Efficacy of spinal additives neostigmine and magnesium sulfate on characteristics of subarachnoid block, hemodynamic stability and postoperative pain relief: A randomized clinical trial.

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, double-blind 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). Group N received Neostigmine 25 μg, Group M received MgSO4 50 mg, Group C received 0.5 ml saline as an adjuvant to 17.5 mg 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 Group C (3.8 h) (P = 0.0134). Analgesic requirement was significantly less in Group N followed by Group M and Group C (P = 0.00232). The pain score was significantly less in Group M (P < 0.05). The incidence of hypotension and vasopressor requirement was lowest (48%) in Group N than in Group M (64%) and Group C 84% (P = 0.0276). The incidence of bradycardia and atropine requirement was the lowest in Group M (P = 0.0354). Sedation was observed in 56% patients in Group M compared to 20% in Group N and 8% in Group C (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 protection against hypotension of SA whereas MgSO4 protects against bradycardia.

RCT Entities:   Population Interventions Outcomes

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.[123] Neuraxial opioids though effective have worrisome respiratory depression, nausea, vomiting, urinary retention, and pruritus that limit their use in the ward.[45] 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.[256] 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.[789] 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 SA-induced hypotension and to increase gastrointestinal motility in the absence of respiratory depression are positive features that stimulated us to undertake this study.[51011]

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, double-blind, 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 (25 μg) and MgSO4 (50 mg) on characteristics of SA, hemodynamic stability, and postoperative analgesia when added to hyperbaric bupivacaine for SA. It is a randomized, double-blind, 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 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 20–60 years weighing 40–70 kg 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 patient's 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 using GraphPad 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 0.25 mg and tablet ranitidine 150 mg orally night before surgery. They were kept fasting for 8 h for solid food. On arrival in the operating room, standard monitoring was established. Intravenous (IV) line was started with 18-gauge canulla followed by preloading with 10 ml/kg lactated ringers solution and maintenance infusion 6–10 ml/kg/h. IV ondansetron 4 mg and ranitidine 50 mg was given as antiemetic prophylaxis. SA was carried out in the lateral position at lumbar 3–4 interspace using 23-gauge 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 (Group C) received mixture of hyperbaric bupivacaine 17.5 mg and 0.5 ml normal saline. Neostigmine group (Group N) received hyperbaric bupivacaine 17.5 mg and 25 μg neostigmine methyl sulfate (Myostigmin 0.5 mg/ml-Neon Laboratories Ltd.) made 0.5 ml with normal saline. Magnesium group (Group M) received hyperbaric bupivacaine 17.5 mg and 50 mg MgSO4 (Magneon 50% w/v, Neon Laboratories Ltd.) made 0.5 ml with normal saline. All the study drugs were preservative free and total volume of drug injected was 4 ml. 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 10–20° 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 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 10 mg or propofol 20 mg 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 2 min interval for 15 min, then every 5 min 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 5 min during surgery. Hypotension was defined as the fall in MAP 30% below baseline or <90 mmHg and was treated with IV fluids bolus of 500 ml lactated ringers solution followed by IV mephentermine 6 mg if required. Bradycardia was defined as the fall in pulse rate < 60 beats/min and treated with IV atropine 0.6 mg. Sedation score was recorded every 15 min intraoperatively and postoperatively for 6 h as described by Chernik et al.[12]

0 no sedation-Wide awake

1 Mild sedation-sleeping comfortably

2 Moderate sedation-Deep sleep but arousable

3 Severe sedation-Deep 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 24 h.

Postoperative assessment was carried out at hourly interval until first analgesic dose followed by 6, 12, 24, 48 h, and 7th day 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 pain-free period and severity of pain at rest and measured using a Rupee scale.[13]

00 paisa - No pain

25 paisa - Mild pain

50 paisa - Moderate pain

75 paisa - Severe pain

100 paisa - Worst 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 1.5 mg/kg if no satisfactory pain relief, additional analgesia was provided with IV tramadol 1 mg/kg given on demand. Injection pentazocine 30 mg and promethazine 25 mg IM was given at bedtime. IV metoclopramide 10 mg and ondansetron 4 mg 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 60 min in the mean duration of analgesia, assuming a standard deviation (SD) of 62 min based on pilot study, a power of 90% and a significance level of 5%. We included 25 patients 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 Chi-square 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 one-way analyses of variance followed by Tukey–Krame multiple comparisons test or Kruskal–Wallis test with Dunn's multiple comparisons test as appropriate. Categorical data are expressed as number (percentage) and analyzed using the Chi-square test. P <0.05 was considered statistically significant.

RESULTS

A total of 88 patients was screened for the study. Eighty subjects satisfying the inclusion criteria were enrolled in the study. In three patients, surgery was postponed after enrollment hence not included in the study. One case each from Group C and Group M were excluded because GA was supplemented for unexpected prolonged duration of surgery. Data from 75 subjects (25 in each group) were analyzed. The three groups were comparable in demographic characters age, duration of surgery, and incision time [Table 1]. The surgical procedures performed were abdominal hysterectomy, exploratory laparotomy, and abdominal sling operation. Table 2 depicts the characteristics of SA. The onset time of sensory block to L1 level and motor block to Bromage score 1 was comparable in all the three groups. All patients attained a block height up to T6 dermatome. There was no significant difference in time required to achieve maximum cephalad spread of sensory level. There was no significant difference in duration of sensory and motor block.

Table 1

Demographic characteristics in study groups

Table 2

Characteristics of spinal anesthesia in study groups

The analgesia characteristics are described in Table 3. The mean duration of analgesia was significantly longer in Group N (308.76 [127.40] min or 5.1 h) followed by Group M (252.2 [86.76] min or 4.2 h) and Group C (229.52 [59.16] min or 3.8 h) (P = 0.0134). The Dunn's multiple comparison reveal difference between Group N and Group C statistically significant (P < 0.05). The diclofenac requirement was comparable in all the three groups (P = 0.1143). Additional analgesia with injection tramadol was required in 10 (40%) patients in Group N, 16 (64%) patients in Group M as against 23 (92%) patients in Group C (P = 0.001). The mean tramadol requirement was the lowest in Group N (20[25] mg) followed by Group M (32 [24.49] mg) and Group C (48 [22.73] mg). The difference between Group N and Group C was statistically significant (P < 0.001). The cumulative analgesic requirement in 24 h (number of doses) was significantly less in Group N 3.48(0.58) followed by Group M 3.64(0.75) compared to Group C 4.2(0.86) (P = 0.00232). The intergroup comparison shows the difference between Group N and Group C statistically significant (P < 0.01). Figure 1 shows postoperative pain score at rest expressed as mean (SD) in study groups. The pain score at 2 h was comparable among all the three groups. At 4 h, pain score in Group N 37 (27.11) and Group M 51 (21.79) was significantly lower compared to control group 61 (32.33) (P = 0.0132). The difference between Group N and Group C was statistically significant (P < 0.05). However, at 6 h and 12 h, pain score in Group M was significantly lower than in the control group (P < 0.05), Group N and Group C were comparable. At 24 h, pain score was comparable among all the three groups (P = 0.1942). Group N and Group M were comparable at 2, 4, 6, 12, and 24 h.

Table 3

Analgesia characteristics in study groups

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. **Intergroup comparison -Group M and Group C (P < 0.05) at 6 and 12 h. P value not significant at 2 and 24 h. P value not significant between Group N and Group M at 2, 4, 6, 12, and 24 h

The baseline hemodynamic variables were comparable among all the three groups [Table 4]. Hypotension was observed in 12 (48%) patients in Group N and 16(64%) patients in Group M compared to 21(84%) patients in Group C (P = 0.0276). The lowest MAP and time for lowest MAP after IT drug injection was comparable among the three groups. The average vasopressor requirement (mg mephentermine) was significantly less in Group N (5.5 mg) when compared to Group M (7.2 mg) and Group C (10.5 mg) (P = 0.045). The difference between Group N and Group C was statistically significant (P < 0.05), Group M and Group N were comparable. The degree of hypotension was 34% in Group C, 30% in Group M and 29% in Group N. Similarly, baseline PR, lowest PR, and time of lowest PR were comparable in all three groups. The incidence of bradycardia was the highest in Group C (44%) compared to 24% in Group N and 12% in Group M (P = 0.0354). On an average, 0.216 (0.252) mg atropine was required in Group C compared to 0.144 (0.24) mg in Group N and 0.048 (0.11) mg in Group M (P = 0.0342). After intergroup comparison difference between Group M and Group C was statistically significant (P < 0.05) whereas Group N and Group C, as well as Group M and Group N, were comparable. The degree of bradycardia was 25% in Group C, 16% in Group M and 18% in Group N.

Table 4

Hemodynamic changes in study groups

Table 5 describes the incidence of adverse effects in study groups. Intraoperative sedation was observed in 56% patients in Group M compared to 20% patients in Group N and 8% patients in Group C (P = 0.0004). The difference in peak sedation score was statistically significant between Group M and Group C (P < 0.001) as well as Group M and Group N (P < 0.05) whereas Group N and Group C were comparable. The incidence of PONV was significantly higher in Group C (56%) compared to 40% each in Group N and Group M (P = 0.0074). The mean antiemetic use was comparable among three Groups C (P = 0.083). Occasional tingling was noted in 3 (12%) patients in Group C and 1 (4%) each in study groups (P = 0.4293). The three groups were comparable with respect to other side effects namely vomiting during surgery, pain on traction, desaturation, shivering, other neurological symptoms, headache, etc.

Table 5

Incidence of adverse effects in study groups

DISCUSSION

Effective treatment of pain represents an important component of postoperative recovery. It serves to blunt autonomic, somatic, and endocrine reflexes with a resultant potential decrease in perioperative morbidity.[14] Despite advances in treatment of postoperative pain, many patients still suffer from pain after surgery, probably due to difficulties in balancing postoperative analgesia with acceptable side effects. In this prospective randomized controlled trial, evidence was provided that patients who received intrathecal neostigmine 25 μg or MgSO4 50 mg with spinal bupivacaine had reduced postoperative pain score and analgesic requirement after major gynecological surgery. Though our main aim was to compare 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.[15161718] 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.[12319] Intrathecal dose of neostigmine 6.25–12.5 μg did not affect SA, 6.25–25 μg improved SB whereas 50–150 μg enhanced onset of SB and prolonged duration of MB.[51820] Difference in pH, baricity of the solution and dose of the drug might have contributed to this variable response.[13]

Our findings of analgesia characteristics are in accordance with the pharmacokinetic profile of neostigmine and MgSO4.[21222324] 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 (5.1 h) 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 24 h after surgery. It was lowest in the neostigmine group than MgSO4 and control groups (P = 0.00232). The analgesic consumption was not significantly reduced with MgSO4. Though lower abdominal surgery is a highly painful procedure, we did not use strong opioid as the first analgesic because neostigmine and MgSO4 both are reported to produce central sedation.[162325] Furthermore, mild sedation was observed in our pilot study. To prevent excessive sedation, a milder form of analgesic was chosen. The Rupee scale is a simple and less time consuming technique for assessment of pain and requirement of 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 4 h whereas MgSO4 group had the lowest pain score at 6 h and 12 h (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.[1719]

The postoperative analgesia of intrathecal neostigmine, a cholinesterase inhibitor was first reported by Hood et al. 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.[5151820] The concentration of acetylcholine in CSF increases with painful stimulus and remains at a plateau for 4–6 h.[10212223] The degree of analgesia depends upon the amount of tonic release of acetylcholine in CNS.[1626] It is likely that CSF neostigmine concentration even after lowest dose was adequate to significantly inhibit cholinesterase in CSF.[61121] 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 alpha-2 adrenergic agonists stimulate release of acetylcholine in the spinal cord and might increase the apparent potency of neostigmine.[5101618] Intrathecal neostigmine causes clear antinociception in first two postoperative days but fails to do so 5 days 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 spinal-supraspinal-spinal loop and descending inhibitory system.[27] Lauretti et al. 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.[2627] Exclusive role of M1 muscarinic receptor subtype in spinal cholinergic analgesia is documented in sheep.[727] 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.[182627] 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 oxide-mediated analgesic action of intrathecal neostigmine may be involved as in diabetic neuropathic pain.[1829] The preliminary dose-response studies suggest that the analgesic effect was dose independent.[22] Smaller dose neostigmine ≥50 μg in volunteers, and ≥10 μg in surgical patients could enhance sensory anesthesia with few side effects when added to bupivacaine.[51618] A smaller dose may have the same efficacy with less adverse effects. Intrathecal neostigmine with 25–50 μg dose produces dose-independent reduction in postoperative rescue analgesic consumption.[510] Postoperative analgesia of about 24 h 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 anti-nociceptive 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 N-methyl-D-aspartate (NMDA) receptors. Activation of these receptors leads to calcium entry into the cell that initiates a series of central sensitization such as wind-up and long-term potentiation in the spinal cord. This NMDA signaling is important in determining the duration and intensity of postoperative pain.[33031] 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 cross-clamping.[253233] 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.[2171934] Further dose-response studies are required to determine whether large doses of intrathecal MgSO4 can produce better potentiation of analgesia and reduction in analgesic requirement.[117] 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 super-additive interaction of MgSO4 and ketamine is also reported.[33]

The hemodynamic effects of intrathecal neostigmine are due to activation of M2 muscarinic receptors in intermedio-lateral cell column.[2735] It directly stimulates preganglionic sympathetic neurons in the spinal cord and can counteract the hypotension of SA.[5101115] The rise in BP is evident within 5 min of administration in animals with small spinal cord but requires at least 30 min 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 group 48% 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 SA-induced hypotension. Previous studies have reported that neostigmine <100 μg does not counteract hypotension of SA in gynecological surgery.[1115] 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 SA-induced 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 dose-dependent, the smaller dose can produce analgesia without nausea.[15161820] 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 30–60 min after injection. To minimize the cephalad spread, injection of neostigmine in hyperbaric solution and maintaining head up position is recommended.[11202123] 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 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 neostigmine-induced emesis.[1522] Mild to moderate sedation was reported in previous human studies with 50 mg 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 7 days follow-up 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.[16172336]

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 24 h compared to neostigmine. Combination of low-dose intrathecal alpha-2 adrenergic agonist or systemic opioids may result in better analgesia with fewer side effects.[56] 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 dose-response. 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 μg and MgSO4 50 mg as adjuvant to hyperbaric bupivacaine for SA does not affect characteristics of block. The postoperative analgesia of 25 μg neostigmine during early recovery was better than 50 mg MgSO4 and saline control with less consumption of rescue analgesic in first 24 h. MgSO4 reduces postoperative pain score to a significant degree up to 12 h after surgery. Neostigmine provides some protection against SA-induced 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.