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Researches

Original Article
Efficacy of spinal additives neostigmine and magnesium
sulfate on characteristics of subarachnoid block,
hemodynamic stability and postoperative pain relief:
Arandomized clinical trial
Suchita Joshi-Khadke, V. V. Khadke1, S. J. Patel, Y. M. Borse, K. V. Kelkar, J. P. Dighe,
R. D. Subhedar

Departments of Anesthesiology and 1Pharmacology, Shri Bhausaheb Hire Government Medical College, Dhule, Maharashtra, India
Corresponding author: Dr.Suchita JoshiKhadke, 35Girija Shankar Vihar, Satara Parisar, Paithan Road, Aurangabad, Maharashtra, India.
Email:suchit_khadke@rediffmail.com

Abstract
Background: Intrathecal neostigmine and magnesium sulfate(MgSO4) produce substantial
antinociception, potentiate analgesia of bupivacaine without neurotoxicity.
Aims: The aim was to investigate the effect of neostigmine and MgSO4 on characteristics of
spinal anesthesia(SA), hemodynamic stability and postoperative analgesia when added to 0.5%
hyperbaric bupivacaine for SA.
Subjects and Methods: In this prospective, randomized, doubleblind study 75 American Society
of Anesthesiologist status I and II adult females posted for major gynecological surgery were
assigned to one of the three groups(n=25). GroupN received Neostigmine 25g, GroupM
received MgSO4 50mg, GroupC received 0.5ml saline as an adjuvant to 17.5mg hyperbaric
bupivacaine. Onset, duration of block, heart rate, mean arterial pressure, postoperative analgesia,
analgesic requirement, and adverse effects were recorded. Data expressed as mean(standard
deviation) or number(%). P<0.05 were statistically significant.
Results: The three groups were comparable in characteristics of SA. The mean duration
of analgesia was significantly longer in Group N (5.1 h) followed by Group M (4.2 h) and
GroupC(3.8h)(P=0.0134). Analgesic requirement was significantly less in GroupN followed by
GroupM and GroupC(P=0.00232). The pain score was significantly less in GroupM(P<0.05).
The incidence of hypotension and vasopressor requirement was lowest(48%) in GroupN than
in GroupM(64%) and GroupC 84%(P=0.0276). The incidence of bradycardia and atropine
requirement was the lowest in GroupM(P=0.0354). Sedation was observed in 56% patients in
GroupM compared to 20% in GroupN and 8% in GroupC(P=0.0004).
Conclusion: Intrathecal Neostigmine and MgSo4 does not affect characteristics of SA.
Postoperative analgesia of neostigmine was better than MgSO4. Neostigmine provides some
Access this article online
protection against hypotension of SA whereas
Website DOI Quick Response Code
MgSO4 protects against bradycardia.
www.aeronline.org 10.4103/0259-1162.150168

Key words: Hyperbaric bupivacaine,

intrathecal magnesium sulfate, intrathecal
neostigmine, major gynecological surgery,
postoperative pain, spinal anesthesia

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Anesthesia: Essays and Researches; 9(1); Jan-Apr 2015 JoshiKhadke, etal.: Spinal neostigmine and magnesium sulfate: Effect on SAB and
INTRODUCTION
Spinal anesthesia(SA) is the most commonly used
anesthetic technique for lower abdominal surgeries.
But it has the drawback of short duration of action
and lack of postoperative analgesia. Larger dose of
analgesic is required to provide pain relief with high
incidence of side effects when local anesthetic is used
alone for SA.[13] Neuraxial opioids though effective have
worrisome respiratory depression, nausea, vomiting,
urinary retention, and pruritus that limit their use in
the ward.[4,5] Recent research has focused on nonopioid
spinal receptors that inhibit transmission of pain signals.
Increased understanding of spinal processing of pain has
led to the development of specific drugs that inhibit pain
transmission. Intrathecal neostigmine and magnesium
sulfate(MgSO4) both produce substantial antinociception
without neurotoxicity, potentiate analgesia of bupivacaine
and opioids as evident from animal and human studies.[2,5,6]
Since their primary site of action is the spinal cord, direct
intrathecal injection is preferable to obtain meaningful
and clinically effective analgesia. The safety profile of
this route has been evaluated in several experimental
settings.[79] Thus, intrathecal neostigmine and MgSO4 in
smaller doses might become useful adjunct analgesics to
spinal bupivacaine anesthesia. Furthermore, the ability
of intrathecal neostigmine to protect against SAinduced
hypotension and to increase gastrointestinal motility
in the absence of respiratory depression are positive
features that stimulated us to undertake this study.[5,10,11]
To the best of our knowledge, there are no trials in the
available literature comparing intrathecal neostigmine and
MgSO4 on characteristics of SA, hemodynamic stability,
and postoperative analgesia. With this background
in mind, we designed this randomized, doubleblind,
prospective clinical study to test the hypothesis
intrathecal neostigmine and MgSO4 when added to
hyperbaric bupivacaine for SA, will improve hemodynamic
stability and reduce postoperative pain and consumption
of analgesic after lower abdominal surgery when
compared to saline control.
SUBJECTS AND METHODS
The aim of present study was to evaluate the effect of
smaller doses of neostigmine(25g) and MgSO4(50mg)
on characteristics of SA, hemodynamic stability, and
postoperative analgesia when added to hyperbaric
bupivacaine for SA. It is a randomized, doubleblind,
prospective, parallel group clinical trial conducted at
Department of Anaesthesiology, Shri Bhausaheb Hire
Government Medical College, Dhule during October
2011 to March 2013. The study was approved by
Institutional Ethics Committee and registered in the
public database(CTRI/2011/08/001948). It was conducted
64
postoperative pain
in strict accordance with the guidelines laid down by
Declaration of Helsinki.
The patient cohort comprised of consecutive American
Society of Anesthesiologist physical status I and II adult
females of age 2060years weighing 4070kg scheduled
for elective gynecological surgery under SA. Patients on
chronic analgesic therapy or having contraindications
to SA(coagulopathy, gross spinal deformity, central or
peripheral neuropathy, etc.), morbid obesity, sensitivity to
study drugs were excluded from the study.
Conduct of the study
Informed written consent was obtained from the subjects
before surgery as per hospital rules. The patients clinical
history, vital data, and investigations were recorded in
the case sheet. Use of the pain scale was explained. They
were randomly assigned to one of the three groups of
25 each using computer generated randomization list
usingGraphPad QuickCalcs (GraphPad Software, Inc.,
7825 Fay Avenue, Suite 230 La Jolla, CA 92037 USA). The
assignment was sealed in opaque envelops along with code
of the group and opened just before entry into the study.
All patients received tablet alprazolam 0.25mg and
tablet ranitidine 150mg orally night before surgery. They
were kept fasting for 8h for solid food. On arrival in the
operating room, standard monitoring was established.
Intravenous(IV) line was started with 18gauge canulla
followed by preloading with 10ml/kg lactated ringers
solution and maintenance infusion 610ml/kg/h. IV
ondansetron 4mg and ranitidine 50mg was given
as antiemetic prophylaxis. SA was carried out in the
lateral position at lumbar 34 interspace using 23gauge
disposable spinal needle. After clear and free flow of
cerebrospinal fluid(CSF), one of the study solutions was
administered intrathecally depending upon the group. The
control group(GroupC) received mixture of hyperbaric
bupivacaine 17.5mg and 0.5ml normal saline. Neostigmine
group(GroupN) received hyperbaric bupivacaine 17.5mg
and 25g neostigmine methyl sulfate(Myostigmin
0.5mg/mlNeon Laboratories Ltd.) made 0.5ml with
normal saline. Magnesium group(GroupM) received
hyperbaric bupivacaine 17.5mg and 50mg MgSO4
(Magneon 50%w/v, Neon Laboratories Ltd.) made 0.5ml
with normal saline. All the study drugs were preservative
free and total volume of drug injected was 4ml. The study
drug was prepared by anesthesiologist not involved in
outcome measurement. The patient, anesthesiologist who
performed the spinal block, and the observer collecting
data about study parameters were blinded to group
allocation. Time of intrathecal injection was noted and
patient repositioned supine. The head end of the operating
table was elevated by 1020 while injecting drug.
Supplementary oxygen via facemask was given at 3 L/min
throughout the surgical procedure. Vital parameters heart
rate(HR) and mean arterial pressure(MAP) were
Anesthesia: Essays and Researches; 9(1); Jan-Apr 2015 JoshiKhadke, etal.: Spinal neostigmine and magnesium sulfate: Effect on SAB and
recorded using automated blood pressure(BP) cuff
(EMCO 4920MPM, serial N0.0612218, EMCO Meditek Pvt.
Ltd.) every 5 min for 30 min, then every 10 min till end
of surgery. Oxygen saturation was continuously monitored.
No additional analgesic was given unless requested by
the patient. Intraoperative sedation was provided with IV
midazolam 1mg when required. Vomiting in absence of
hypotension was treated with IV metoclopramide 10mg or
propofol 20mg bolus. Patients in whom sensory block was
inadequate and those requiring general anesthesia(GA)
supplement were excluded from the study.
A dermatomal sensory level up to eighth thoracic segment(T8)
was considered satisfactory. Following confirmation of spinal
block by loss of sensation to pinprick(assessed every 2min
interval for 15min, then every 5min until maximum sensory
level) at desired level surgery was started. Motor block to be
assessed with modified Bromage scale as 0 No paralysis, 1
Unable to raise extended leg, 2 Unable to flex knee, 3
Unable to flex ankle.
Following parameters were recorded. (All durations were
calculated considering time of intrathecal injection as
time 0).
Characteristics of spinal anesthesia
Time of onset of sensory block to L1 level, onset of motor
block to Bromage score 1, maximum level of sensory
block, time to achieve maximum sensory level, duration
of sensory block, that is, time for two segment regression
of sensory level, duration of motor block, that is, time for
complete motor recovery to Bromage score 0 or ability to
move lower limbs.
Hemodynamic stability
Variation in HR, MAP, hemoglobin oxygen saturation
was recorded every 5min during surgery. Hypotension
was defined as the fall in MAP 30% below baseline or
<90 mmHg and was treated with IV fluids bolus of 500ml
lactated ringers solution followed by IV mephentermine
6mg if required. Bradycardia was defined as the fall in
pulse rate<60 beats/min and treated with IV atropine
0.6mg. Sedation score was recorded every 15min
intraoperatively and postoperatively for 6h as described
by Chernik etal.[12]
0 no sedationWide awake
1 Mild sedationsleeping comfortably
2 Moderate sedationDeep sleep but arousable
3 Severe sedationDeep sleep not arousable.
Duration of analgesia
Calculated from intrathecal injection till demand of first
analgesic dose.
Analgesic requirement
Requirement of intramuscular(IM) diclofenac sodium(mg),
IV tramadol(mg), and the total number of analgesic doses
in 24h.
postoperative pain
Postoperative assessment was carried out at hourly
interval until first analgesic dose followed by 6, 12, 24,
48h, and 7thday postoperatively by anesthesiologist who
performed the spinal block and collecting data about study
parameters and trained staff nurse both were blinded to
group allocation. The patients were carefully questioned
regarding duration of painfree period and severity of pain
at rest and measured using a Rupee scale.[13]
00 paisaNo pain
25 paisaMild pain
50 paisaModerate pain
75 paisaSevere pain
100 paisaWorst imaginable pain.
A resting pain<50 paisa was considered satisfactory
pain relief. Perception of pain 50 paisa indicates
the need for supplemental analgesic. Postoperative
analgesia was provided with IM diclofenac 1.5mg/kg
if no satisfactory pain relief, additional analgesia was
provided with IV tramadol 1mg/kg given on demand.
Injection pentazocine 30 mg and promethazine 25 mg
IM was given at bedtime. IV metoclopramide 10mg
and ondansetron 4mg were used as rescue antiemetic.
The patients were also observed for side effects like
postoperative nausea and vomiting(PONV), drowsiness,
respiratory depression(respiratory rate<10 breaths/min)
shivering, nystagmus, sweating, salivation, hallucinations,
agitation bowel/bladder dysfunction, itching, neurological
deficit, headache etc., recorded as and when they occur.
They were free to report any problems although no direct
questions were asked.
A sample size of 23 subjects in each group was required
to detect a difference of 60min in the mean duration of
analgesia, assuming a standard deviation(SD) of 62min
based on pilot study, a power of 90% and a significance
level of 5%. We included 25patients in each group to
allow for dropout and protocol violation.
Statistical analysis
At the end of the study, the data were unblinded
and statistical analysis was carried out using
software GraphPad InStat 3 (www.graphpad.com),
(GraphPad Software, Inc.7825 Fay Avenue, Suite 230 La
Jolla, CA 92037 USA), Version 3.10 and online statistical
calculator for the Chisquare test(www.physics.csbsju.
edu). The continuously distributed variables(demographic
data, duration of surgery, characteristics of SA,
hemodynamic parameters cumulative analgesic use and
pain score) are expressed as mean(SD) and analyzed
using oneway analyses of variance followed by Tukey
Krame multiple comparisons test or KruskalWallis test
with Dunns multiple comparisons test as appropriate.
Categorical data are expressed as number(percentage)
and analyzed using the Chisquare test. P<0.05 was
considered statistically significant.
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Anesthesia: Essays and Researches; 9(1); Jan-Apr 2015 JoshiKhadke, etal.: Spinal neostigmine and magnesium sulfate: Effect on SAB and
postoperative pain
RESULTS characteristics of SA. The onset time of sensory block
to L1 level and motor block to Bromage score 1 was
A total of 88patients was screened for the study. Eighty comparable in all the three groups. All patients attained
subjects satisfying the inclusion criteria were enrolled a block height up to T6 dermatome. There was no
in the study. In three patients, surgery was postponed significant difference in time required to achieve maximum
after enrollment hence not included in the study. One cephalad spread of sensory level. There was no significant
case each from GroupC and GroupM were excluded difference in duration of sensory and motor block.
because GA was supplemented for unexpected prolonged
The analgesia characteristics are described in Table 3.
duration of surgery. Data from 75 subjects(25 in each
The mean duration of analgesia was significantly
group) were analyzed. The three groups were comparable
longer in Group N (308.76 [127.40] min or 5.1 h)
in demographic characters age, duration of surgery, and
followed by GroupM(252.2[86.76] min or 4.2h) and
incision time[Table1]. The surgical procedures performed
Group C (229.52 [59.16] min or 3.8 h) (P = 0.0134). The
were abdominal hysterectomy, exploratory laparotomy,
Dunns multiple comparison reveal difference between
and abdominal sling operation. Table2 depicts the
GroupN and GroupC statistically significant(P<0.05).
The diclofenac requirement was comparable in all the
Table1: Demographic characteristics in study three groups(P = 0.1143). Additional analgesia with
groups injection tramadol was required in 10(40%) patients
Variable n=25 P in GroupN, 16(64%) patients in GroupM as against
Group M Group N Group C 23 (92%) patients in Group C (P=0.001). The mean
Age(years) 39.40(8.36) 41.36(7.03) 40.28(9.36) 0.460 tramadol requirement was the lowest in GroupN
Duration of surgery(min) 62.12(23.07) 68.16(24.32) 56.56(26.70) 0.260 (20[25] mg) followed by Group M (32 [24.49] mg) and
Incision time(min) 5.0(1.97) 6.20(2.19) 5.04(2.05) 0.537 GroupC(48[22.73] mg). The difference between GroupN
Data expressed as mean(SD) and analyzed by oneway analysis of variance and GroupC was statistically significant(P<0.001).
or Kruskal-Wallis test as appropriate; P<0.05 significant. Group M=Intrathecal
bupivacaine and magnesium sulfate, GroupN=Intrathecal bupivacaine and neostigmine, The cumulative analgesic requirement in 24h(number
GroupC=Intrathecal bupivacaine and saline, SD=Standard deviation of doses) was significantly less in Group N 3.48(0.58)
followed by Group M 3.64(0.75) compared to Group C
Table2: Characteristics of spinal anesthesia in 4.2(0.86)(P = 0.00232). The intergroup comparison
study groups shows the difference between GroupN and GroupC
Variable n=25 P statistically significant(P<0.01). Figure1 shows
Group M Group N Group C postoperative pain score at rest expressed as mean(SD)
Onset of sensory 1.69(0.82) 2.02(1.08) 1.83(0.70) 0.423 in study groups. The pain score at 2h was comparable
block (min) among all the three groups. At 4h, pain score in GroupN
Onset of motor 1.82(1.05) 1.98(1.43) 1.83(0.69) 0.814 37(27.11) and GroupM 51(21.79) was significantly lower
block (min) compared to control group 61 (32.33) (P = 0.0132). The
Peak sensory level T6(T4-T8) T6(T2-T8) T6(T2-T8) 0.148 difference between GroupN and GroupC was statistically
(thoracic segment) significant(P<0.05). However, at 6h and 12h, pain
Time for maximum 14.92(7.14) 13.72(6.10) 14.56(8.47) 0.797 score in GroupM was significantly lower than in the
cephalad spread(min) control group(P<0.05), GroupN and GroupC were
Two segment 74.56(17.07) 84.36(26.08) 80.44(16.99) 0.198 comparable. At 24h, pain score was comparable among
regression time(min)
all the three groups(P=0.1942). GroupN and GroupM
Time to complete 239.6(75.17) 226.28(64.08) 245.28(101.11) 0.672
motor recovery(min)
were comparable at 2, 4, 6, 12, and 24h.
Data expressed as mean(SD) and analyzed by Kruskal-Wallis test; P<0.05 significant. The baseline hemodynamic variables were comparable
Group M=Intrathecal bupivacaine and magnesium sulfate, Group N=Intrathecal
bupivacaine and neostigmine, Group C=Intrathecal bupivacaine and saline,
among all the three groups[Table4]. Hypotension
SD=Standard deviation was observed in 12(48%) patients in GroupN and

Table3: Analgesia characteristics in study groups

Variable n=25 P
Group M Group N Group C
Time for first analgesic demand(min) 252.2(86.76) 308.76(127.40) 229.52(59.16) 0.0134*
Analgesic requirement diclofenac sodium(mg) 150(30.61) 156(20.76) 168(39.21) 0.1142
Number of patients demanding additional analgesia(%) 16(64) 10(40) 23(92) 0.001
Rescue analgesic requirement tramadol (mg) 32(24.49) 20(25) 48(22.73) 0.001***
Total analgesic requirement in 24h (number of doses) 3.64(0.75) 3.48(0.58) 4.2(0.86) 0.00232**
Data expressed as mean(SD) and analyzed by oneway analysis of variance or Kruskal-Wallis test with post hoc test as appropriate, Data analyzed using the chisquare test; P<0.05
significant. Dunns multiple comparisons tests: *Group N and group C(P<0.05), **Group N and group C(P<0.01), ***Group N and group C(P<0.001). SD=Standard deviation

66
Anesthesia: Essays and Researches; 9(1); Jan-Apr 2015 JoshiKhadke, etal.: Spinal neostigmine and magnesium sulfate: Effect on SAB and
postoperative pain
Table4: Hemodynamic changes in study groups
Variable n=25 P
Group M Group N Group C
Baseline MAP mmHg 102.04(10.33) 98.40(9.63) 100.88(8.51) 0.3902
Incidence of hypotension number of patients (%) 16(64) 12(48) 21(84) 0.0276
Lowest MAP mmHg 69.36(12.16) 68.88(8.73) 65.92(8.23) 0.415
Time for lowest MAP (min) 24.08(12.17) 29.08(18.35) 24.36(14.41) 0.5416
Vasopressor requirement mephenteramine (mg) 7.2(8.12) 5.52(6.91) 10.56(8.17) 0.045*
Baseline PR (beats/min) 86.48(16.85) 87.68(15.55) 87.92(12.66) 0.9371
Lowest PR (beats/min) 71.84(10.98) 67.92(11.92) 65.76(10.92) 0.1625
Time for lowest(min) 28.04(19.72) 33.04(27.97) 32.56(20.01) 0.6968
Incidence of bradycardia number of patients (%) 3(12) 6(24) 11(44) 0.0354
Atropine requirement (mg) 0.048(0.11) 0.144(0.24) 0.216(0.252) 0.0342**
Data expressed as mean(SD) and analyzed by oneway analysis of variance or Kruskal-Wallis test with post hoc test as appropriate, Data analyzed by chisquare test; P<0.05
significant, *Intergroup comparisongroup N and group C(P<0.05), **Intergroup comparisongroup M and group C(P<0.05). SD=Standard deviation, MAP=Mean arterial pressure,
PR=Pulse rate

 intergroup comparison difference between GroupM and


GroupC was statistically significant(P<0.05) whereas
*URXS0


GroupN and GroupC, as well as GroupM and GroupN,
*URXS1 were comparable. The degree of bradycardia was 25% in
 GroupC, 16% in GroupM and 18% in GroupN.
*URXS&


 
 Table5 describes the incidence of adverse effects in

study groups. Intraoperative sedation was observed

   in 56% patients in GroupM compared to 20% patients
in GroupN and 8% patients in GroupC(P=0.0004).
  The difference in peak sedation score was statistically

significant between GroupM and GroupC(P<0.001)

as well as GroupM and GroupN(P<0.05) whereas


 GroupN and GroupC were comparable. The incidence of
+RXUV +RXUV +RXUV +RXUV +RXUV PONV was significantly higher in GroupC(56%) compared
to 40% each in GroupN and GroupM(P=0.0074).
Figure 1: Graph showing postoperative pain score at rest in study
groups. *Intergroup comparison - Group N and Group C (P < 0.05) at 4 h. The mean antiemetic use was comparable among three
**Intergroup comparison - Group M and Group C (P < 0.05) at 6 and 12 h. GroupsC(P = 0.083). Occasional tingling was noted
P value not significant at 2 and 24 h. P value not significant between GroupN in 3 (12%) patients in Group C and 1 (4%) each in study
and Group M at 2, 4, 6, 12, and 24 h groups(P = 0.4293). The three groups were comparable
with respect to other side effects namely vomiting during
16(64%) patients in GroupM compared to 21(84%) surgery, pain on traction, desaturation, shivering, other
patients in GroupC(P=0.0276). The lowest MAP neurological symptoms, headache, etc.
and time for lowest MAP after IT drug injection was
comparable among the three groups. The average DISCUSSION
vasopressor requirement(mg mephentermine) was
significantly less in GroupN(5.5mg) when compared to Effective treatment of pain represents an important
GroupM(7.2mg) and GroupC(10.5mg)(P=0.045). component of postoperative recovery. It serves to blunt
The difference between GroupN and GroupC was autonomic, somatic, and endocrine reflexes with a
statistically significant(P<0.05), GroupM and GroupN resultant potential decrease in perioperative morbidity.[14]
were comparable. The degree of hypotension was Despite advances in treatment of postoperative pain, many
34% in Group C, 30% in Group M and 29% in Group N. patients still suffer from pain after surgery, probably due
Similarly, baseline PR, lowest PR, and time of lowest PR to difficulties in balancing postoperative analgesia with
were comparable in all three groups. The incidence of acceptable side effects. In this prospective randomized
bradycardia was the highest in GroupC(44%) compared controlled trial, evidence was provided that patients who
to 24% in GroupN and 12% in GroupM(P = 0.0354). received intrathecal neostigmine 25 g or MgSO450mg
On an average, 0.216(0.252) mg atropine was required with spinal bupivacaine had reduced postoperative pain
in GroupC compared to 0.144(0.24) mg in GroupN score and analgesic requirement after major gynecological
and 0.048(0.11) mg in GroupM(P = 0.0342). After surgery. Though our main aim was to compare

67
Anesthesia: Essays and Researches; 9(1); Jan-Apr 2015 JoshiKhadke, etal.: Spinal neostigmine and magnesium sulfate: Effect on SAB and
Table5: Incidence of adverse effects in study
groups
Variable n=25(%)
Group M Group N Group C
Sedation 14(56) 05(20) 02(08)
Sedation score* 0.56(0.5) 0.2(0.4) 0.08(0.27) 0.0005**
Desaturation(SpO2<90%) 01(4) 0(0) 01(4)
Vomiting during surgery 01(4) 08(32) 04(16)
PONV 10(40) 10(40) 14(56)
Neurological symptoms 01(4) 01(4) 03(12)
Shivering 04(16) 04(16) 05(20)
Data expressed as number of patients(%) and analyzed by chisquare test; P<0.05
significant, *Data expressed as mean (SD) and analyzed Kruskal-Wallis test with
posthoc test, **Intergroup comparisonGroup M and group N(P<0.05); Group M
and group C(P<0.001). Group M=Intrathecal bupivacaine and magnesium sulfate,
GroupN=Intrathecal bupivacaine and neostigmine, Group C=Intrathecal bupivacaine and
saline, PONV=Postoperative nausea and vomiting, SD=Standard deviation, SpO2=Oxygen
saturation
neostigmine and MgSO4 we thought it worthwhile to
add placebo group for some additional inference so that
we could compare each drug with placebo as well. The
parameters of SA itself may be affected by adjuvant used
with local anesthetics. In our study, sensory block was
slightly prolonged with neostigmine and motor block with
MgSO4 but it was not statistically significant. This indicates
neither the spread nor the potency of spinal bupivacaine
was affected by addition of neostigmine and MgSO4 in
given dose.[1518] Furthermore, onset and duration of motor
block were similar in all the groups. Our findings are
not consistent with the previous studies reporting delay
in onset, time to peak level, and prolongation of motor
block by MgSO4.[13,19] Intrathecal dose of neostigmine
6.2512.5 g did not affect SA, 6.2525 g improved SB
whereas 50150 g enhanced onset of SB and prolonged
duration of MB.[5,18,20] Difference in pH, baricity of the
solution and dose of the drug might have contributed to
this variable response.[1,3]
Our findings of analgesia characteristics are in accordance
with the pharmacokinetic profile of neostigmine
and MgSO4.[2124] The duration of analgesia was more
prolonged in the neostigmine group than in MgSO4
group when compared to saline group. The time to first
analgesic demand was longest with neostigmine(5.1h)
followed by MgSO4 (4.2 h) and saline control (3.8 h).
Diclofenac sodium was first analgesic given on demand.
Further doses were given at fixed interval after first dose.
Diclofenac requirement was slightly less with neostigmine
and MgSO4, but it was not statistically significant. Only
40% subjects in the neostigmine group required additional
analgesia with tramadol after first dose of analgesic
compared to 64% in MgSO4 group and 92% in the saline
group(P=0.001). Furthermore, the total dose of tramadol
was significantly less with intrathecal neostigmine. The
cumulative analgesic requirement was indicated by the
total number of analgesic doses required during first
68
postoperative pain
24h after surgery. It was lowest in the neostigmine
group than MgSO4 and control groups(P = 0.00232).
P The analgesic consumption was not significantly reduced
with MgSO4. Though lower abdominal surgery is a highly
0.0004
painful procedure, we did not use strong opioid as the
first analgesic because neostigmine and MgSO4 both are
0.3629
reported to produce central sedation.[16,23,25] Furthermore,
mild sedation was observed in our pilot study. To prevent
0.1816
excessive sedation, a milder form of analgesic was chosen.
0.0074
The Rupee scale is a simple and less time consuming
0.4253
technique for assessment of pain and requirement of
0.9111
analgesics in a clinic setting of an Indian hospital where
level of literacy is variable. It can be compared with visual
rating scales.[13] The pain score in the recovery room was
reduced to a significant degree by neostigmine and MgSO4
both. The neostigmine group had the lowest pain score at
4h whereas MgSO4 group had the lowest pain score at
6h and 12h(P<0.05). Analgesic consumption and pain
score at rest both have been shown to be correlated with
primary hyperalgesia caused by increased responsiveness
of primary afferent nociceptors.[19] It seems that the
higher dose of MgSO4 is necessary to decrease analgesic
consumption.[17,19]
The postoperative analgesia of intrathecal neostigmine, a
cholinesterase inhibitor was first reported by Hood etal. in
1995, the effectiveness being comparable to morphine.[23]
Spinal administration of neostigmine produces analgesia
in a novel manner. It inhibits the breakdown of
endogenous neurotransmitter acetylcholine(Ach) that has
intrinsic analgesic properties.[5,15,18,20] The concentration
of acetylcholine in CSF increases with painful stimulus
and remains at a plateau for 46h.[10,2123] The degree of
analgesia depends upon the amount of tonic release of
acetylcholine in CNS.[16,26] It is likely that CSF neostigmine
concentration even after lowest dose was adequate to
significantly inhibit cholinesterase in CSF.[6,11,21] The dose of
intrathecal neostigmine required in postoperative patients
is much smaller than that required in volunteers.[18]
Postoperative pain status, systemic opioids, pregnancy,
and spinal alpha2 adrenergic agonists stimulate release
of acetylcholine in the spinal cord and might increase
the apparent potency of neostigmine.[5,10,16,18] Intrathecal
neostigmine causes clear antinociception in first two
postoperative days but fails to do so 5days after surgery.[27]
Thus, there is amplification of postoperative analgesia of
intrathecal neostigmine by postoperative pain. Pain itself
activates a pain inhibitory system at the level of spinal
cord.[27] This effect is due to spinalsupraspinalspinal loop
and descending inhibitory system.[27] Lauretti etal. recently
hypothesized that spinally released norepinephrine from
this pathway activates intrinsic spinal cholinergic neurons
to cause acetylcholine release which produces analgesia.
High density of muscarinic cholinergic receptor binding
sites has been demonstrated in substantia gelatinosa and
lamina III and V of dorsal grey matter of spinal cord.[26,27]
Anesthesia: Essays and Researches; 9(1); Jan-Apr 2015 JoshiKhadke, etal.: Spinal neostigmine and magnesium sulfate: Effect on SAB and
Exclusive role of M1 muscarinic receptor subtype in
spinal cholinergic analgesia is documented in sheep.[7,27]
Both M1 and M2 receptor subtypes are demonstrated
in superficial dorsal horn.[27] Thus, spinal neostigmine
apparently activates descending pain inhibitory systems
that relay on a spinal cholinergic interneuron probably
exacerbating a cholinergic tonus that is already activated
during the acute postoperative pain.[18,26,27] Intrathecal
neostigmine was found to be extremely efficient for
alleviating somatic pain.[28] Analgesic effect also reflects
blocking of sympathetic ganglion through nicotinic
receptors or a direct antispasmodic effect on the
viscera through muscarinic receptors.[28] Further spinal
nitric oxidemediated analgesic action of intrathecal
neostigmine may be involved as in diabetic neuropathic
pain.[18,29] The preliminary doseresponse studies suggest
that the analgesic effect was dose independent.[22] Smaller
dose neostigmine 50 g in volunteers, and 10 g
in surgical patients could enhance sensory anesthesia
with few side effects when added to bupivacaine.[5,16,18] A
smaller dose may have the same efficacy with less adverse
effects. Intrathecal neostigmine with 2550 g dose
produces doseindependent reduction in postoperative
rescue analgesic consumption.[5,10] Postoperative analgesia
of about 24h after intrathecal neostigmine has been
reported in patients undergoing surgery under GA.[11] The
unimpeded nociceptive input during GA might increase
the activity of spinal cholinergic system enhancing
the effectiveness of intrathecal cholinergic drugs. This
mechanism is not relevant during SA. Neostigmine
induced increase in gut motility might be beneficial in
reducing postoperative ileus.[11]
Magnesium sulfate reveals antinociceptive effect
in animal and human pain models; it has potential
to prevent central sensitization from peripheral
nociceptive stimuli. Painful stimulus releases glutamate
and aspartate neurotransmitters which bind to the
NmethylDaspartate(NMDA) receptors. Activation of
these receptors leads to calcium entry into the cell
that initiates a series of central sensitization such as
windup and longterm potentiation in the spinal cord.
This NMDA signaling is important in determining the
duration and intensity of postoperative pain.[3,30,31]
Magnesium blocks the calcium influx into the cell,
that is, natural physiological calcium antagonism and
noncompetitively antagonizes the NMDA receptors.
Mg++ is a neuroprotectant protecting cerebellar neurons
against glutamate toxicity and spinal cord from ischemic
injury during aortic crossclamping.[25,32,33] Selective NMDA
receptor antagonists are not available for clinical pain
management. However, several compounds like MgSO4
and ketamine approved for use in humans for other
indications have significant NMDA receptor blocking
properties. The dose of MgSO4 was based on data from
previous human studies and rat models of postoperative
pain.[2,17,19,34] Further doseresponse studies are required to
postoperative pain
determine whether large doses of intrathecal MgSO4 can
produce better potentiation of analgesia and reduction
in analgesic requirement.[1,17] It is possible that effects of
MgSO4 on NMDA receptor complex are weaker, or they
do not play an important role in the maintenance of
postoperative pain.[24] But the superadditive interaction
of MgSO4 and ketamine is also reported.[33]
The hemodynamic effects of intrathecal neostigmine
are due to activation of M2 muscarinic receptors in
intermediolateral cell column.[27,35] It directly stimulates
preganglionic sympathetic neurons in the spinal cord and
can counteract the hypotension of SA.[5,10,11,15] The rise in
BP is evident within 5min of administration in animals
with small spinal cord but requires at least 30min raising
BP in sheep which has large spinal cord similar to those
of humans.[36] This ability of the cholinergic agonist to
raise BP by activation of endogenous regulatory pathway
may better preserve organ blood flow compared to
conventional peripheral acting vasopressors.[35] We
observed the lowest incidence of hypotension in the
neostigmine group48% compared to 64% in MgSO4
group and 84% in the saline group(P=0.0276). Fewer
episodes of hypotension and vasopressor requirement
with neostigmine represent its protective effect against
SAinduced hypotension. Previous studies have reported
that neostigmine<100 g does not counteract
hypotension of SA in gynecological surgery.[11,15] The
incidence of bradycardia and atropine requirement was
reduced significantly by MgSO4. Such protective effect
from bradycardia was not observed with neostigmine
which exhibited a similar degree of bradycardia like that
of the control group. Thus, intrathecal neostigmine in
given dose provides some protection against SAinduced
hypotension whereas MgSO4 protects against bradycardia
of SA. The exact mechanism responsible for this effect of
MgSO4 is not clear.
Nausea and vomiting due to neostigmine is
dosedependent, the smaller dose can produce analgesia
without nausea.[15,16,18,20] Klamt et al. ascribed the vomiting
to the effect of neostigmine on brain.[11] The rostral
spread to brainstem may contribute to the severity of
adverse effects(bradycardia, nausea and vomiting, urinary
retention, motor weakness, etc.). The side effects occur
3060 min after injection. To minimize the cephalad
spread, injection of neostigmine in hyperbaric solution
and maintaining head up position is recommended.[11,20,21,23]
The hyperbaric solution produced analgesia limited to
lower limbs without producing nausea and vomiting.[15]
Similarly, in our study, the risk of nausea and vomiting
could be minimized using neostigmine with hyperbaric
bupivacaine and maintaining head up position. The
increased vomiting and antiemetic use in the control group
could be because of more tramadol consumption. Solution
of MgSO4 itself is hyperbaric compared to CSF limiting its
cephalad spread. Isotonic saline was used for dilution of
69
Anesthesia: Essays and Researches; 9(1); Jan-Apr 2015 JoshiKhadke, etal.: Spinal neostigmine and magnesium sulfate: Effect on SAB and
study drugs as it does not alter the pH and osmolality of
drug and CSF, the volume administered intrathecally was
held constant in all the groups.[37] Propofol is effective
in controlling neostigmineinduced emesis.[15,22] Mild
to moderate sedation was reported in previous human
studies with 50mg intrathecal MgSO4 but there was no
significant difference in sedation score or somnolence
score in those studies.[14] Central cholinergic stimulation
can result in sedation in the neostigmine group.[21] In the
present study mild sedation was observed in 56% subjects
with MgSO4, the patients were sleeping comfortably. The
incidence was similar to that reported previously.[2] Only
20% patients in neostigmine reveal sedation. No patient
was sedated in the recovery room. We did not observe
any other central cholinergic effects of neostigmine like
hallucination, agitation, mydriasis, nystagmus, pruritus,
increased sweating or salivation. There was no evidence
of bradycardia from systemic absorption of neostigmine.
Urinary retention could not be evaluated as all the patients
were catheterized. The incidence of other adverse effects
did not differ among the three groups. Significant adverse
effects were not observed during the intraoperative period
like desaturation, respiratory depression, shivering, etc.,
No significant neurological complains, or adverse physical
finding was noted at 7days followup visit. Though
our study is not adequately powered to comment upon
neurotoxicity clinical trials performed to date have not
reported any evidence of neurological complications
following intrathecal neostigmine and MgSO4.[16,17,23,36]
To summarize, analgesia of neostigmine is found to
be dose independent, hence low dose is sufficient
for effective postoperative analgesia. The intrathecal
neostigmine requirement is much smaller in postoperative
patients than that required in volunteers. This smaller
dose of neostigmine is also effective in reducing
hypotension of SA. The addition of MgSO4 to SA reduces
postoperative pain score but did not reduce analgesic
consumption in first 24h compared to neostigmine.
Combination of lowdose intrathecal alpha2 adrenergic
agonist or systemic opioids may result in better analgesia
with fewer side effects.[5,6] We did not asses the incidence
and severity of chronic pain after gynecological surgery
which might have further revealed the action MgSO4 in
pain modulation and inhibition of central sensitization.
Our findings reinforce the role of MgSO4 as an effective
spinal adjuvant. One of the limitations of our study is
we did not evaluate the doseresponse. More controlled
studies are required to define benefits and outcomes with
different dose of neostigmine and MgSO4 and comparison
with established analgesic drugs will clearly establish their
role in postoperative pain management.
CONCLUSION
Intrathecal administration of neostigmine 25 g and
MgSO4 50mg as adjuvant to hyperbaric bupivacaine
70
postoperative pain
for SA does not affect characteristics of block. The
postoperative analgesia of 25 g neostigmine during early
recovery was better than 50mg MgSO4 and saline control
with less consumption of rescue analgesic in first 24h.
MgSO4 reduces postoperative pain score to a significant
degree up to 12h after surgery. Neostigmine provides
some protection against SAinduced hypotension whereas
MgSO4 protects against bradycardia of SA. Intrathecal
neostigmine and MgSO4 can provide a low cost simple
change in anesthesia practice leading to significant
decrease in postoperative pain and analgesic need.
ACKNOWLEDGMENTS
We thank the Medical Research Council of Maharashtra
for funding this project. All authors contributed to various
aspects of the trial. The authors thank the nursing and
paramedical staff associated with operation theater
and gynecology ward. Special thanks to Department
of Obstetrics and Gynecology for their cooperation
for smooth conduct of the study. Finally, thanks to the
patients and their relatives for providing us the platform
to conduct the clinical work.
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How to cite this article: Joshi-Khadke S, Khadke VV, Patel
SJ, Borse YM, Kelkar KV, Dighe JP, et al. Efficacy of spinal
additives neostigmine and magnesium sulfate on characteristics
of subarachnoid block, hemodynamic stability and postoperative
pain relief: A randomized clinical trial. Anesth Essays Res
2015;9:63-71.
Source of Support: Project funded by Medical Research
Council of Maharashtra under star research scheme and
institutional support, Conflict of Interest: None declared.
71
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