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Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 10  |  Issue : 3  |  Page : 538-545  

Comparative evaluation of different doses of intrathecal neostigmine as an adjuvant to bupivacaine for postoperative analgesia


1 Department of Anaesthesia and Critical Care, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
2 Department of Anaesthesia and Critical Care, Mohan Dai Oswal Cancer Hospital, Ludhiana, Punjab, India

Date of Web Publication27-Sep-2016

Correspondence Address:
Vandana Pandey
B79, Rajved Colony, Nayapura, Kolar Road, Bhopal - 462 042, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0259-1162.180779

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   Abstract 

Objective: To study the efficacy and safety of intrathecal neostigmine at dose of 50 μg and 150 μg as an adjuvant to bupivacaine for postoperative analgesia under spinal anesthesia. Materials and Methods: 75 patients of either sex, belonging to American Society of Anesthesiologists (ASA) physical status I and II in the age group of 30-65 years scheduled to undergo lower abdominal and lower limb surgeries were allocated randomly into 3 groups of 25 each. Spinal anesthesia was administered in Group I (control group) with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine, in Group II (50 μg group) with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine and 50 μg (0.1 ml) of neostigmine methylsulphate and in Group III (150 μg group) with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine and 150 μg (0.3 ml) of neostigmine methylsulphate. Hemodynamic parameters, onset and level of sensory block were recorded. Postoperative analgesic assessment was made in terms of total Visual Analogue Scale-Pain (VAS-P) scores in 24 hrs, duration of analgesia (time to requirement of first analgesic) and total number of rescue analgesic (diclofenac sodium 75 mg intramuscularly) consumption in 24 hours. Side effects were recorded. Results: The total VAS-P score in group I was 23.12 ± 3.21, which was higher than the VAS-P score in group II (18.4 ± 2.92) and group III (16.24 ± 1.85). The total duration of analgesia was significantly prolonged in neostigmine groups (224.40 ± 23.28 min in group I, 367.60 ± 42.15 min in group II and 625.60 ± 87.70 min in group III). In group I, the patients required 2.48 ± 0.51 number of analgesics in 24 hours, which was much higher than required in group II (1.92 ± 0.64) and group III (1.32 ± 0.47). The incidence of nausea and vomiting was more with 150 μg neostigmine group compared to 50 μg neostigmine. Conclusions: The administration of intrathecal neostigmine in dose of 50 μg as an adjuvant to bupivacaine produces hemodynamically stable analgesia with minimal side effects.

Keywords: Intrathecal neostigmine, postoperative analgesia, visual analog scale for pain


How to cite this article:
Pandey V, Mohindra B K, Sodhi GS. Comparative evaluation of different doses of intrathecal neostigmine as an adjuvant to bupivacaine for postoperative analgesia. Anesth Essays Res 2016;10:538-45

How to cite this URL:
Pandey V, Mohindra B K, Sodhi GS. Comparative evaluation of different doses of intrathecal neostigmine as an adjuvant to bupivacaine for postoperative analgesia. Anesth Essays Res [serial online] 2016 [cited 2019 Oct 22];10:538-45. Available from: http://www.aeronline.org/text.asp?2016/10/3/538/180779




   Introduction Top


Anesthesiologists are leaders in the development of pain services in the current era. Pain has been defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”[1] Intrathecal local anesthetics have been most commonly used for regional analgesia. To enhance bupivacaine-induced analgesia, various adjuvant drugs were used such as adrenaline, morphine, fentanyl, clonidine, and ketamine but were associated with many side effects. Acetylcholine of muscarinic cholinergic system was found to be one of the endogenous spinal neurotransmitter to have role in antinociception by direct action on spinal cholinergic muscarinic receptor M1 and M3 and nicotinic receptor subtypes as well as indirectly by stimulating release of second messenger nitric oxide in the spinal cord.[2],[3],[4] Neostigmine exerts its effect by inhibiting the breakdown of the neurotransmitter acetylcholine.[5] According to recent literature, the inhibition of acetylcholine degradation by neostigmine enhances the descending control of afferent nociceptive stimuli and provides new approach for enhancement of desirable analgesia with few dose-related side effects.[6]

The use of neostigmine intrathecally does not cause any hypotension, sedation, respiratory depression, or neurological dysfunction.[7] Therefore, in the present study, we intend to compare intrathecal neostigmine at dose of 50 µg and 150 µg as an adjuvant to bupivacaine for postoperative analgesia after surgery under spinal anesthesia. In developing countries where affordability of health care is a major concern, neostigmine is a cost effective, easily available nonopioid alternative to ameliorate, mostly undertreated postoperative pain.


   Materials and Methods Top


A randomized control study was conducted in the Department of Anaesthesiology and Critical Care at a comprehensive cancer care hospital of North India between 2010 and 2011 after approval by Hospital Ethics Committee. A written informed consent was obtained from all patients selected for the study.

A total of 75 patients of either sex, belonging to the American Society of Anesthesiologists (ASA) physical status class I and II in the age group of 30–65 years scheduled to undergo lower abdominal and lower limb surgeries were chosen randomly. Patients with bleeding disorder or on anticoagulant therapy, patients allergic to bupivacaine or neostigmine, unconscious or mentally retarded patients, patients with infection at the site of lumbar puncture, patients with increased intracranial pressure, alcoholics, drug addicts, and patients with weight more than 100 kg were excluded from the study.

For the study, patients were randomly allocated into three groups, each group consisting of 25 patients. The patients were allocated using random number table into one of the three groups: Group I (control group) included 25 patients who were given 12.5 mg of 0.5% hyperbaric bupivacaine intrathecally, Group II (50 µg group) included 25 patients who were given 12.5 mg of 0.5% hyperbaric bupivacaine and 50 µg (0.1 ml) of neostigmine methylsulfate intrathecally, and Group III (150 µg group) included 25 patients who were given 12.5 mg of 0.5% hyperbaric bupivacaine and 150 µg (0.3 ml) of neostigmine methylsulfate intrathecally. Saline was added to the syringes to make an equivalent volume of 3 ml. Neostigmine used was preservative free, was measured by insulin syringe and mixed with bupivacaine. The contents of the syringe were concealed using serially numbered opaque sealed envelope approach. The patient, anesthesiologist injecting the drug, and the observer were blind to the group that the patient belonged to.

A day before surgery, preanesthetic check-up comprising detailed history, general physical examination, and systemic examination of all patients was undertaken. Routine investigations such as hemogram, bleeding time, clotting time, random blood sugar, renal function test, liver function test, chest X-ray, and electrocardiogram were obtained and checked. Patient's height and weight were recorded. The patients were explained about the procedure of spinal anesthesia, the drugs being administered along with their side effects and written informed consent was taken. All patients were also explained about the concept of visual analog scale for pain (VAS-P) and nausea (VAS-N) which consists of 100 mm line with “0” equaling no pain or no nausea at all and “10” being worst pain or worst possible nausea.

All patients were kept nil orally for 6 hours (h) before surgery. Patients were given premedication with tablet midazolam 7.5 mg and tablet ranitidine 150 mg at bedtime and 3 h preoperatively. Systemic narcotics were not administered to avoid the analgesics effects of any other drug interfering with the study. After shifting the patient to operation theatre, preoperative vital signs including pulse rate, respiratory rate, noninvasive blood pressure, electrocardiogram, and arterial oxygen saturation was recorded. Intravenous access was secured using 18-gauge intravenous cannula, and patients were preloaded with 10 ml/kg of crystalloid solution (Ringer lactate) over 20–30 min and then infused at 10 ml/kg body weight per hour after spinal anesthesia. Patients were subsequently placed in lateral position. Using all aseptic precautions, L3–L4 or L4–L5 intervertebral space was located, and 2% lignocaine was infilterated. The 25-gauge Quincke's spinal needle was used to access subarachnoid space. Successful dural puncture was confirmed by withdrawing the stylet to verify free flow of cerebrospinal fluid (CSF). Syringe loaded with injection bupivacaine alone or in combination with neostigmine, depending on the group was attached to the hub of the needle and whole of the drug was injected slowly into subarachnoid space. Patients were immediately turned supine after administration of subarachnoid block. All patients were given oxygen at 5 L/min by mask throughout the surgical procedure.

Pulse rate, noninvasive blood pressure - systolic and diastolic blood pressure, respiratory rate, and oxygen saturation by pulse oximetry were monitored every 5 min for the first 20 min after the block and then at 30, 45, 60, 75, 90, 120, and 150 min. The time of administration of intrathecal drug and the duration of procedure from time of commencement till the end of operation was noted. The onset of sensory block, i.e., time of intrathecal administration of drug to absence of pin prick was noted. The level of sensory block was assessed by pinprick test by using a short beveled 23-gauge needle after subarachnoid block at 5 min and at 10 min. Postoperatively, patients were assessed for pain scores at hourly intervals till 4 h, then 2 h for the next 6 h and then at 24 h. The intensity of postoperative pain during first 24 h was assessed by VAS-P which was already explained to the patient in the preoperative period. When patient was asleep, no VAS assessment was made and VAS of “0” was given. The duration of analgesia was measured as the time to requirement of first analgesia in recovery room and was recorded in minutes. Patients with VAS above four received rescue analgesic in form of injection diclofenac sodium 75 mg intramuscularly. The total analgesic requirement in 24 h was recorded. The occurrence of nausea was assessed by VAS-N which consisted of 10 cm horizontal line, similar to VAS-P. The end mark “0” meant no nausea and the other end marked “10” meant worst possible nausea. Patient with VAS-N above two or vomiting at any time was treated with injection metoclopramide 10 mg intravenously.

The primary outcome of our study was enhancement of duration of postoperative analgesia with use of intrathecal neostigmine as an adjuvant to bupivacaine. The secondary outcome was enhanced efficacy of 50 µg intrathecal neostigmine as an adjuvant to bupivacaine due to lesser side effects over 150 µg neostigmine, increased patient comfort and lower VAS-P scores in test groups.

A sample size of 25 patients in each group was selected to detect a difference of 60 min in the mean duration of analgesia assuming a standard deviation of 62 min and allowing for dropouts. The power of the study was kept at 90% and significance level at 5%.

On completion of study, recorded data were analyzed statistically using analysis of variance or ANOVA and Student's t-test. P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 16.0 (IBM Corp., Armonk, NY, USA).


   Results Top


In the present study, all the three groups were similar with respect to patient demographics such as age, sex ratio, weight, and ASA physical status. The mean age of patients in Group I was 47.32 ± 8.3 years, in Group II 49.68 ± 11.05 years, and in Group III 49.60 ± 8.86 years. The mean weight of patients in Group I was 64.24 ± 5.23 kg, in Group II 65.68 ± 4.11 kg, and in Group III 63.96 ± 5.20 kg. The mean height of patients in Group I was 161.32 ± 4.34 cm, in Group II 162.64 ± 5.11 cm, and in Group III 163.08 ± 5.24 cm. The sex distribution among the groups showed 19 males and 6 females in Group I, 18 males and 7 females in Group II, and 18 males and 7 females in Group III and the difference was not statistically significant. The three groups were also comparable in terms of the type of surgery [Table 1]. The mean duration of surgery in Group I was 111.80 ± 17.3, in Group II was 114 ± 17.3, and in Group III was 113.80 ± 17.9. The difference was not statistically significant.
Table 1: Type of surgeries

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The onset of blockade was 4.52 ± 0.65 min in Group I, 4.56 ± 0.71 min in group II, and 4.48 ± 0.65 min in Group III [Table 2]. The difference was statistically insignificant between the three groups. It was also found that the difference in sensory level achieved at 5 min and 10 min in the three groups was comparable [Table 3] and [Table 4].
Table 2: Onset of blockade (in min)

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Table 3: Sensory blockade at 5 min

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Table 4: Sensory blockade at 10 min

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The pulse rate, systolic blood pressure, diastolic blood pressure, oxygen saturation, and' respiratory rate were comparable in all the three groups throughout the intraoperative and the postoperative period.

The mean VAS-P scores in Group I, Group II, and Group III in the 1st h postoperatively was recorded as zero. On statistical analysis, the VAS-P score in the test groups (Group II and Group III) was significantly lower up to 8 h postoperatively (P < 0.05). There was statistically no difference in Group I and Group II after 8 h of observation, but statistically significant difference was observed after 8 h between Group I and Group III. There was no statistically significant difference in VAS-P score between Group II and Group III [Table 5] and [Figure 1].
Table 5: Visual analog scale for pain scores at different postoperative intervals

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Figure 1: Mean visual analog scale for pain score

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The total VAS-P score in Group I was 23.12 ± 3.21, which was much higher than the VAS-P score in Group II (18.4 ± 2.92) and Group III (16.24 ± 1.85). The total duration of analgesia was 224.40 ± 23.28 min in Group I, 367.60 ± 42.15 min in Group II, and 625.60 ± 87.70 min in Group III [Table 6]. The difference was statistically highly significant in between the three groups. The requirement of rescue analgesia in form of injection diclofenac sodium 75 mg intramuscularly was significantly lower in both test groups as compared to control group (P < 0.05). In Group I, the patients required 2.48 ± 0.51 number of analgesics in 24 h, which was much higher than required in Group II (1.92 ± 0.64) and Group III (1.32 ± 0.47) [Table 6].
Table 6: Analgesia assessment

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The mean VAS-N scores in the Group I (0) was significantly lower than Group II and Group III up to 3 h postoperatively (P < 0.05) though Group II recorded the lowest mean throughout the postoperative period. There was no significant difference in the VAS-N scores between Group II and Group III except in the 1st h of the postoperative period [Table 7] and [Figure 2].
Table 7: Visual analog scale for nausea scores at different postoperative intervals

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Figure 2: Mean visual analog scale for nausea score

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The incidence of nausea and vomiting was higher in the neostigmine groups. None of the patients in Group I, four patients (16%) in Group II, and eight patients (32%) in Group III developed nausea and vomiting. The difference in the incidence of nausea and vomiting was statistically significant (P < 0.05) in the three groups. Four patients (16%) in Group I, three patients (12%) in Group II, and one patient (4%) in Group III developed hypotension. Although the incidence of hypotension was lower in the neostigmine groups as compared to control group, the difference was not statistically significant. The hypotension occurred 10–20 min after intrathecal drug administration and was treated with injection mephentermine 5 mg intravenously in all groups.

In our study, two patients (8%) in Group I, three patients (12%) in Group II, and six patients (24%) in Group III developed bradycardia. There was increased incidence of bradycardia in the neostigmine groups, but the results were statistically insignificant (P > 0.05).

The incidence of other side effects such as sweating and sedation was higher in the neostigmine groups, but the results were not statistically significant (P > 0.05) [Figure 3].
Figure 3: Adverse effects

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   Discussion Top


Intrathecal administration of neostigmine produces antinociception, which is mediated by spinal muscarinic receptors in animals and human beings.[8] It produces analgesia by inhibiting the metabolism of acetylcholine without causing any neurotoxicity in animals and humans.[9] This was first demonstrated in 1942 by use of cholinergic and anticholinesterase agents to produce analgesia in hemiplegic patient.[10] The systemic analgesic effects of anticholinesterase agents and morphine was studied in 1945.[11] In the 70's a link between anticholinesterase agents and opioids was studied.[12],[13] The interest in cholinergic mechanisms of pain was rekindled by Pleuvry and Tobias in 1971.[12] In the present study, the two doses of neostigmine 50 and 150 µg were selected on the basis of previous study by Saini et al. who demonstrated that intrathecal neostigmine in dose of 50 µg was ineffective for analgesia and associated with increased incidence of vomiting whereas intrathecal neostigmine in the dose of 150 µg provided postoperative analgesia for 8–10 h and is associated with increased incidence of adverse effects such as nausea, vomiting, sweating, and salivation.[14]

Saini et al. did not observe any enhancement of sensory blockade with 50 µg and 150 µg intrathecal neostigmine.[14] These findings were in concordance with our study as we also did not find any statistically significant difference in onset of sensory block among the three groups. The difference in sensory level achieved at 5 min and 10 min in the three groups was also found to be statistically insignificant. These findings were similar to the study in which 50 µg neostigmine and 300 µg morphine were compared and no difference in the sensory level was found as compared to saline group.[15]

Variability and unpredictability of the CSF volume have been said to account for the extent of cephalad spread and effect of a given dose of intrathecal local anesthetic in any given patient. It has been seen that lumbosacral CSF volume is the primary determinant of sensory block height with smaller CSF volumes resulting in higher block heights.[16] The patients in the present study underwent elective procedures, were adequately hydrated and had comparable demographic characteristics. The factors that would determine CSF volume were thus comparable in these patients explaining the lack of variability in peak dermatomal levels attained.

In the present study, comparability of baseline (0 min) volume status of all the patient groups was ensured by an intravenous infusion of lactated Ringer's solution 10 ml/kg over 20–30 min. Intraoperative blood loss as assessed by measuring irrigation fluid and weighing surgical sponges used for blood and fluid collection during surgery was replaced adequately by crystalloids or blood products as and when required.

In the present study, pulse rate, systolic blood pressure, and diastolic blood pressure were comparable.

Neostigmine can cause increase in blood pressure and heart rate which occurs due to excitatory actions on preganglionic sympathetic neurons. This effect was seen more after injection directly into the intermediolateral cell column than after intrathecal injection and at much higher doses (more than 750 µg).[17] The oxygen saturation and respiratory rate were also comparable between the three groups in intraoperative and postoperative period which was consistent with the studies cited in literature.[17],[18]

Intrathecal administration of neostigmine produces analgesia in healthy subjects by inhibiting acetylcholine metabolism which acts on muscarinic binding sites in the substantia gelatinosa and to a lesser extent, in lamina III and V of gray matter of spinal systems to produce antinociception.[8]

On statistical analysis, the VAS-P score in the test groups (Group II and Group III) was significantly lower up to 8 h postoperatively (P < 0.05) as compared to the control group. The total duration of analgesia was 224.40 ± 23.28 min in Group I, 367.60 ± 42.15 min in Group II, and 625.60 ± 87.70 min in Group III. The requirement of rescue analgesia in form of injection diclofenac sodium 75 mg intramuscularly was significantly lower in both test groups (P < 0.05).

We found that intrathecal neostigmine in dose of 50 µg and 150 µg prolonged the postoperative analgesia in terms of total VAS-P scores, duration of analgesia and total number of rescue analgesic consumption as compared to control group. The use of 25–50 µg neostigmine intrathecally during vaginal hysterectomy produced significant analgesia.[19] The study attributed analgesia with smaller doses of neostigmine to increased potency of neostigmine in response to painful stimulus as well as to use of intravenous morphine through patient controlled analgesia in all their patients.

The addition of neostigmine to bupivacaine caused significant increase in duration of analgesia up to 270 ± 43 min as compared to bupivacaine alone (85 ± 10 min).[7] The use of hyperbaric neostigmine intrathecally in dose of 100 µg was effective for pain relief and reduced postoperative opiate requirement after single level discectomy.[20]

The onset of analgesia was decreased, and duration was prolonged with 50 µg intrathecal neostigmine.[21] However, the mean duration of analgesia provided by intrathecal neostigmine in our study was slightly longer than that reported by Hood et al. who observed that intrathecal neostigmine at a dose of 100 µg produced mild analgesia (30–40% reduction in pain scores in response to a noxious cold stimulus) lasting 3–4 h in volunteers whereas 50 µg produces no detectable analgesia.[17] This may be explained on the basis of different patterns of noxious stimuli used in their study.

Our results were similar to Saini et al. who observed greatly enhanced analgesia by intrathecal neostigmine in the 150 µg dose as is shown by significantly less consumption of rescue analgesics. They also concluded that intrathecal neostigmine in dose of 50 µg was ineffective for analgesia which was in contrast to our study in which intrathecal neostigmine in a dose of 50 µg was associated with lower VAS score prolonged duration of analgesia and lesser consumption of rescue analgesic in 24 h as compared to the control group.[14]

The use of intrathecal neostigmine in dose of 75 µg along with bupivacaine produced better postoperative analgesia as compared to its use in a dose of 50 µg, but was associated with increased frequency of side effects like nausea, vomiting, bradycardia and hypotension.[22]

The incidence of nausea and vomiting was higher in the neostigmine groups. None of the patients (0%) in Group I, four patients (16%) in Group II, and eight patients (32%) in Group III developed nausea and vomiting which was promptly relieved by injection metoclopramide 10 mg intravenously. Intrathecal neostigmine produces nausea in a dose-dependent manner. This high incidence of nausea and vomiting could be due to cephalad migration of neostigmine to the brain stem where it causes accumulation of acetylcholine. This increased acetylcholine causes vomiting by stimulating the chemoreceptor trigger zone.[15] The injection of neostigmine in hyperbaric dextrose solution while maintaining the patient in head up position reduces the incidence of vomiting.[16] In a study done by Klamt et al., nausea and vomiting started within 30 min and lasted for more than 1 h despite use of metoclopramide or droperidol.[23] This may be attributed to the maintenance of head down position in their patients by the authors. This was in contrast to our study where most of the patients responded to injection metoclopramide given intravenously.

Hypotension occurred in all the three groups, and the difference was statistically insignificant. The reason of this hypotension is blockade of the sympathetic nervous system during subarachnoid block, and subsequent decreases in systemic vascular resistance and cardiac output. The addition of neostigmine to bupivacaine intrathecally did not reduce hypotension.[24] However, in contrast, some studies had observed that intrathecal neostigmine can counteract the hypotension induced by intrathecal local anesthetics by directly stimulating preganglionic sympathetic neurons in spinal cord.[25],[26]

The incidence of bradycardia was more in the neostigmine groups though the difference was not statistically significant. All the patients responded to intravenous atropine. Neostigmine 50 µg caused bradycardia at 65–70 min after administration of spinal anesthesia and bradycardia was successfully treated with atropine.[27]

Neostigmine caused increase in the incidence of sweating which is a sign of sympathetic system stimulation. This might account for protective effect of neostigmine against the hypotension caused by spinal anesthesia.[23] None of the patients in the present study developed respiratory depression, ejaculation, or increased salivation. This is consistent with the study by Chung et al. who did not report any respiratory depression leading to desaturation with intrathecal neostigmine.[28]


   Conclusion Top


Administration of intrathecal neostigmine as an adjuvant to bupivacaine produces effective, prolonged and hemodynamically stable postoperative analgesia as compared to administration of intrathecal bupivacaine alone. Intrathecal neostigmine in dose of 50 µg provided effective analgesia as shown by lower VAS-P and reduced consumption of rescue analgesic whereas the dose of 150 µg was associated with much more prolonged duration of analgesia but at the cost of higher incidence of side effects such as nausea and vomiting. In developing nations, it can be used as a low-cost nonopioid adjuvant in low doses, without fear of hemodynamic instability or respiratory depression for undertreated postoperative pain.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.

 
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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.  Back to cited text no. 28
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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