|Year : 2015 | Volume
| Issue : 4 | Page : 617-622
Transdermal nitroglycerine as a coadjuvant to intrathecal nalbuphine with bupivacaine in lower abdominal surgery
Hatem Saber Mohamed, Gad Sayed Gad
Lecturer of Anesthesia and Intensive Care, Qena University Hospital, South Valley University, 85823, Egypt
|Date of Submission||22-May-2014|
|Date of Acceptance||19-Feb-2015|
|Date of Web Publication||29-Dec-2015|
Hatem Saber Mohamed
Lecturer of Anesthesia and Intensive Care, Qena University Hospital, South Valley University, 85823
Source of Support: None, Conflict of Interest: None
The purpose of this study was to evaluate the effect of transdermal nitroglycerine patch as a coadjuvant to intrathecal nalbuphine with bupivacaine in patients undergoing lower abdominal surgery.
Patients and methods
A total of 120 patients (ASA I or II) were randomized into two equal groups in this double-blind, placebo-controlled trial. The control group (group C) received intrathecal 0.5% hyperbaric bupivacaine 15 mg (3 ml) plus 0.8 mg (0.4 ml) preservative-free nalbuphine plus transdermal placebo patch, and the study group (group NG) received intrathecal 0.5% hyperbaric bupivacaine 15 mg (3 ml) plus 0.8 mg (0.4 ml) preservative-free nalbuphine plus transdermal nitroglycerine patch (5 mg). The transdermal patch (either nitroglycerine or placebo) was applied on the chest 20 min after spinal injection. Pain intensity, hemodynamics, and adverse effects were evaluated.
Patients in group NG had longer duration of effective analgesia with subsequent longer time for the first rescue analgesic (482.6 ± 16.3 min) compared with group C (334.2 ± 15.6 min) (P < 0.05). Moreover, group NG required less rescue analgesics in 24 h compared with group C (P < 0.05) and had lesser overall 24-h pain visual analogue scale scores. The incidence of perioperative adverse effects was similar between the two groups (P > 0.05).
Transdermal nitroglycerine (5 mg) significantly prolonged the analgesic effect of intrathecal nalbuphine and provided effective postoperative analgesia after lower abdominal surgery.
Keywords: intrathecal nalbuphine, spinal anesthesia, transdermal nitroglycerine
|How to cite this article:|
Mohamed HS, Gad GS. Transdermal nitroglycerine as a coadjuvant to intrathecal nalbuphine with bupivacaine in lower abdominal surgery. Ain-Shams J Anaesthesiol 2015;8:617-22
|How to cite this URL:|
Mohamed HS, Gad GS. Transdermal nitroglycerine as a coadjuvant to intrathecal nalbuphine with bupivacaine in lower abdominal surgery. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2019 Sep 21];8:617-22. Available from: http://www.asja.eg.net/text.asp?2015/8/4/617/172753
| Introduction|| |
Spinal anesthesia with 0.5% hyperbaric bupivacaine is routinely performed for lower abdominal and lower limb procedures. To increase the quality and duration of analgesia produced by local anesthetics, a number of adjuvants are added through the central axial route ,,, . Intrathecal opioids provide effective postoperative analgesia and have synergistic effect in augmenting the block without prolonging the motor recovery  .
Nalbuphine is an opioid drug classified as agonist-antagonist, with mixed m antagonist and k agonist properties that provide good intraoperative analgesia and prolonged postoperative analgesia with reduced incidence and severity of m agonist side effects such as pruritus, nausea, vomiting, urine retention, and respiratory depression. Thus, it may become an alternative to other centrally acting opioids such as morphine and fentanyl , .
However, because of its ceiling effect, which produces a submaximal response compared with an agonist, intrathecal nalbuphine has a shorter duration of analgesia compared with intrathecal morphine  .
Transdermal nitroglycerine has been found to be useful for augmenting the postoperative analgesic effect of intrathecal fentanyl, sufentanyl, clonidine, and neostigmine ,,, by release of nitric oxide (NO), which increases the intracellular concentration of cyclic guanosine monophosphate (cGMP). cGMP produces pain modulation in the central and peripheral nervous system , . Therefore, we performed this study to determine whether transdermal nitroglycerine would enhance the analgesic efficacy of intrathecal nalbuphine in patients undergoing lower abdominal procedures under spinal anesthesia.
| Patients and methods|| |
This prospective, randomized, placebo-controlled, double-blind clinical study was conducted in Qena University Hospital between October 2012 and October 2013. The study protocol was approved by the ethics committee of Qena Faculty of Medicine, and written informed consent was obtained from every patient participating in the study.
A total of 120 patients with ASA grade I and II, scheduled for elective lower abdominal surgery under spinal anesthesia and aged between 30 and 50 years, were included in the study. Patients who had a known allergy to nalbuphine or nitroglycerine, opioid abuse patients, patients with a contraindication to spinal anesthesia, those with failed or partial spinal block or those who did not agree to participate in the study were excluded.
Patients were randomized using a computer-generated random number into two equal groups, with 60 patients in each group. The control group (group C) received 3 ml (15 mg) hyperbaric bupivacaine 0.5% (Marcaine; Astra) plus 0.8 mg preservative-free nalbuphine (Nalbuphine 20 mg; SERB, Paris, France) plus transdermal placebo patch. The study group (group NG) or the nitroglycerine group received 3 ml (15 mg) hyperbaric bupivacaine 0.5% plus 0.8 mg preservative-free nalbuphine plus transdermal nitroglycerine patch (5 mg).
The nalbuphine ampoule (20 mg in 2 ml) was diluted to 10 ml with normal saline. Thus, the 0.8 mg dose was contained in 0.4 ml.
The nitroglycerine patch (Nitroderm T.T.S 5; Novartis Pharma, Basel, Switzerland) has a total nitroglycerine content of 25 mg and delivers nitroglycerine at 20-25 Ug/cm 2 /h. The placebo patch is an adhesive patch similar in shape and size to that of the nitroglycerine patch. All patches were applied on a dry, clean, nonhairy, nonanesthetized area and were covered with white opaque envelope to reduce observation bias.
The drug combinations and patches were prepared by the first anesthesiologist; however, observations were made by the second anesthesiologist, who was involved only after the procedure had been performed.
All patients were premedicated with intravenous 0.05 mg/kg of midazolam. An intravenous infusion of 1000 ml lactated Ringer's solution through a peripheral vein was started before performance of spinal anesthesia and was continued at a rate of 10 ml/kg/h after spinal anesthesia. Intravenous ranitidine 50 mg was given half an hour before surgery. Patients were placed in the sitting position and under aseptic precautions. They received local infiltration anesthesia with 2% lidocaine 2 ml to the skin over the level of L3-L4. Spinal puncture was performed using a 25-G Quincke spinal needle (Becton Dickinson, New Jersy, USA). After confirming clear and free flow of cerebrospinal fluid, all patients in the two groups received a drug volume of 3.4 ml containing 3 ml (15 mg) hyperbaric bupivacaine hydrochloride 0.5% and 0.4 ml (0.8 mg) preservative-free nalbuphine. Patients were placed in supine position and the transdermal patch (whether nitroglycerine or placebo) was placed on the chest 20 min after spinal injection according to the group. If hair was likely to interfere with patch adhesion or removal, it could be clipped but not shaved. In addition, areas with cuts or irritation were avoided. Oxygen at 4 l/min with a face mask was administered to all patients during the surgery. Heart rate, noninvasive mean arterial blood pressure, and oxygen saturation (SpO 2 ) were recorded at baseline and every 5 min throughout surgery. The level of sensory block was assessed with the pin-prick test after spinal anesthesia; dermatome levels were tested every 2 min until the highest level of sensory block was reached. The time to reach T10 dermatome sensory block was recorded before surgery was allowed. Sensory testing was then performed every 10 min until the time of two segment regression of the block was observed and recorded. The degree of motor blockade was assessed using the modified Bromage scale  : 0, none; 1, just able to move the knee but not hip; 2, able to move the foot only; 3, unable to move the knee or foot.
The onset of motor blockade was defined as the time from intrathecal drug administration until attainment of Bromage grade 3 motor blockade. The duration of motor blockade was defined as the time from attainment of Bromage grade 3 motor blockade until the full recovery of motor power.
Sedation was assessed using the Ramsay Sedation Scale  : 1, awake and alert; 2, awake but drowsy, responding to verbal stimulus; 3, drowsy but arousable, responding to verbal stimulus; 4, unarousable, not responding to physical stimulus.
Sedation was assessed preoperatively and at 4, 8, 12, and 24 h after spinal block.
Hypotension (defined as a 20% decrease in the mean arterial pressure from baseline value or systolic blood pressure <90 mmHg) was treated with intravenous boluses of 6 mg ephedrine and intravenous fluid as required, and the total intraoperative ephedrine consumption was recorded. Bradycardia, defined as heart rate less than 55 beats/min was treated with intravenous atropine 0.3-0.6 mg.
Postoperatively, the pain score was recorded using the visual analogue pain scale (VAS) between 0 and 10 (0 = no pain, 10 = most severe pain), initially every 1 h for 2 h, every 2 h for the next 8 h, and every 4 h until 24 h, and the 24-h overall VAS was recorded for the two groups.
Rescue analgesic was provided by injection of 30 mg ketorolac intramuscularly in the gluteal region with VAS greater than 4, and rescue analgesic requirements were recorded for 24 h. The duration of effective analgesia was defined as the time from intrathecal drug administration to the patient's first request for rescue analgesic.
The following adverse effects were observed and recorded, if happened, for 24 h:
The transdermal nitroglycerine and placebo patches were removed after 24 h.
- Respiratory depression (respiratory rateͳ8 breaths/min or SpO 2 < 90%).
- Nausea and vomiting, with 0 = no symptoms, 1 = symptoms present but treatment not required, and 2 = symptoms present and treatment given.
- Pruritus recorded, with four point ordinal scale with 0 = none, 1 = mild, 2 = moderate, and 3 = severe.
- Headache, shivering, and euphoria.
A follow-up was carried out at 2 weeks postoperatively during the surgical visit by the blinded anesthesiologist, who asked about any neurological deficit (persistent headache, dysesthesia in the buttock, thighs, or lower limbs).
Sample size calculation was carried out using online power/sample size calculator (http://www.stat.ubc.ca.). The duration of effective analgesia was considered the primary endpoint of this study. We hypothesized that the addition of transdermal nitroglycerine patch as a coadjuvant to intrathecal nalbuphine in the study group (group NG) would increase the time to administration of first rescue analgesic by 20% compared with the control group.
If we estimated an SD for this prospective power analysis as 20% and an a value of 0.05, the power of the study would be 80%. Thus, the calculated size for each group was 54 patients. To augment the desired effect, it was decided to include 60 patients in each group  .
Statistical analysis was performed using SPSS statistical package, version 16 (SPSS Inc., Chicago, Illinois, USA). Data were presented as mean ± SD or n (%), as appropriate. The Student t-test was used for comparison between means of continuous variables and normally distributed data.
Categorical data, including ASA grade, incidence of adverse effects (hypotension, bradycardia, respiratory depression, nausea and vomiting, headache, shivering, and euphoria) were compared using the c2 -test or Fisher's exact test, as appropriate; otherwise Mann-Whitney U-test was used.
A P-value of less than 0.05 was considered statistically significant.
| Results|| |
A total of 120 patients were enrolled in this study. Spinal block was performed successfully in all the patients.
The two groups were comparable with respect to age, sex, weight, height, ASA medical status, and duration and type of surgery [Table 1]. Moreover, there was no significant difference in the dermatome sensory block level at 10 min and total intraoperative ephedrine consumption [Table 2].
|Table 2 Dermatome sensory block (at 10 min) and total ephedrine consumption (mg)|
Click here to view
The characteristics of sensory and motor blockade are summarized in [Table 3]. There was no statistically significant difference between group C and group NG as regards the onset of sensory or motor block. Moreover, the time to two segment regression and total duration of motor block were comparable between the two groups. The total duration of effective analgesia (time to first rescue analgesic) was significantly longer in group NG (482.6 ± 16.3 min) compared with group C (334.2 ± 15.6 min) (P < 0.05). Consequently, the requirement of ketorolac during the first 24 h was significantly lower in group NG (40.1 mg) compared with group C (84.2 mg) (P < 0.001). The overall 24-h VAS was lower in group NG compared with group C, but not statistically significant [Table 3].
The mean sedation score was equal in both groups (none of the patients were sedated in the two studied groups) [Table 4].
There were no significant differences between the two groups as regards the incidence of perioperative adverse effects [Table 5]. None of the patients in the two groups developed nausea or vomiting, respiratory depression, pruritus, or shivering. One patient in each group developed hypotension requiring treatment. Moreover, one patient in each group developed bradycardia. Two patients in the control group developed headache as opposed to three in the study group. One patient in each group developed euphoria. The patients in both groups remained hemodynamically stable, with minimal variation intraoperatively [Figure 1] and [Figure 2].
|Figure 1: Changes in the mean arterial blood pressure (MAP) over the first 2 h (mmHg)|
Click here to view
| Discussion|| |
The results of our study showed that the concomitant use of 5 mg transdermal nitroglycerine (NO donor) prolonged the analgesic effect of intrathecal nalbuphine. The combination of bupivacaine-nalbuphine and nitroglycerine (group NG) resulted in 482 min of postoperative analgesia, whereas bupivacaine and nalbuphine alone (group C) provided only 334 min of postoperative analgesia. The time to first rescue analgesic was significantly longer in group NG compared with group C.
Several studies reported that transdermal nitroglycerine patch prolonged postoperative analgesia when combined with various intrathecal adjuvants such as morphine  , fentanyl  , sufentanyl  , clonidine  , and neostigmine  .
Nalbuphine is an agonist-antagonist opioid with mixed k receptor agonist and m receptor antagonist properties. Therefore, its analgesic properties are attributed to binding mainly to k opioid receptors, which are located mainly in laminae I and II of Rexed in the dorsal horn of spinal cord  . Experimental studies on primates and rodents have shown that analgesia produced by systemically administered nalbuphine is reversed by a k-receptor antagonist in these animals. This is true whether the k antagonist is given intraventricularly or intrathecally. However, the antagonism is 10 times more potent if the k antagonist is given intrathecally  . Moreover, intrathecal administration of nalbuphine in mice suppresses transmission of visceral pain  .
In human studies, intrathecal nalbuphine at a dose of 0.8 mg seems to provide a duration of postoperative analgesia after cesarean section similar to that provided by 10 mg of intrathecal fentanyl or 2-5 mg of sufentanyl, but without side effects , .
Compared with intrathecal morphine, intrathecal nalbuphine provides a significantly faster onset of pain relief probably because of its lipophilic properties  . However, it does not seem to be as effective as intrathecal morphine in prolonging postoperative analgesia. This may be due to the ceiling effect of nalbuphine  . Wang et al.  reported that intrathecal nalbuphine at a dose of 0.8-1.6 mg seems to improve the quality of postoperative analgesia during cesarean sections and that increasing the nalbuphine dose to 1.6 mg did not further improve analgesia, as this drug has a characteristic ceiling effect above 0.8 mg due to its lipophilic properties. Ceiling effect means that increasing doses of drug produce increasing intensity of analgesia up to a point beyond which further increases in dose do not increase intensity of analgesia and adverse effects of drug appear. Such ceiling analgesic effect is a significant limitation of nalbuphine.
Back to our study, application of transdermal nitroglycerine patch 5 mg prolonged postoperative analgesia following intrathecal nalbuphine and negates its ceiling analgesic effect. This synergistic effect is mediated through the release of NO. The mechanism by which NO enhances analgesia is not clear. NO is an important messenger in tonic cholinergic inhibition of pain  . NO-cyclic monophosphate (C-GMP) cascade is involved in acetylcholine or morphine-induced peripheral antinociception  . NO is involved in the activation of descending pain pathways through activation of C-GMP  . Other studies have reported the activation of ATP-sensitive potassium channels by NO, resulting in peripheral antinociception  . The synergistic effect of NO when given concomitantly with intrathecal nalbuphine can be attributed to neurons containing NO synthase in lamina I of dorsal horn of spinal cord  .
The overall 24-h VAS pain score was lower in group NG compared with group C, but it did not reach significant value. This could be attributed to the usage of intramuscular ketorolac as a rescue analgesic. However, patients in group C required more dosage of intramuscular ketorolac compared with group NG to achieve this analgesic effect.
Our study revealed no clinically important difference in the hemodynamic and adverse effects between the two groups. Similarly, several studies reported no significant hemodynamic or adverse effects when transdermal nitroglycerine patch 5 mg was added to various intrathecal opioid adjuvants , .
| Conclusion|| |
Our study suggests that transdermal nitroglycerine patch enhances the analgesic effect of intrathecal preservative-free nalbuphine (0.8 mg) and negates the problem of its ceiling effect without any significant alteration in hemodynamics or increase in incidence of adverse effects.
| Acknowledgements|| |
Conflicts of interest
| References|| |
Alahuhta S, Kangas-Saarela T, Hollmén AI, Edström HH Visceral pain during caesarean section under spinal and epidural anaesthesia with bupivacaine. Acta Anaesthesiol Scand 1990; 34: 95-98.
Culebras X, Gaggero G, Zatloukal J, et al.
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.
Elia N, Culebras X, Mazza C, Schiffer E, Tramèr MR Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials. Reg Anesth Pain Med 2008; 33:159-167.
Al-Ghanem SM, Massad IM, AL-Mustafa MM, et al.
Effect of adding dexmedetomidine versus fentanyl to intrathecal bupivacaine on spinal block characteristics in gynecological procedures: a double-blind controlled study. Am J Appl Sci 2009; 6:882-887.
Cohen SE, Ratner EF, Kreitzman TR, Archer JH, Mignano LR. Nalbuphine is better than naloxone for treatment of side effects after epidural morphine. Anesth Analg 1992; 75:747-752.
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; 44:940-945.
Garg A, Ahmed F, Khandelwal M, et al.
The effect of transdermal nitroglycerine on intrathecal fentanyl with bupivacrime for post-operative analgesia following gynaecological surgery. Anaesth Intensive Care 2010; 38:285-290.
Lauretti GR, de Oliveira R, Reis MP, et al.
Transdermal nitroglycerine enhances spinal sufentanil post-operative analgesia following orthopedic surgery. Anesthesiology 1999; 90:734-739.
Mamta K, Fareed A, Ashish G, et al.
Transdermal nitroglycerine enhances the postoperative analgesic effect of intrathecal clonidine in abdominal hysterectomies. Indian J Anaesth 2012; 56:79-81.
Lauretti GR, Oliveira AP, Julião MC, Reis MP, Pereira NL Transdermal nitroglycerine enhances spinal neostigmine postoperative analgesia following gynecological surgery. Anesthesiology 2000; 93:943-946.
Duarte ID, Lorenzetti BB, Ferreirs SH. Moncada S, Higgs EA. A cetylcholine induces peripheral analgesia by the release of nitric oxide from L. arginine.A bioregulatory system. 1990; Amsterdam: Elsevier. 165-170.
Zhuo M, Meller ST, Gebhart GF. Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission. Pain 1993; 54:71-78.
Bromage PR. A comparison of the hydrochloride and carbon dioxide salts of lidocaine and prilocaine in epidural analgesia. Acta Anaesthesiol Scand Suppl 1965; 16: :55-69.
Ramsay MA, Savege TM, Simpson BR, Goodwin R Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2:656-659.
Murphy KR, Myors B. Statistical power analysis: a simple and general model for traditional and modern hypothesis tests
. 2nd ed. Mahwah, NJ: Lawrence Erlbaum Associates; 2004.
Yamangushi H, Naito H. Antinociceptive synergistic interaction between morphine and N
-nitro l-arginine methyl ester on thermal nociceptive tests in rats. Can J Anaesth 1996; 43:1-17.
Desouza EB, Schmidt WK, Kuhai MJ. Nalbuphine an auto radiographic opioid receptor binding profile in the central nervous system of an agonist/antagonist analgesic. J Pharmacol Exp Ther 1988; 244:391-402.
Pick CG, Paul D, Pasternak GW. Nalbuphine, a mixed kappa 1 and kappa 3 analgesic in mice. J Pharmacol Exp Ther 1992; 262:1044-1050.
Fioramonti J, Bueno L. Centrally acting agents and visceral sensitivity. Gut 2002; 51 :Suppl 1 :i91-i95.
Dahlgren G, Hultstrand C, Jakobsson J, Norman M, Eriksson EW, Martin H. Intrathecal sufentanil, fentanyl, or placebo added to bupivacaine for cesarean section. Anesth Analg 1997; 85:1288-1293.
Connelly NR, Dunn SM, Ingold V, Villa EA The use of fentanyl added to morphine-lidocaine-epinephrine spinal solution in patients undergoing cesarean section. Anesth Analg 1994; 78:918-920.
Lin ML. [The analgesic effect of subarachnoid administration of tetracaine combined with low dose morphine or nalbuphine for spinal anesthesia]. Ma Zui Xue Za Zhi 1992; 30:101-105.
Wang JJ, Shwei SP, Can KH, Lee TY, Chan TH, Liu SE, Mok MS. Postoperative pain relief with various epidural narcotics: demerol, butorphanol, nalbuphine, and morphine. Ma Zui Xue Za Zhi 1988; 26:15-24.
Zhuo M, Meller ST, Gebhart GF. Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission. Pain 1993; 54:71-78.
Duarte ID, Ferreira SH, Duarte ID, Ferreira SH, Ferreira SH, Duarte ID, Lorenzetti BB. The molecular mechanism of central analgesia induced by morphine or carbachol and the l-arginine-nitric oxide-cGMP pathway. Eur J Pharmacol 1992; 221:171-174.
Lin Q, Peng YB, Wu J, Willis WD. Involvement of cGMP in nociceptive processing by and sensitization of spinothalamic neurons in primates. J Neurosci 1997; 17:3293-3302.
Soares A, Leite R, Tatsu M, et al.
Activation of A.T.P. sensitive K channels mechanism of peripheral antinociceptive action of nitric oxide donor sodium nitroprusside. Eur J Pharmacol 2000; 400:67-71.
Saito S, Kidd GJ, Trapp BD, Dawson TM, Bredt DS, Wilson DA, et al
. Rat spinal cord neurons contain nitric oxide synthase. Neuroscience 1994; 59:447-456.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]