European Journal of Cardiovascular Medicine

Spinal anaesthesia is a widely used regional anaesthetic technique, particularly for infraumbilical and lower limb surgeries. Its simplicity, rapid onset, and cost-effectiveness make it the preferred choice in many clinical settings, especially in resource-limited regions. However, one of the primary limitations of spinal anaesthesia is its relatively short duration of action when using local anaesthetics alone, necessitating early postoperative analgesic intervention.

To address this limitation, various adjuvants have been investigated to prolong sensory and motor blockade and enhance postoperative analgesia. Opioids such as fentanyl, morphine1, and nalbuphine2 have been commonly used as intrathecal adjuvants to improve the quality and duration of analgesia. Nalbuphine, a mixed κ-agonist and μ-antagonist opioid, has gained attention for its ability to provide effective analgesia while reducing the adverse effects typically associated with pure μ-opioid agonists, such as pruritus, respiratory depression, and sedation.

Several studies have explored the effectiveness of nalbuphine as an intrathecal adjuvant, demonstrating its potential to enhance the duration of analgesia with minimal side effects3. However, most research has focused on its combination with bupivacaine, and limited data exist regarding its efficacy when combined with levobupivacaine4, an S-enantiomer of bupivacaine known for its reduced cardiotoxicity5 and favourable safety profile.

This study aims to evaluate and compare the analgesic efficacy of intrathecal nalbuphine in combination with levobupivacaine versus levobupivacaine alone in patients undergoing infraumbilical and lower limb surgeries. The primary objective is to assess the duration of postoperative analgesia, while secondary objectives include evaluating sensory and motor block characteristics, intraoperative hemodynamic variations, and postoperative complications. By investigating these parameters, this study seeks to provide insights into optimizing spinal anaesthesia techniques for better patient outcomes.

This prospective, randomized, double-blind study was conducted at Vels Medical College and Hospital from November 2023 to June 2024 after obtaining approval from the institutional ethical committee. Written informed consent was obtained from all patients before enrollment.

Study Population

A total of 80 patients scheduled for elective infraumbilical surgeries under spinal anesthesia were recruited. The sample size was determined using a standard formula based on previous studies to ensure statistical significance while accounting for potential dropouts. Patients were randomly assigned to two groups using computer-generated randomization.

Inclusion Criteria

• Age between 18-65 years
• American Society of Anesthesiologists (ASA) physical status I and II
• Height between 150-170 cm
• Body Mass Index (BMI) < 30 kg/m²

Exclusion Criteria

• Known allergy or hypersensitivity to study drugs
• Patients with spinal deformities, peripheral neuropathies, or contraindications to neuraxial blockade (e.g., infection, coagulation disorders, raised intracranial pressure, uncontrolled hypertension)
• Pregnant patients
• Obese patients with BMI > 30 kg/m²

Pre-Anesthetic Examination and Preparation

All patients underwent a thorough pre-anesthetic evaluation, including medical history, systemic examination, and laboratory investigations. Patients were instructed to fast for at least six hours for solids and two hours for clear liquids before the procedure. The spinal anesthesia technique was explained in detail, and informed consent was obtained.

On the day of surgery, baseline vital parameters, including heart rate (HR), blood pressure (BP), respiratory rate (RR), and oxygen saturation (SpO₂), were recorded. A 20-gauge intravenous (IV) cannula was secured in the dorsum of the hand, and patients were preloaded with 10 ml/kg Ringer’s lactate over 30 minutes before the spinal block.

Study Drug Preparation and Blinding

The study drugs were prepared by an independent anesthesiologist who was not involved in patient management. Nalbuphine (10 mg/ml) was diluted with normal saline to achieve a concentration of 1 mg/ml. A total volume of 3.5 ml was prepared for each patient as follows:

• Group N (n=40): 3 ml of 0.5% isobaric levobupivacaine + 0.5 mg nalbuphine (0.5 ml)
• Group C (n=40): 3 ml of 0.5% isobaric levobupivacaine + 0.5 ml normal saline

The anesthesiologist administering the spinal anesthesia and the patients were blinded to the group allocation.

Procedure

Under strict aseptic precautions, subarachnoid block (SAB) was performed in the L3/L4 or L4/L5 intervertebral space using a 25-gauge Quincke spinal needle with the patient in the lateral position. After free flow of cerebrospinal fluid (CSF) was confirmed, the study drug was injected slowly over 10 seconds. Patients were immediately placed in the supine position.

Intraoperative fluid replacement was managed as per blood loss and hemodynamic parameters. Hypotension (SBP < 90 mmHg or >30% decrease from baseline) was treated with IV crystalloids and incremental doses of IV mephentermine (6 mg). Bradycardia (HR < 60 bpm) was treated with IV atropine (0.6 mg). Supplemental oxygen (6 L/min via face mask) was provided in case of respiratory depression.

Monitoring And Data Collection

Hemodynamic parameters (HR, SBP, DBP, RR, SpO₂) were recorded at baseline, 5, 10, 20, 30 minutes, and then at 30-minute intervals up to 120 minutes post-SAB.

The following sensory and motor block characteristics were evaluated:

• Sensory Block: Assessed using a pinprick method at L1, T12, T10, T8, and T6 dermatomes.
• Motor Block: Assessed using the Modified Bromage Scale (0–3) at 5-minute intervals post-SAB.
• Postoperative Analgesia: Assessed using the Visual Analog Scale (VAS). A VAS score ≥4 triggered rescue analgesia with IM diclofenac 75 mg.

Adverse effects such as nausea, vomiting, pruritus, respiratory depression, sedation (Ramsay Sedation Scale), and shivering were recorded and managed accordingly.

The present study was conducted in  Vels Medical College and Hospital from the year January 2023- June 2024 to compare the efficacy of intrathecal nalbuphine as an adjuvant toisobaric 0.5% levobupivacaine compared to intrathecal isobaric 0.5% levobupivacaine alone. 80 patients were divided in to two groups.

Group N(n=40)- Received 3 ml of 0.5 % isobaric levobupivacaine with 0.5mg of nalbuphine.

Group C(n=40)- Received 3 ml of 0.5% isobaric levobupivacaine with 0.5ml of normal saline.

Graph 1: Mean Age Groups                                                           

The mean age of the patients in Group N was 38.37 ± 11.24 years and in Group C was 39.17 ± 10.60 years. The differences in the mean age between the two groups were statistically insignificant, p = 0.884.

Table 1: Sex distribution by groups

In group N there were 12 males and 18 females. In group C there were 19 males and 21 females. The mean weight, height in either groups were also identical. It was statistically insignificant with p value of 0.178.

GRAPH 2:  ASA Grading by groups

There were 13 patients of ASA Grade 1 in Nalbuphine group and 13 patients of ASA Grade 1 in Levobupivacaine group. 27 patients were present in each group in ASA Grade 2.

ONSET OF SENSORY BLOCK-

Table 2:  Time for Onset Of Sensory Block

 Graph 3: Onset Of Sensory Block

The mean time for onset of sensory block in Group N was 240.50 ±15.51 seconds and 329.50±20.37 seconds in Group C. Hence there was earlier onset of sensory block in Group N which was significant (p value <0.001) statistically significant.

ONSET OF MOTOR BLOCK-

Table 3:  Time for Onset Of Motor Block

Graph 4: Time for Onset Of Motor Block

The mean time for onset of motor block in Group S was 281±20.48 seconds and 351±21.45 seconds in Group C. The difference between the two groups statistically significant. (p <0.001)

TIME FOR MAXIMUM HEIGHT OF SENSORY BLOCK AT T6-

Table 4:  Time for Maximum Height of Sensory Block at T6

Graph 5:  Time for Maximum Height Of Sensory Block at T6

The mean time for maximum onset of sensory blockade at T6 dermatome level was 505.75±18.10 seconds in Group N and 565.75±18.38 seconds in Group C. It was statistically significant in Group N with p value <0.001.

Two Segment Regression Time-

Table 6:  Two Segment Regression Time

Graph 6:  Two Segment Regression Time

The mean time for 2 segment regression in Group N was 71.12±8.65 minutes and 67.87±8.15 minutes in Group C. The difference between the two groups was not statistically significant. (p = 0.079)

DURATION OF MOTOR BLOCK-

Table 7:  Duration Of Motor Block

Graph 7:  Duration Of Motor Block

mean time for duration of motor block was 202.62±13.15 minutes in Group N and 165.50±9.32 minutes in Group C. Hence the total duration of motor block was statistically significant (p<0.001).

DURATION OF POSTOPERATIVE ANALGESIA-                                                          

Table 8: Duration Of Postoperative Analgesia

Graph 8:  Duration Of Postoperative Analgesia

The mean time for duration of postoperative analgesia in Group N was 263.50±12.71 minutes and 198.50±12.31 minutes in Group C. The difference between the two groups was statistically significant. (p <0.01)

HAEMODYNAMIC PARAMETERS: -

Graph 9: Mean Heart Rate (in beats per minute) – Baseline and throughout surgery in the two study groups

The trend of mean heart rate (HR) (in beats per minute) – baseline and during the surgery in the two study groups was similar throughout with P = 0.55 and hence, the differences being statistically insignificant.

Graph 10: Mean Systolic Blood Pressure (mmHg) – Baseline and throughout surgery in the two study groups

The trend of mean Systolic Blood Pressure (SBP) (mmHg) – baseline and during the surgery in the two study groups was similar throughout and hence, the differences being statistically insignificant.

Graph 10: Mean Diastolic Blood Pressure (mmHg) – Baseline and throughout surgery in the two study groups

The trend of mean Diastolic Blood Pressure (SBP) (mmHg) – baseline and during the surgery in the two study groups was similar throughout and hence, the differences being statistically insignificant.

Respiratory Rate-

Graph 11- Respiratory Rate

The mean respiratory rate between two groups were similar throughout being statistically insignificant.

Graph 12- Oxygen Saturation

The mean oxygen saturation between the two groups were similar throughout being statistically insignificant.

Neuraxial anaesthetic techniques are preferred for infra umbilical surgeries due to their rapid onset of surgical anesthesia with complete muscular relaxation. It is also beneficial in patients of anticipated difficult airway or who are suffering from comorbid conditions. These advantages are sometimes offset by a relatively short duration of action of local anesthetics.

The duration of subarachnoid block can be improved by using intrathecal adjuvants in the form of opioid analgesics or non-opioid drugs, which act synergistically with local anesthetic agents to intensifying the sensory block without increasing the level of sympathetic block as they act independently via different mechanism. Several clinical studies have shown that opioids and α2- adrenergic agonists are able to do so.

Nalbuphine is a semi-synthetic opioid agonist-antagonist analgesic of the phenanthrene series. It is an agonist-antagonist opioid that is structurally related to oxymorphone and naloxone. It  binds to µ-receptors, as well as to κ- and δ-receptors. It acts as an antagonist at the µ-receptor and as an agonist at the κ-receptor. Activation of supraspinal and spinal κ-receptors results in limited analgesia, respiratory depression and sedation. Nalbuphine, like other agonist-antagonist compounds interferes with the analgesia produced by pure µ-agonists.

Studies with nalbuphine as an adjuvant to hyperbaric bupivacaine showed no reports of neurotoxicity, even the studies performed on pregnant women showed no neurotoxicity.

Eighty patients admitted in Vels medical college and hospital in year 2023  January-2024 June with ASA physical status I and II, aged between 18-60 years, scheduled for elective infra umbilical and lower limb surgeries under SAB, were included in the study. Patients were randomly allocated to one of two groups (n=40). Group  N (n=40)receives 3 ml of 0.5 % isobaric levobupivacaine with 0.5mg of nalbuphine. Group C (n=40) receives 3 ml of 0.5% isobaric levobupivacaine with 0.5ml of normal saline.

Various authors have used intrathecal Nalbuphine in doses from 0.4 mg to 2 mg. Mukherjee et al⁶ have compared 3 doses of 0.2,0.4 and 0.8 mg Nalbuphine along with 12.5 mg of 0.5% hyperbaric bupivacaine. The authors concluded that patients who received 0.4 mg and 0.8 mg of nalbuphine had a longer duration of analgesia but the patients who received 0.4 mg of nalbuphine had least incidence of side effects. Tiwari et al ⁷ have compared 0.2 mg and 0.4 mg of Nalbuphine along with bupivacaine for intrathecal anaesthesia and found out that 0.4 mg of Nalbuphine prolonged the duration of analgesia

Nalbuphine is used as an additive for intrathecal anaesthesia in doses from 200 to 1600microgram in several clinical settings. However for the ease of dilution we have selected 0.5 mg of Nalbuphine as intrathecal adjuvant which is near to 0.4mg which is used in various studies.

DEMOGRAPHIC PROFILE ACROSS THE GROUP

In our study, we selected patients in the age between 18-60 years. In Nalbuphine group there were 12 males and 18 females. In Clonidine group there were 19 males and 21 females. The mean weight, height in either groups were also identical. The type of surgeries performed was also identical in both the groups.

ONSET OF SENSORY BLOCK:

The first characteristic studied was the duration of onset of sensory block.  Time in seconds was noted.

In present study, the mean time for onset of sensory block in Nalbuphine group was 240.50±15.51 seconds and 329.50±20.37 seconds in control group. There was statistical significant difference with regard to onset of sensory block between the groups (p<0.001).

Osama M et al ⁸ different low doses of intrathecal levobupivacaine (5mg in one group1 and 7.5mg in group 2) with the same dose of 1mg nalbuphine in both group1 and 2 for TURP surgeries. Patients in group 1 who received 5 mg of levobupivacaine and 1mg nalbuphine had onset of sensory block at 6.73±0.83 seconds and patients in group 2 who received 7.5mg levobupivacaine and 1mg nalbuphine had onset of sensory block at 5.63±0.62 seconds. The earlier onset of sensory block in group 2 couldn’t be attributed to the ability of nalbuphine as the dose of levobupivacaine is higher in group 2. However nalbuphine as an adjuvant to spinal anaesthesia shortens the onset of sensory blockade (pooja bhosle).

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ONSET OF MOTOR BLOCK 

In our study mean time for onset of motor block in Nalbuphine group was 281±20.48 seconds and in control group was 354±21.45 seconds which is statistically significant (p<0.001).

Sandeep S et al compared the efficacy of intrathecal levobupivacaine with buterphenol or nalbuphine and levobupivacaine alone for infraumbilical surgeries. They divided patients into three groups. Group L received  intrathecal 0.5% isobaric levobupivacaine 2.8ml with 0.4 ml of normal saline .Group LB received intrathecal 0.5% isobaric levobupivacaine 2.8ml with butorphanol 25microgram. Group LN received intrathecal 0.5% isobaric levobupivacaine 2.8ml with nalbuphine 400microgram. The time of onset of motor block in LN group was 5.87±0.73min and 15.33±1.85 min in levobupivacaine alone group. The duration of onset of motor blockade was later when compared to our study(281±20.48 seconds). This is because they have considered onset of motor blockade only when Bromage score becomes 3 whereas we have considered onset of motor blockade when Bromage scale reaches 1 after injection of the drug.4

 TIME FOR TWO SEGMENT REGRESSION OF SENSORY BLOCKADE

In our study, the time for two segment regression was 71.12±8.65 min in Nalbuphine group when compared to control group 67.87±8.15 minutes. The difference was not statistically significant.

Kajal A Bhatt in a study compared the effects of 15mg levobupivacaine and 15 mg ropivacaine intrathecally for lower limb surgeries. The two segment  regression time was 60±7.15 minutes in the levobupivacaine group which was in consonance to our study.

Osama M et al ⁸ who studied the different doses of levobupivacaine (5mg in group1 and 7.5 mg in group 2) with 1mg nalbuphine in both group1 and group 2 for TURP surgeries had two segment regression times of 58.78±5.33 in 5mg levobupivacaine group and 65±5.40 in 7.5 mg levobupivacaine studies. The two segment regression time in this study was slightly shorter than our study because in this study a lower dose of levobupivacaine was used when compared to our study. 

DURATION OF MOTOR BLOCK:

In our study, the mean of total duration of motor block in Nalbuphine group was 202.62±13.15 min compared to 165.50±9.32 min in control group. This is statistically highly significant (p <0.001).

Kataria AP⁹ et al in a study compared the effects of levobupivacaine with dexmeditomedine (Group LD) and levobupivacaine alone (Group L) for infraumblical surgeries.  Group L patients received 3 ml (15 mg) of 0.5% isobaric levobupivacaine + 0.3 ml normal saline while Group LD patients received 3 ml (15 mg) of 0.5% isobaric levobupivacaine + 0.3 ml (3 μg) Dexmedetomidine. The patients in group L had duration of motor block of 150.83±9.17 minutes which was similar to the results of our study.

Sandeep S et al who compared the effects of levobupicaine alone and with either buterphenol and nalbuphine found out that the duration of motor block in nalbuphine group was 189.19±9.45min which was in concordance to our study.

POSTOPERATIVE ANALGESIA

In our study total duration of postoperative analgesia was 263.50±12.71 mins in Nalbuphine group and 198.50±12.31 min in control group. The difference is highly significant (p<0.001).

The study done by Osama et al ⁸ in which different doses of low dose levobupivacaine (5mg in group1 and 7.5 mg in group2) with 1mg nalbuphine in both groups was used in TURP surgeries had a duration of analgesia of 170.78±23.76 minutes in 5mg levobupivacaine group (group1)  and 230±56.88 minutes in 7.5mg levobupivacaine group (group2). The duration of postoperative analgesia was quite similar to our study even though they have used lower dose of levobupivacaine than our study, however they have used a higher dose of nalbuphine 1mg when compared to 0.5 mg nalbuphine used in our study.

There are limited literatures with the use of Levobupivacaine with nalbuphine and levobupivacaine alone as a control intrathecally. Majority of the studies were with bupivacaine with nalbuphine as an adjuvant intrathecally. Hence we intended to do this study and found out that nalbuphine provided a good postoperative analgesia without any major systemic adverse effects.

HEMODYNAMICS - - HEART RATE & BLOOD PRESSURE

Monitoring of heart rate, blood pressure, SpO₂ and respiratory rate were done to assess the hemodynamic stability and respiratory effects . In our study it was observed that mean heart rate when compared between patients in Group N and Group C at 0,5,10,20,30,60 minutes after the injection showed no significant difference. Mean arterial pressure was lower during the first 10-20 minutes after spinal injection in both groups.

The haemodynamic parameters like HR, Blood Pressure, SpO2 and respiratory rate were comparable in both the groups without any statistical significance between the two groups. This is in agreement with the study by Girgin et al showed no significance related to hypotension or bradycardia in patients who received 5mg levobupivacaine and 7.5 mg levobupivacaine. A study by Mostafa et al ¹⁰ with intrathecal nalbuphine showed no significant hypotension, bradycardia or respiratory depression.

ADVERSE EFFECTS

In our study two patients in Group N had sedation but were arousable according to Ramsey sedation score. No patients in both the groups had pruritis, vomiting, constipation or urinary retention.

Limitations and Future Directions

Despite its promising findings, this study has limitations. The sample size, although adequate for statistical significance, was relatively small. Additionally, long-term follow-up was not conducted to assess chronic pain outcomes. Future studies should explore nalbuphine’s effects in different surgical settings and in patients with varying ASA classifications to further validate its efficacy.

We conclude that nalbuphine as an adjuvant to isobaric levobupivacaine 0.5% for spinal anaesthesia shortens the onset of sensory and motor block, prolongs the duration of motor block, provides effective postoperative analgesia with comparable haemodynamic and without any significant adverse effects. Hence nalbuphine can be considered as a suitable adjuvant with levobupivacaine for subarachnoid block for infra-umbilical surgeries

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