nalbuphine are considered to be convenient for clinical use in TURP surgery with spinal anesthesia. Levobupivacaine of 7.5 mg had a better sensory block quality and prolonged early postoperative analgesia with similar hemodynamic stability without increasing complications.
Keywords: levobupivacaine, nalbuphine, spinal anesthesia, transurethral resection of the prostate
How to cite this article:
Rehab OM, Al Shreif SI, Amr YM, El Kalla RS. Different low doses of levobupivacaine 0.5% with nalbuphine in spinal anesthesia for transurethral resection of prostate surgery. Tanta Med J 2017;45:57-63 |
How to cite this URL:
Rehab OM, Al Shreif SI, Amr YM, El Kalla RS. Different low doses of levobupivacaine 0.5% with nalbuphine in spinal anesthesia for transurethral resection of prostate surgery. Tanta Med J [serial online] 2017 [cited 2023 May 31];45:57-63. Available from: http://www.tdj.eg.net/text.asp?2017/45/2/57/216692 |
| Introduction | |  |
Spinal anesthesia is preferred in transurethral resection of the prostate (TURP) surgery compared with general anesthesia because it allows early detection of symptoms resulted from overhydration, TURP syndrome, and bladder perforation [1].
Levobupivacaine, which is an S-enantiomer of bupivacaine, is a local anesthetic reported to have fewer central nervous system and cardiovascular side effects [2].
Opioids are added to local anesthetic drugs intrathecally to provide synergistic effect and to improve the quality of intraoperative and postoperative analgesia. These agents when combined together result in a reduction in the dose of both classes of drugs, decreasing the likelihood of side effects related to each, which is particularly beneficial for geriatric patients [3], but it has adverse effects such as pruritus, respiratory depression, nausea, vomiting, urine retention, and sedation [4].
Nalbuphine is a mixed agonist–antagonist opioid. It attenuates the µ-opioid effects and enhances the κ-opioid effects. We used it together with levobupivacaine as an adjuvant in intrathecal anesthesia to produce analgesia without the unwanted adverse effects of a µ-agonist opioid [5].
| Aim/objective | | |
The aim of this study was to evaluate the efficacy of two different doses of levobupivacaine 0.5% when they are combined with nalbuphine in spinal anesthesia for TURP surgery, their efficiency for postoperative analgesia, and its side effects.
| Patients and methods | | |
After obtaining the approval from the research ethics committee and informed written consent from the patients, 90 patients above the age of 60 years, American Society of Anesthesiologists I–III, scheduled for TURP under spinal anesthesia were enrolled in the present study. Patients with a history of allergy to local anesthetics, local infection at the site of the block, coagulopathies (bleeding time>4 min, platelet count<80 000–100 000, prolonged activated partial thromboplastin time<45 s, and international normalized ratio<1.5%), previous neurological deficit in lower limb, spinal deformity, and those who refused the technique were excluded from the study.
Patients were divided randomly into two groups (I and II). In group I, 5 mg of levobupivacaine 0.5% plus 1 mg of nalbuphine in 1 ml normal saline as a total volume of 3 ml was injected intrathecally. In group II, 7.5 mg levobupivacaine 0.5% plus 1 mg of nalbuphine in 0.5 ml normal saline as a total volume of 3 ml was injected intrathecally.
On arrival at the operation theater, routine monitoring in the form of pulse oximetry, automated noninvasive blood pressure, and ECG was applied, and the baseline parameters were observed and recorded. A good venous access was secured. ECG and oxygen saturation were monitored continuously, and arterial blood pressure was measured every 5 min until 30 min and then every 10 min until the end of the operation.
Spinal anesthesia was induced with the patients in sitting position. Povidone iodine solution was used as antiseptic for skin preparation, L3–L4 or L4–L5 interspace was chosen and the overlying skin was anesthetized by means of local infiltration with xylocaine 2% using a 27 G hypodermic needle. Lumbar puncture was performed in the midline using a 22 G beveled tip Quincke spinal needle.
After the needle was passed into the subarachnoid space and the appearance of clear cerebrospinal fluid, the intrathecal local anesthetic was injected. Assessment of sensory block by loss of sensation to pinprick using a 23 G hypodermic needle and dermatomal levels were tested every 2 min until the highest level of block had stabilized. When T10 sensory blockade level was achieved, surgery was allowed. Testing was carried out every 10 min until the point of two-segment regression was observed.
Assessment of motor block was carried out using the Bromage score [6] (0: no motor loss, 1: inability to flex the hip, 2: inability to flex the knee, and 3: inability to flex the ankle joint). When the mean arterial blood pressure decreased by 20% in relation to baseline, 5 mg ephedrine intravenously was given. Bradycardia (heart rate<60 beats/min) was managed by giving 0.5 mg atropine intravenously. Ephedrine and atropine were repeated if required.
The only pain killer given for postoperative pain control was morphine, and no other sedatives or analgesics were given during the first 24 h. The following demographic data were evaluated: age, weight, height, American Society of Anesthesiologists class, and duration of surgery. Mean arterial blood pressure and heart rate were recorded at 0, 5, 10, 15, 20, 25, 30, 40, 50, and 60 min and at the end of surgery.
Onset of sensory block at T10 (defined as the interval between the end of intrathecal local anesthetic injection to complete loss of pinprick sensation) was evaluated. Maximum sensory block levels achieved and time to reach it were evaluated. Duration of sensory block (defined as the interval from achievement of complete sensory block to the time of the first requirement of analgesia) was evaluated.
Onset of motor block: This is defined as the time from end of the injection until the loss of motor power using the Bromage score. (Time to reach Bromage score 1 was determined.) Duration of motor block is defined as the time taken from establishment of motor block to complete recovery from motor block as observed by a decrease in Bromage score. Bromage score at the beginning of surgery and Bromage score at the end of surgery were recorded. Two-segment regression time was evaluated.
Postoperative pain was assessed using visual analogue scale (VAS) between 0 and 10 (0=no pain and 10=most severe pain). It was initially assessed hourly for 2 h, and then every 2 h for the next 8 h and every 4 h until 24 h have been elapsed postoperatively; rescue analgesic medication with morphine was given if VAS was 4 or more. Total dose consumption of analgesic used over 24 h was evaluated.
Side effects
The occurrence of any complication such as hypotension, bradycardia, nausea, vomiting, pruritus, respiratory depression, and sedation, and any other complications were recorded during and after the operation.
Statistical analysis
Statistical analysis and presentation of the present study was performed using the mean, SD, and χ2-test using SPSS, SPSS for MS Windows software (version 20.0; IBM, Armonk, NY, USA). Value of P less than 0.05 was considered significant.
| Results | | |
A total of 90 patients who underwent TURP surgery were enrolled for the study and were randomly divided into two groups.
The demographic characteristics ([Table 1]) in both groups showed marked similarities and did not show a statistically significant difference (P>0.05). There was a nonsignificant difference in heart rate and mean arterial pressure between the two groups ([Figure 1] and [Figure 2]).
The onset of sensory block at T10 showed a significant (P=0.001) rapid onset in group II in comparison with group I. There was a significant (P=0.001) increase in the maximum sensory block level in group II compared with group I. The number of patients reaching maximum sensory level was as follows: T5, 2 and 7; T6, 7 and 16; T7, 15 and 14; T8, 12 and 7; T9, 7 and 1; and T10, 2 and 0 in groups I and II, respectively. There was a significantly higher level in group II in comparison with group I (P<0.015). Two-segment regression time showed a significant (P=0.001) increase in group II in comparison with group I. There was a significant (P=0.001) increase in the duration of sensory block in group II compared with group I ([Table 2]).
There was no significant difference (P=0.403) in the mean values of the onset of motor block in the two studied groups. There was a significant (P=0.001) increase in the duration of motor block in group II compared with group I ([Table 3]).
As regards Bromage score at the beginning of surgery ([Table 4]) in the two studied groups, there was a significant (P<0.05) increase in the number of patients who achieved higher Bromage score (2, 3) in group II as compared with group I. As regards Bromage score at the end of surgery ([Table 5]) in the two studied groups, there was a significant (P<0.05) increase in the number of patients who had higher Bromage score (2) in group II as compared with group I.
There was a significant (P=0.001) increase in the total dose of consumption of analgesia in group I compared with group II ([Table 6]). | Table 6 Total dose of consumption of analgesia (mg) used over 24hr in both groups
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No significant difference was found between the two groups as regards side effects and complications.
| Discussion | | |
Spinal anesthesia is a commonly used technique for TURP surgery in the elderly, especially in those with cardiac and respiratory problems. TURP surgery usually lasts less than 60 min, and early recovery and discharge are desirable [7]. Conventional spinal anesthesia has complications such as bradycardia, hypotension, urinary retention, postdural puncture headache, and transient or permanent neurological symptoms. Many of these complications, especially hemodynamic effects are due to the local anesthetic agent sympatholytic effect [8].
These hemodynamic effects can be minimized by using a low dose of local anesthetic agent at a lower concentration or by adding an adjuvant. Moreover, this provides minimum motor block and allows faster recovery and mobilization of the patient [9]. Opioids are added to local anesthetics intrathecally to provide synergistic effect and to improve the quality of intraoperative and postoperative analgesia [10]. These agents when combined together result in a reduction in the dose of both classes of drugs, decreasing the likelihood of side effects related to each, which is particularly beneficial for geriatric patients [3], but on the other side it has adverse effects such as pruritus, respiratory depression, nausea, vomiting, urine retention, and sedation [4].
Levobupivacaine, which is an S-enantiomer of bupivacaine, is a local anesthetic reported to have fewer central nervous system and cardiovascular side effects [2]. Smaller doses (5–10 mg) used in ambulatory surgery allow rapid recovery and early discharge to home [11].
In our study we used nalbuphine as an adjuvant to levobupivacaine intrathecally. Nalbuphine produces an agonist activity at the κ-opioid receptor and an antagonist activity at the µ-opioid receptor, and hence it can produce analgesia without the unwanted side effects of the µ-agonist opioids [5]. Nalbuphine is used as an additive for intrathecal anesthesia in doses from 200 to 1600 µg in several clinical settings [12].
Moreover, studies had investigated nalbuphine with hyperbaric bupivacaine in spinal anesthesia without reports of neurotoxicity [13]; even the studies performed on pregnant women showed no neurotoxicity [14]. In agreement with our results, Girgin et al. [15], who compared different two doses of levobupivacaine, found that maximum sensory block level achieved in patients who received 7.5 mg levobupivacaine was T6 and in patients who received 5 mg levobupivacaine mixed with 25 μg fentanyl it was T7.
Moreover, two-segment regression time increased in patients who received 7.5 mg levobupivacaine (73±15 min) than those who received 5 mg levobupivacaine plus 25 µg fentanyl (61±12 min).
Further, similar to our results, in a study performed by Borazan et al. [7] in which they used 7.5 mg levobupivacaine plus 2.5 μg sufentanil and found that onset of sensory block at T10 was 5.31±2.1 min, the highest level of sensory block was T7, onset of motor block was 4.76±1.6 min, and duration of motor block was 119.74±44.8 min. In this study, increasing the dose of levobupivacaine to 10 mg prolonged the duration of motor block, and higher Bromage score at the end of surgery was achieved which is consistent with our results.
Moreover, Akcaboy et al. [16] found that 5 mg of 0.5% levobupivacaine with 25 μg fentanyl in spinal anesthesia for TURP surgery can provide adequate sensory block without motor block. In agreement with the results of our study, maximum sensory block level achieved was T7, time to two-segment regressions was 67.41±8.13 min, and Bromage scores at the beginning and at the end of the surgery was 0 and 1 in the majority of patients, respectively. However, onset of sensory block at T10 was 11.27±1.42 min, which is longer than that reported in our results.
Akan et al. [1] used 7.5 mg levobupivacaine plus 25 μg fentanyl in spinal anesthesia for TURP surgery, and their results are similar to our results with regard to two-segment regression time (61.58±13.7 min) and duration of motor block (100±21.8 min). Moreover, in this study, using a higher dose of levobupivacaine (10 mg) prolonged the duration of motor block and increased the number of patients who had complete motor block at the end of surgery.
Moreover, Brahmbatt et al. [2] used 7.5 mg of levobupivacaine plus 25 μg fentanyl in spinal anesthesia and their results showed that two-segment regression time was 71.87±7.49 min and onset of motor block was 4.60±0.98 min. However, they achieved faster onset of sensory block (1.71±0.52 min) and longer duration of motor block (170.62±16.05 min). The difference from our results can be attributed to the use of fentanyl rather than nalbuphine as an additive to levobupivacaine.
Cuvas et al. [17] used a larger dose of levobupivacaine (2.2 ml+15 μg fentanyl) for TURP operation and their results differ from our results with regard to two-segment regression time, which was 106.00±48.62 min and duration of motor block, which was 213.75±59.49 min.
In this study, although the maximum sensory block level achieved was T6, which is similar to our results, three patients developed hypotension and four patients developed bradycardia. Low doses of levobupivacaine used in our study provide satisfactory sensory block quality with minimum motor block as well as better hemodynamic stability. In our study postoperative pain was assessed using VAS score and rescue analgesic medication with morphine was given when VAS became 4 or more. We used the same dose of nalbuphine (1 mg) in both groups to provide intraoperative and early postoperative analgesia and we found that a larger dose of levobupivacaine 7.5 mg had more synergetic effect with nalbuphine compared with 5 mg levobupivacaine to produce early postoperative analgesia extending to the second hour postoperatively as shown by lower VAS score in group II compared with group I at second hour postoperatively. Moreover, the total dose of consumption of analgesia used over 24 h was lower in group II compared with group I.
Culebras et al. [14] compared intrathecal morphine (0.2 mg) added to hyperbaric bupivacaine with different doses of intrathecal nalbuphine (0.2, 0.8, and 1.6 mg) added to hyperbaric bupivacaine in cesarean section and their study concluded that intrathecal nalbuphine 0.8 mg provides good intraoperative and early postoperative analgesia without side effects (no postoperative nausea and vomiting or pruritus). Nalbuphine 1.6 mg did not increase efficacy but increased the incidence of complications. Therefore, the dose 0.8 mg was chosen in this study. In our study we used 1 mg nalbuphine; the difference in results from that reported in the study by Culebras et al. [14] can be attributed to the use of a low dose of local anesthetic levobupivacaine and we used different patient population (nonpregnant old-aged patients).
Lin et al. [18] had compared intrathecal nalbuphine 400 μg added to hyperbaric tetracaine with intrathecal morphine 400 μg and concluded that intrathecal nalbuphine at a dose of 400 μg prolongs intraoperative and postoperative analgesia with fewer side effects.
Moreover, Mukherjee et al. [13] used different doses of nalbuphine intrathecally (200, 400, and 800 μg) added to 0.5% hyperbaric bupivacaine. They concluded that the duration of sensory block and the duration of effective analgesia were prolonged with the doses 400 and 800 μg.
In our study, adding nalbuphine to levobupivacaine produces early postoperative analgesia and this is in agreement with the findings of Fournier et al. [19], who found a faster onset of pain relief in the group that received intrathecal nalbuphine, but the duration of analgesia was shorter than that in the group that received intrathecal morphine.
Moreover, a recent study performed by Gomaa et al. [5] concluded that intrathecal nalbuphine 0.8 mg combined with 10 mg bupivacaine or intrathecal fentanyl 25 μg combined with 10 mg bupivacaine improves intraoperative analgesia and prolongs early postoperative analgesia in cesarean section.
As regards hemodynamic changes, our results showed that mean arterial blood pressures and heart rates were comparable and stable during the surgery with no significant difference between the two groups. Hypotension and bradycardia were not seen in any of the patients during the operation. This is in agreement with the study by Borazan et al. [7], who found that no patient suffered from hypotension or bradycardia. Moreover, the study by Girgin et al. [15] showed no significance related to hypotension or bradycardia between patients who received 5 mg levobupivacaine and patients who received 7.5 mg levobupivacaine. Moreover, Erdil et al. [20] had shown that levobupivacaine was preferred in elderly patients undergoing a urological intervention under spinal anesthesia because intrathecal levobupivacaine showed better hemodynamic stability and fewer side effects.
As regards adverse effects observed during the study, one patient in each group suffered from nausea and only one patient in group II suffered from vomiting. No pruritus, sedation, or respiratory depression was observed in any of the patients of both groups. This is in agreement with the study performed by Culebras et al. [14], who suggested that intrathecal nalbuphine 0.8 mg provides good intraoperative and early postoperative analgesia without side effects such as pruritus, nausea, and vomiting.
Moreover, in the study by Mostafa et al. [21], intrathecal 2 mg nalbuphine when used with 0.5% bupivacaine for pain relief after transurethral resection of bladder tumor provided postoperative analgesia without producing significant side effects such as nausea, vomiting, pruritus, and respiratory depression.
Moreover, Phosle [22] added 0.8 mg nalbuphine to hyperbaric bupivacaine to observe its effect on pain relief; they demonstrated that no patient had any significant side effect such as pruritus or respiratory depression, and the side effects noted in the nalbuphine group were nausea, vomiting, and urinary retention in one patient each.
| Conclusion | | |
Levobupivacaine 0.5% of 5 and 7.5 mg with the addition of 1 mg nalbuphine is considered to be convenient for clinical use in TURP surgery with spinal anesthesia. Levobupivacaine of 7.5 mg had a better sensory block quality and prolonged early postoperative analgesia with similar hemodynamic stability without increasing complications.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Akan B, Yagan O, Bilal B, Erdem D, Gogus N. Comparison of levobupivacaine alone and in combination with fentanyl and sufentanil in patients undergoing transurethral resection of the prostate. J Res Med Sci 2013; 18:378–382.  |
| 2. | Brahmbhatt NP, Prajapati AI, Upadhyay MR. Combination of low dose isobaric levobupivacaine 0.5% and fentanyl compared with isobaric levobupivacaine 0.5% in spinal anaesthesia for lower abdominal and perineal surgeries. Int J Res Med 2015; 4:55–60. |
| 3. | Ben-David B, Frankel R, Arzumonov T, Marchevsky Y, Volpin G. Minidose bupivacaine-fentanyl spinal anaesthesia for surgical repair of hip fracture in the aged. Anesthesiology 2000; 92:6–10. |
| 4. | Chattopadhyay A, Maitra S, Sen S. A study to compare the analgesic efficacy of intrathecal bupivacaine alone with intrathecal bupivacaine midazolam combination in patients undergoing elective infraumbilical surgery. Anesthesiol Res Pract 2013; 2013:567134. |
| 5. | Gomaa H, Nabil N, Zoheir H. A comparison between post-operative analgesia after intrathecal nalbuphine with bupivacaine and intrathecal fentanyl with bupivacaine after cesarean section. Egypt J Anesth 2014; 30:405–410. |
| 6. | Lanz E, Theiss D, Kellner G, Zimmer M, Staudte HW. Assessment of motor blockade during epidural anesthesia. Anesth Analg 1983; 62:889–893. |
| 7. | Borazan H, Davarcı I, Keçecioğlu A, Otelcioğlu S. The effects of low dose levobupivacaine with or without sufentanil intrathecally in transurethral resection of prostate. Eur J Gen Med 2011; 8:134–140. |
| 8. | Jamison RN, Ross MJ, Hoopman P, Griffin F, Levy J, Daly M, Schafer JL. Assessment of postoperative pain management: patient satisfaction and perceived helpfulness. Clin J Pain 1997 13:229–236. |
| 9. | Hocking G, Wildsmith J. Intrathecal drug spread. Br J Anaesth 2004; 93:568–578. |
| 10. | Kamphuis ET, Kuipers PW, Venrooij GE, Kalkman CJ. The effects of spinal anesthesia with lidocaine and sufentanil on lower urinary tract functions. Anesth Analg 2008; 107:2073–2078. |
| 11. | Cappelleri G, Aldegheri G, Danelli G. Spinal anesthesia with hyperbaric levobupivacaine and ropivacaine for outpatient knee arthroscopy: a prospective, randomized, double-blind study. Anesth Analg 2005; 101:77–82. |
| 12. | 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; 20:592–595. |
| 13. | Mukherjee A, Pal A, Agrawal J. Intrathecal nalbuphine as an adjuvant to subarachnoid block: what is the most effective dose? Anesth Essays Res 2011; 5:171–175. [Full text] |
| 14. | Culebras X, Gaggero G, Zatloukal J, Kern C, Marti R. Advantages of intrathecal nalbuphine, compared with intrathecal morphine, after cesarean delivery: an evaluation of postoperative analgesia and adverse effects. Anesth Analg 2000; 91:601–605. |
| 15. | Girgin NK, Gurbet A, Turker G, Bulut T, Demir S, Kilic N, Cinar A. The combination of low-dose levobupivacaine and fentanyl for spinal anaesthesia in ambulatory inguinal herniorrhaphy. J Int Med Res 2008; 36:1287–1292. |
| 16. | Akcaboy EY, Akcaboy ZN, Gogus N. Low dos levobupivacaine 0.5%with fentanyl in spinal anaesthesia for transurethral resection of prostate surgery. J Res Med Sci 2011; 16:68–73. |
| 17. | Cuvas O, Basar H, Yeygel A, Sunay MM, Turkyilmaz E. Spinal anesthesia for transurethral resection operation: levobupivacaine with or without fentanyl. Middle East J Anesthesiol 2010; 20:547–552. |
| 18. | Lin ML. The analgesic effect of subarachnoid administration of tetracaine combined with low dose of morphine or nalbuphine for spinal anaesthesia. Ma Zui Xue Za Zhi 1992; 30:101–105. |
| 19. | Fournier R, Gamulin Z, Macksay M. Onset and offset of Intrathecal morphine versus nalbuphine for post-operative pain relief after total hip replacement. Acta Anesthesiol Scand 2000; 44:940–945. |
| 20. | Erdil F, Bulut S, Demirbilek S, Gedik E, Gulhas N, Ersoy MO. The effects of intrathecal levobupivacaine and bupivacaine in the elderly. Anaesthesia 2009; 64:942–946. |
| 21. | Mostafa MG, Mohamad MF, Farrag WS. This has greater analgesic effect: intrathecal nalbuphine or intrathecal tramadol. J Am Sci 2011; 7:480–484. |
| 22. | Phosle SSP. Intrathecal nalbuphine: an effective adjuvant for post-operative analgesia. Innovative J Med Health Sci 2014; 4:79–82. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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