Spinal anesthesia is widely preferred for major lower abdominal, gynecological, perineal, and lower limb surgeries due to its rapid onset, safety profile, and ability to provide adequate surgical anaesthesia with minimal systemic effects [1]. Hyperbaric bupivacaine remains one of the most commonly used local anesthetics for spinal blocks because of its potency and duration of sensory and motor blockade. Because of its limited duration of action, it tends to have a short postoperative analgesic efficacy, resulting in early development of pain postoperatively and increased opioid use [2, 3]. This has led to a search for adjuvants that have the ability to extend the analgesia duration without causing serious side effects. Intrathecal neostigmine has become the focus of attention among various adjuvants, whose mechanism is unique, that is, it inhibits acetylcholinesterase but promotes acetylcholine action in the spinal cord and thus becomes more useful in nociceptive modulation [4]. In comparison to traditional adjuvants, including opioids or clonidine, neostigmine is cholinergic, and it can offer sustained analgesia without respiratory depression or profound sedation [5]. It was demonstrated that intrathecal neostigmine may be useful in augmenting postoperative analgesia when applied concomitantly with local anesthetic agents, but optimum dosage and side effects are still under investigation [6]. The need for effective postoperative pain control is well recognised. Poorly managed pain can delay mobilization, prolong hospital stay, impair respiratory function, and increase the risk of chronic pain syndromes [7].  Thus, the extension of analgesia is essential in regional anesthesia, which is important for enhancing patient recovery and satisfaction. Despite providing satisfactory anesthesia, hyperbaric bupivacaine has a limited duration and requires the use of rescue analgesics, particularly after major abdominal or orthopedic surgeries [3, 8]. Therefore, bupivacaine, along with adjuvants like neostigmine, is a reliable combination. According to previous research, intrathecal neostigmine, with local anesthetics, increases the analgesia period following surgery, but can be linked to dose-related nausea and vomiting [9, 10]. Multimodal analgesia is the latest anesthetic practice strategy to reduce opioid dependence and enhance the postoperative outcomes [11]. Intrathecal adjuvants like neostigmine can be used in these circumstances, although there is limited evidence on its use along with 0.6% hyperbaric bupivacaine, especially in major lower abdominal, perineal, and lower limb surgeries in the Indian population.  Therefore, this study aims to evaluate the efficacy, safety, and analgesic profile of intrathecal neostigmine combined with 0.6% hyperbaric bupivacaine, compared to hyperbaric bupivacaine alone, for postoperative analgesia in major lower abdominal, gynecological, perineal, and lower limb surgeries. The findings of this study may contribute to a better understanding of the role of neostigmine as a promising intrathecal adjuvant and help optimize postoperative pain management strategies.

The prospective observational study was carried out in the Department of Anesthesiology, in patients who were electively posted for major lower abdominal, gynecological, perineal, and lower limb surgeries under spinal anaesthesia at Mahatma Gandhi Memorial Hospital, Warangal, and Government Maternity Hospital, Hanumakonda, Telangana. The duration of the study was from April 2023 to March 2025. Institutional Ethical approval was obtained for the study. Written consent was obtained from all the participants of the study after explaining the nature of the study in the vernacular language.

Inclusion Criteria

1. Patients aged between 20 and 60 years.
2. Patients of either gender.
3. Patients who come under ASA classifications 1 and 2.
4. Patients devoid of comorbidities
5. Patients are willing to give consent.
6. Patients willing to participate in the study.

Exclusion Criteria

1. Patients meeting the following criteria were excluded from the study.
2. Patient aged less than 18 years and more than 60 years.
3. Patients who come under ASA classification III and IV.
4. High-risk patients.
5. Patients with unstable medical conditions.
6. Patients with pre-existing neurological and spinal disorders.
7. Patients allergic to study drugs.
8. Patients on anticoagulants
9. Patients with coagulation disorders.
10. Patients are not willing to participate in the study.
11. Patients are not willing to give consent.

A total of n=60 cases fulfilling the inclusion and exclusion criteria were selected for the study. They were informed about the details of the disease process, options of treatment, outcome, possible effects, complications, and chances of recurrence in both procedures, and a written informed consent was obtained before enrolment. They were informed of their right to withdraw from the study at any stage if they wanted.

Preanesthetic evaluation:  During the pre-anesthetic checkup (PAC), all patients were briefed about the linear visual analogue scale (VAS), which was used for pain assessment, and they were shown a 10 cm scale for clarity.  The patients were randomly assigned to one of the two groups:

Group B: Patients receiving 0.5% hyperbaric bupivacaine (3 ml).

Group N: Patients receiving 50 mcg of preservative-free intrathecal neostigmine methylsulfate combined with 0.5% hyperbaric bupivacaine (3 ml).

Sensory and motor block were assessed intraoperatively every 30 minutes and every 2 hours for the first 8 hours. Pain was assessed intraoperatively every 30 minutes and postoperatively at 2-hour intervals for the first 8 hours. From 8 hours to 24 hours postoperatively, pain assessment occurred every 4 hours. These values were recorded and noted down in the master charts. All the data was documented and analyzed by subjecting it to statistical analysis.

Statistical Analysis: The collected data were entered into a Microsoft Excel Worksheet 2010, and the data were taken into IBM SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, N.Y., USA) software for calculations. The continuous variables were represented as mean, standard deviation, frequency, and percentages. The categorical variables were calculated by the square test for differences between two groups. Values of p (<0.05) were considered significant.

The baseline demographic characteristics of the cases included in the study are depicted in Table 1. A critical analysis of the table showed that there were no statistically significant differences between the two groups based on age, gender distribution, ASA status, or duration of surgeries. This shows that both group distributions were homogeneous for comparison without any influence of confounding factors. The majority of the cases in the study were from the age group 31 – 40 years, indicating that these groups were commonly involved in abdominal surgeries. Although the gender distribution in the groups showed a slight male preponderance, it could be because males are commonly involved in below-the-knee surgeries. Since the cohort has a high number of ASA grade I category patients, indicating they were generally healthy, for comparison. The duration of surgery was also similar in both groups. Overall, this table shows that groups were well distributed for comparative analysis.

The characteristics of sensory and motor blockade in the cohort are presented in Table 2. A critical analysis of the table showed that Group N using bupivacaine alone had significantly faster onset of sensory and motor blockade as compared to Group B, as given by p-values. It is also notable that the duration of sensory blockade in group N was considerably longer than that in group B, with the values being highly significant. This showed that the addition of neostigmine will lead to faster onset and increased duration of blockade. In addition, the duration of motor blockade was also increased in the group N. The two-dermatome regression time was slower in the neostigmine group. These findings showed that intrathecal neostigmine enhances the onset of anesthesia and duration of blockade.

The characteristics of postoperative analgesia in both groups are given in Table 3. A critical analysis of the table showed that overall analgesic efficacy was significantly better in the neostigmine group N. The time for the first rescue analgesic was almost double the time required for the plain bupivacaine group (7.47 ± 0.83 hours versus 3.31 ± 0.11 hours), and significant p-values. The duration of absolute analgesia was also significantly prolonged in group N. It was noted that 43% of cases of group N required rescue analgesics as compared to 70% of group B, indicating better pain control in the neostigmine group.

The assessment of postoperative pain scores by the visual analogue scale is presented in Table 4. Analysis of the table showed that VAS scores were generally lower in group N as compared to group B. In group B, the scores were 4.21 ± 0.93 at 6 hours, which required the use of rescue analgesia. At the end of 24 hours, the overall pain scores were lower in group N, showing better analgesic control.

The parameters indicating hemodynamic parameters such as heart rate and systolic blood pressure are given in Table 5. The overall analysis showed that parameters remained comparable in both groups during preoperative and intraoperative periods, with no statistically significant differences. This indicates that neostigmine did not adversely affect cardiovascular stability, establishing a favorable safety profile.

The results analysis of this study confirms that inclusion of intrathecal neostigmine to 0.6% hyperbaric bupivacaine significantly improves the analgesic efficacy as seen by faster onset of blockade, prolonged sensory and motor block duration, and postoperative analgesic requirements. Thus, neostigmine emerges as an effective adjuvant for postoperative pain management in below-knee surgeries.

The present study was conducted to evaluate the efficacy of neostigmine when added to 0.6% intrathecal bupivacaine in comparison to plain bupivacaine for postoperative analgesia in lower abdominal, gynecologic, perineal, and lower limb surgeries.  The demographic profile of the cohort showed that both groups were comparable based on demographic variables, ASA grades, and duration of surgery; therefore, the comparison of the results excluded any of the confounding factors. The results of this study showed that Group N (neostigmine + bupivacaine) demonstrated faster onset of sensory and motor blockade (Table 2), indicating the potential of local anaesthetic action. Our findings are in concordance with previous reports, which showed that the addition of neostigmine augments the actions of local anesthetics by inhibiting acetylcholinesterase and increasing acetylcholine levels at the spinal level. This leads to increased activation of muscarinic receptors involved in antinociceptive pathways [12, 13]. Chhabra et al. [14] in a similar study showed that there was a prolonged duration of sensory and motor block because of synergistic effects between neostigmine and bupivacaine. Our study supported these findings.

The results of our study showed a markedly superior postoperative analgesia in Group N, as seen by increased duration of time when the use of the first rescue analgesic begins. We also found that the total number of patients receiving rescue analgesics in group N was significantly lower compared to the plain bupivacaine group B. Similar findings were reported in the literature by previous studies by Lauretti et al. [15] and Kung et al. [16]. The overall VAS scores remained significantly lower across the postoperative time intervals in group N, indicating its improved pain control. This could be because of previous studies, which have reported that neostigmine acts centrally on cholinergic pathways to promote analgesia, particularly by modulating nociceptors through spinal M1 and M2 activation [17].

The analysis of hemodynamic stability and cardiovascular parameters of both groups showed no significant cardiovascular complications or hemodynamic stability issues. This is interesting because previous reports have indicated that an increase in doses of intrathecal neostigmine can result in bradycardia and hypotension [18]. Nonetheless, a low-dose regimen (5µg) as employed in our study revealed a good safety profile, which supports the need to optimize the dosage. Although mild adverse events like nausea and vomiting were more commonly reported in Group N, they were manageable and did not require intervention. This is consistent with findings that neostigmine can cause parasympathetic system stimulation, resulting in gastrointestinal side effects [19]. Notably, there were no registered respiratory depressions or severe complications in any patient, which further supports the idea that neostigmine is a safe adjuvant. Generally, the results of this study strongly favor the application of the intrathecal neostigmine as an efficient adjuvant to the hyperbaric bupivacaine, especially in surgery that involves the use of long postoperative analgesia. Its promising contribution to multimodal pain management strategies is by improved quality and duration of analgesia, lesser opioid dependence, and the hemodynamic profile remains stable at 5µg dose, showing its usefulness. Further studies could be done with dose titration, adjuvant combination, and follow-up to determine functional recovery and patient satisfaction.

The present study, within its own limitations, showed that intrathecal neostigmine (5µg) to 0.6% hyperbaric bupivacaine significantly enhances analgesic efficacy during the postoperative period as compared to bupivacaine alone. Neostigmine accelerated the onset of sensory and motor block, prolonged the duration of blockade, reduced pain scores, and delayed the need for rescue analgesics. Although mild gastrointestinal side effects were more common, no major complications were observed, indicating a favorable safety profile. These findings suggest that neostigmine is an effective and safe adjuvant for enhancing spinal anesthesia and improving postoperative recovery. Its integration into multimodal analgesic protocols may reduce opioid dependence and improve patient comfort.

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