|Year : 2010 | Volume
| Issue : 1 | Page : 24-28
Transdermal nitroglycerine enhances postoperative analgesia of intrathecal neostigmine following abdominal hysterectomies
Fareed Ahmed, Ashish Garg, Vipul Chawla, Mamta Khandelwal
Department of Anaesthesia and Critical Care, Sawai Man Singh Medical College and Hospital, Jaipur - 302 004, Rajasthan, India
|Date of Web Publication||9-Mar-2010|
H.No. 699, Frontier Colony, Adarsh Nagar. Jaipur - 4, Rajasthan
Source of Support: None, Conflict of Interest: None
This study was carried out to assess the effect of nitroglycerine (transdermal) on intrathecal neostigmine with bupivacaine on postoperative analgesia and note the incidence of adverse effects, if any. After taking informed consent, 120 patients of ASA Grade I and II were systematically randomised into four groups of 30 each. Patients were premedicated with midazolam 0.05 mg/kg intravenously and hydration with Ringer's lactate solution 10ml/kg preoperatively in the holding room. Group I patients received Intrathecal injection of 15 mg bupivacaine with 1ml of normal saline and transdermal placebo patch. Group II patients received Intrathecal injection of 15 mg bupivacaine with 5 mcg of neostigmine and transdermal placebo patch. Group III patients received Intrathecal injection of 15 mg bupivacaine with 1ml of normal saline with transdermal nitroglycerine patch (5 mg/24 hours). Group IV patients received Intrathecal injection of 15 mg bupivacaine with 5mcg of neostigmine and transdermal nitroglycerine patch (5 mg/24 hours), applied on a non anaesthetised area after 20 minutes. Groups were demographically similar and did not differ in intraoperative characteristics like sensory block, motor block, haemodynamic parameters and SpO 2 . The mean duration of analgesia was 202.17 minutes, 407.20 minutes, 207.53 minutes and 581.63 minutes in control group (I), neostigmine group (II), nitroglycerine group (III) and nitroglycerine neostigmine group (IV) respectively (P<0.01). To conclude, our results show that transdermal nitroglycerine itself does not show any analgesic potential but it enhances the analgesic potential of intrathecal neostigmine.
Keywords: Abdominal hysterectomy, neostigmine, nitroglycerine, nitric oxide, postoperative analgesia
|How to cite this article:|
Ahmed F, Garg A, Chawla V, Khandelwal M. Transdermal nitroglycerine enhances postoperative analgesia of intrathecal neostigmine following abdominal hysterectomies. Indian J Anaesth 2010;54:24-8
|How to cite this URL:|
Ahmed F, Garg A, Chawla V, Khandelwal M. Transdermal nitroglycerine enhances postoperative analgesia of intrathecal neostigmine following abdominal hysterectomies. Indian J Anaesth [serial online] 2010 [cited 2020 Sep 27];54:24-8. Available from: http://www.ijaweb.org/text.asp?2010/54/1/24/60492
| Introduction|| |
Nitric oxide (NO) has been suggested to act as a second messenger in the central nervous system (CNS) ,,, and has been shown to play an important role in the mechanisms that underlie pain. ,, NO, produced from L-arginine by NO synthase, , produces an increase in intracellular cyclic GMP (cGMP) through activation of soluble guanylate cyclase. This NO-cGMP cascade in endothelial cells has been reported to mediate acetylcholine-induced vasodilation , as well as to be involved in acetylcholine or morphine induced antinociception. , Therefore, as acetylcholine-induced responses have been shown to involve NO, the present experiments were designed to examine whether a combination of transdermal nitroglycerine (source of exogenous nitric oxide) would enhance the analgesic efficacy of intrathecal neostigmine (source of acetylcholine) in patients undergoing abdominal hysterectomy. There is paucity of work done involving humans subjects.
| Methods|| |
This prospective, randomised, double blind study was approved by the Ethical Committee of Rajasthan University of Health Sciences, Jaipur. After taking informed consent, 120 patients of ASA Grade I and II, aged between 30 to 50 years, scheduled for elective total abdominal hysterectomy were selected.
A total of 126 patients were selected for the study. Six patients were excluded because of failed/partial spinal block (effective sample size n=120). The principles of simple randomisation were applied. Patients were randomised by computer into one of the four groups consisting of 30 patients in each group and prospectively studied.
Group I patients received 3 ml (15 mg) of hyperbaric bupivacaine (0.5%) plus 1 ml normal saline with transdermal placebo patch. Group II patients received 3 ml (15 mg) of hyperbaric bupivacaine (0.5%) plus 5mcg neostigmine and transdermal placebo patch. Group III received 3 ml (15 mg) of hyperbaric bupivacaine (0.5%) plus 1 ml normal saline and transdermal nitroglycerine patch (5 mg/24 hours). Group IV received 3 ml (15 mg) of hyperbaric bupivacaine (0.5%) plus 5 mcg neostigmine and transdermal nitroglycerine patch (5 mg/24 hours).
In the preanaesthesia room, patients were premedicated with midazolam 0.05 mg/kg IV and preloaded with crystalloid 10 ml/kg. Inside the operation theatre, lumbar puncture was performed at L3-L4 level, with 25 gauge spinal needle and 4 ml of the drug solution was injected intrathecally over 30 seconds as per the group allocation. They were then placed in supine position, with a 15° head low tilt immediately after spinal injection. An eye cover was placed and O 2 was given by Hudson mask at the rate of 4 L/min by the anaesthesia machine. The transdermal patch (placebo or nitroglycerine) was applied on the thorax (ventral, T2-T4), in a non-anaesthetised area, 20 minutes after spinal puncture (after haemodynamic stabilisation). The total nitroglycerin content of transdermal nitroglycerine patch was 25 mg; the total drug releasing area was 10 cm 2 . It delivered nitroglycerine at the rate of 20-25 µg/cm 2 .h or. 5 mg/24 hours.
The drug solution was prepared by the anaesthesiologist who performed the lumbar puncture, administered the drug solution and monitored the patient intraoperatively. Patients were evaluated for postoperative analgesia and adverse effects by another anaesthesiologist blinded to the drug groups.
Level of sensory loss was assessed by pinprick test. Motor blockade was determined according to the Bromage scale. Blood pressure was monitored every five minutes throughout the surgery and a decrease greater than 15% below the baseline value was treated by the incremental dose of Injection ephedrine 4 mg IV. Heart rate and SpO 2 were monitored continuously. Any fall in the heart rate below 60 beats per minute was treated with incremental doses of Inj. atropine 0.3 mg IV. Intraoperative nausea was treated with Inj. metaclopromide 10 mg intravenous.
All patients were familiarised with 0-10 cm visual analogue scale, for pain (VAS); 0 equal to "no pain" and 10 equal to "worst possible pain". VAS was assessed at the time of giving rescue analgesia. Postoperatively, patients were assessed for pain by VAS rating scale and duration of motor blockage according to the Bromage scale. Patients were also assessed for the side-effects like nausea, vomiting, hypotension, bradycardia, sweating and palpitation.
Duration of effective analgesia was measured from the time of intrathecal drug administration to the patient's first request for analgesic. Patients were allowed to receive rescue analgesics on demand. Intramuscular Diclofenac (75 mg) was given as rescue analgesic. Groups were compared with regard to demographic data (age, weight), duration of surgery and duration of analgesia with use of one-way analysis of variance. P value<0.05 was considered statistically significant.
| Results|| |
There was no statistically significant (P>0.5) difference among all four groups in terms of demographic data, type and duration of surgery and changes in the haemodynamic parameters [Table 1]. The onset of sensory block, measured by pinprick was 6.23±1.65, 3.13±0.90, 5.80±1.75 and 3.27±0.83 minutes in Group I, II, III and IV respectively [Table 2]. Onset of sensory block was faster (statistically significant) in neostigmine using groups (Group II, IV) c.f. non-neostigmine using groups (Group I, III) (P<0.05) [Table 2]. The mean duration of analgesia was 202.17 minutes, 407.20 minutes and 207.53 minutes in control group (I), neostigmine group (II) and nitroglycerine group (III) respectively, while the mean duration of analgesia in nitroglycerine neostigmine group (IV) was 581.63 minutes [Table 2]. A statistically significant longer duration of analgesia in Group IV was observed when compared to Group II (P<0.01). The onset of motor block was 12.47±2.78 minutes and 11.17±2.76 minutes in Group I and III while it was 5.47±1.04 and 5.33±1.09 minutes in Group II and IV (P<0.05) [Table 2]. The mean duration of motor block was 79.77±6.73, 102.87±5.99, 77.77±5.26 and 103.13±6.14 minutes in Group I, II, III and IV respectively [Table 2]. The average VAS pain score at the time of giving rescue analgesic medication was 22.81±7.29, similar among all four groups (P>0.05). [Table 3] shows the haemodynamic parameters i.e. mean arterial pressure (MAP), pulse rate (PR) during the preoperative, intraoperative and postoperative period. The incidence of side-effects seen in all four groups is shown in [Table 4].
| Discussion|| |
In clinical practice, a number of adjuvant have been added to the intrathecal local anaesthetics for supplementation of intraoperative anaesthesia and postoperative analgesia. They have advantages as they reduce the dose of local anaesthetic; provide long lasting postoperative analgesia with reduced incidence of central nervous system depression, motor effects or hypotension.
The results of this study show a significant increase in postoperative analgesia when neostigmine is added to intrathecal bupivacaine in patients undergoing total abdominal hysterectomy. Neostigmine-induced augmentation of analgesia, when supplemented to bupivacaine, has been shown in other studies. ,, Further, the present study showed that the combination of 5 mg/day transdermal nitroglycerine patch and intrathecal low dose neostigmine (5 mcg) resulted in an average of 10 hours of postoperative analgesia after total abdominal hysterectomy during bupivacaine spinal block, compared to 3.5 hours in the control group. The combination increased the duration of analgesia, as the first requirement of rescue analgesia was delayed by 6.5 hours in this group compared from the control group. In a similar study, authors observed that intrathecal neostigmine along with transdermal nitroglycerine patch provided longer duration of analgesia and significantly minimized the analgesic consumption than only intrathecal neostigmine.  Another worker reported 6.50 hours of analgesia in neostigmine group, compared to 9.10 hours of analgesia in nitroglycerine-neostigmine group.  Transdermal nitroglycerine has been shown to increase the postoperative analgesia of intrathecal opioids.  Our study demonstrates no clinically significant difference in the haemodynamic parameters and adverse effects among all four groups. Similarly, a study reported no increase in adverse effects using intrathecal neostigmine with transdermal nitro-glycerine.  Intrathecal neostigmine doses varying from 10 mcg to 200 mcg resulted in side-effects (namely, nausea and vomiting) when doses varied between 25 and 200 mcg. ,
Analgesic effect of intrathecal neostigmine is secondary to acetylcholine release in the spinal cord tissue. , During surgical stimuli, a pre-existent spinal cholinergic tonus is activated.  Neostigmine, an anticholinsterase drug increases the concentration of acetylcholine in the cerebrospinal fluid and acetylcholine bioavailability at the cholinergic nerves within the spinal cord. Elevated acetylcholine due to the surgical stimulus and also acetylcholine preserved from cholinesterase activity after intrathecal neostigmine, binds to muscarinic  and nicotinic  nerve terminals in the spinal cord.
The existence of a cholinergic system in the spinal dorsal horn involved in sensory transmission and modulation is supported by anatomical, pharmacological and electrophysiological studies. For example, Choline Acetyltransferase (ChAT)-positive terminals are found in the spinal dorsal horn , and both cholinergic muscarinic and nicotinic binding sites have been demonstrated in the spinal dorsal horn , The origin of ChAT terminals has been suggested to be from local spinal cholinergic interneuron and/or descending pathways from supraspinal structures. 
Electrophysiological studies have demonstrated that cholinergic receptor agonists produce inhibitory effects on spinal dorsal horn neurons, including spinothalamic tract neurons. , This suggests that a spinal cholinergic system plays an important inhibitory role in the modulation of nociceptive transmission. Pharmacological studies in 'awake' rats have found that this spinal cholinergic inhibition is tonically active and is mediated by spinal muscarinic, but not nicotinic receptors. 
Since nitric oxide (NO) was shown to be a central neurotransmitter, , there have been several reports of the relationship between NO and pain processing in the brain and the spinal cord. , It is widely accepted that NO may occupy a key position in the antinociceptive and in the endogenous mediation of pain. Acetylcholine and morphine induce analgesia via activation of the arginine-NO-cGMP pathway. , Guanylate cyclase activity in the brain is markedly stimulated by NO, generated from L-arginine or provided through an exogenous source,  as in the present study through transdermal nitroglycerine. Evidence exists that NO modulates the synaptic transfer of signals in both the central and the peripheral nervous system.  The transdermal nitroglycerine patch has been related to NO formation during degradation of organic nitrates.  In accordance to animal  and clinical research,  NO generators did not result in analgesia. Nevertheless, a current study provides evidence that acetylcholine stimulate nitric oxide synthesis in the spinal cord,  and this synthesis is necessary for the expression of analgesia secondary to the cholinomimetic agent,  such as spinal neostigmine.
In addition, the activation of descending pain pathways involves the participation of nitric oxide, which mechanisms of action are likely to include activation of second messengers such as cyclic guanosine monophosphate (cGMP).  Wide-dynamic-range neurons in the superficial dorsal horn and high-threshold cells in the superficial or deep layers show reduced response after exposure to cyclic guanosine monophosphate.  Therefore, analgesia would be a result of predominant analgesic action on superficial spinal layers.
Anatomic evidence also supports the connection between NO and acetylcholine. As explained earlier, ChAT-positive terminals are found in the spinal dorsal horn and both cholinergic muscarinic and nicotinic binding sites have been demonstrated in the spinal dorsal horn. Recent studies show that Nitric Oxide Synthase (NOS) contain neurons located in Laminae I through III of the dorsal horn  (the superficial dorsal horn and the intermediolateral cell column regions of the spinal cord)  and probably function as interneuron modulating the sensory processing  in the spinal cord that contain choline acetyl transferase 
| Conclusions|| |
Our results show that neostigimise increases the duration of analgesia of bupivicaine and transdermal nitroglycerine increases this postoperative analgesia further, though nitroglycerine itself does not show any analgesic potential of its own.
| References|| |
|1.||Böhme GA, Bon C, Stutzmann JM, Doble A, Blanchard JC. Possible involvement of nitric oxide in long-term potentiation. Eur J Pharmacol 1991;199:379-81. |
|2.||Shibuki K, Okada D. Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature 1991;349:326-8. |
|3.||Schuman EM, Madison DV. A requirement for the interceiluiar messenger nitric oxide in long-term potentiation. Science 1991;254:1503-6. |
|4.||Moncada S, Palmer RM, Higgs EA. Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43:109-42. |
|5.||Kitto KF, Haley JE, Wilcox GL. Involvement of nitric oxide in spinally-mediated hyperalgesia in the mouse. Neurosci Lett 1992;148:1-5. |
|6.||Meller ST, Pechman PS, Gebhart GF, Maves TJ. Nitric oxide mediates the thermal hyperalgesia produced in a mdoef of neuropathic pain in the rat. Neuroscience1992;50:7-10. |
|7.||Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 1993;52:127-36. |
|8.||Hope BT, Michael GJ, Knigge KM, Vincent SR. Neuronal NADPH diaphorase a nitric oxide synthase. Proc Natl Acad Sci USA 1991;88: 2811-4. |
|9.||Förstermann U, Schmidt HH, Pollock JS, Sheng H, Mitchell JA, Warner TD, et al. Isoforms of nitric oxide synthtase: characterization and purification from different cell types. Biochem Pharmacol 1991;42:1849-57. |
|10.||Whittle BJ, Lopez-Belmonte J, Rees DD. Modulation of the vasodepressor actions of acetylcholine, bradykinin, substance P and endotheiin in the rat by a specific inhibitor of nitric oxide formation. Br J Pharmacol 1989;9:646-52. |
|11.||Durate ID, Lorenzetti BB, Ferreira SH. Peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Eur J Pharmacol 1990;186:289-93. |
|12.||Ferreira SH, Duarte ID, Lorenzetti BB. The molecular mechanism of action of peripheral morphine analgesia: stimulation of the cGMP system via nitric oxide release. Eur J Pharmacol 1991;201:121-2. |
|13.||Lauretti GR, Reis MP, Prado WA, Klamt JG. Dose response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty. Anesth Analg 1996;82:1182-7. |
|14.||Kaur G, Osahan N, Afzal L. Effect of transdermal nitroglycerine patch on analgesia of low dose intrathecal neostigmine: An evaluation. J Anesth Clin Pharmacol 2007;23:159-62. |
|15.||Batra YK, Arya VK, Mahajan R, Chari P. Dose response study of caudal neostigmine for postoperative analgesia in paedriatic patients undergoing genitourinary surgery. Paediatr Anaesth 2003;13:515-21. |
|16.||Lauretti GR, Oliveira AP, Julião MC, Reis MP, Pereira NL. Transdermal nitroglycerine enhances spinal neostigmine postoperative analgesia following gynecological surgery. Anesthesiology 2000;93:943-6. |
|17.||Lauretti GR, de Oliveira R, Reis MP, Mattos AL, Pereira NL. Transdermal nitroglycerine enhances spinal sufentanil postoperative analgesia following orthopedic surgery. Anesthesiology 1999;90:734-9. |
|18.||Krukowski JA, Hood DD, Eisenach JC, Mallak KA, Parker RL. Intrathecal neostigmine for post-cesarean section analgesia: Dose response. Anesth Analg 1997;84:1269-75. |
|19.||Chung CJ, Kim JS, Park HS, Chin YJ. The efficacy of intrathecal neostigmine, intrathecal morphine, and their combination for post-cesarean section analgesia. Anesth Analg 1998;87:341-6. |
|20.||Yaksh TL, Grafe MR, Malkmus S, Rathbun ML, Eisenach JC. Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology 1995;82:412-27. |
|21.||Abram SE, Winne RP. Intrathecal acetyl cholinesterase inhibitors produce analgesia that is synergistic with morphine and clonidine in rats. Anesth Analg 1995;81:501-7. |
|22.||Bouaziz H, Tong C, Eisenach JC. Postoperative analgesia from intrathecal neostigmine in sheep. Anesth Analg 1995;80:1-5. |
|23.||Naguib M, Yaksh TL. Characterization of muscarinic receptor subtypes that mediate antinociception in the rat spinal cord. Anesth Analg 1997;85:847-53. |
|24.||Chiari A, Eisenach JC. Sex differences in cholinergic analgesia in normal rats. Anesthesiology 1998;89:A1079. |
|25.||Borges LF, Iversen SD. Topography of choline acetyltransferase immuoreactive neurons and fibers in the rat spinal cord. Brain Res 1986;362:140-8. |
|26.||Ribeiro-da-Silva A, Cuello AC. Choline acetyltransferase-immunoreactive profiles are presynaptic to primary sensory fibers in the rat superficial dorsal horn. J Comp Neurol 1990;295:370-84. |
|27.||Gillberg PG, Aquilonius SM. Choiinergic, opioid and glycine receptor binding sites localized in human spinal cord in vitro autoradiography. Acta Neurol Scand 1985;72:299-306. |
|28.||Spencer DG, Horvath E, Trdher J. Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: relation to cholinergic nuclei and projections. Brain Res 1986;380:59-68. |
|29.||Sherriff FE, Henderson Z, Morrison JF. Further evidence for the absence of a descending cholinergic projection from the brainstem to the spinal cord in the rat. Neurosci Lett 1991;128:52-6. |
|30.||Willcockson WS, Chung JM, Hori Y, Lee KH, Willis WD. Effects of iontophoretically released amino acids and amines on primate spinothalamic tract cells. J Neurosci 1984;4:732-40. |
|31.||Urban L, Willetts J, Murase K, Randiæ M. Cholinergic effects on spinal dorsal horn neurons in vitro : an intracellular study. Brain Res 1989;500:12-20. |
|32.||Zhuo M, Meller ST, Gebhart GF. Tonic cholinergic inhibition of spinal mechanical transmission. Pain 1991;46:211-22. |
|33.||Dawson TM, Dawson VL, Snyder SH. A novel neuronal messenger molecule in brain: the free radical, nitric oxide. Ann Neurol 1992;32:297-311. |
|34.||Snyder SH. Nitric oxide: first in a new class of neurotransmitters. Science 1992;257:494-6. |
|35.||Haley JE, Dickenson AH, Schachter M. Electrophysiological evidence for a role of nitric oxide in prolonged chemical nociception in the rat. Neuropharmacology 1992;31:251-8. |
|36.||Nozaki-Taguchi N, Yamamoto T. The interaction of FK409, a novel nitric oxide releaser, and peripherally administered morphine during experimental inflammation. Anesth Analg 1998;86:367-73. |
|37.||Feelisch M, Noack EA. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Pharmacol 1987;139:19-30. |
|38.||Xu Z, Tong C, Eisenach JC. Acetylcholine stimulates the release of nitric oxide from rat spinal cord. Anesthesiology 1996;85:107-11. |
|39.||Bouaziz H, Hewitt C, Eisenach JC. Subarachnoid neostigmine potentiation of alpha 2-adrenergic aganist analgesia. Reg Anesth 1995;20:121-7. |
|40.||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;17:3293-302. |
|41.||Saito S, Kidd GJ, Trapp BD, Dawson TM, Bredt DS, Wilson DA. Rat spinal cord neurons contains nitric oxidesynthase. Neuroscience 1994;59:447-56. |
|42.||Terenghi G, Riveros-Moreno V, Hudson LD, Ibrahim NB, Polak JM. Immunohistochemistry of nitric oxide synthase demonstrates immunoreactive neurons in spinal cord and dorsal root ganglia of man and rat. J Neurol Sci 1993;118:34-7. |
|43.||Xu Z, Li P, Tong C, Figueroa J, Tobin JR, Eisenach JC. Location and characteristics of nitric oxide synthase in sheep spinal cord and its interaction with a2-adrenergic and cholinergic antinociception. Anesthesiology 1996;84:890-9. |
[Table 1], [Table 2], [Table 3], [Table 4]