European Journal of Cardiovascular Medicine

Spinal anaesthesia is widely used for lower limb surgeries due to its effectiveness in providing adequate sensory and motor blockade while maintaining hemodynamic stability. Bupivacaine, a long-acting amide-type local anaesthetic, remains a popular choice for intrathecal administration due to its prolonged duration of action and minimal neurotoxicity [1]. However, despite its advantages, a major drawback of bupivacaine is its limited postoperative analgesic effect, necessitating the use of adjuvants to prolong analgesia and improve patient comfort [2].

Nalbuphine, a synthetic opioid analgesic, has emerged as a promising adjuvant to bupivacaine in spinal anaesthesia. It is a mixed kappa agonist and mu antagonist with potent analgesic properties and minimal risk of respiratory depression, making it an attractive option for intrathecal administration [3,4]. Several studies have reported that intrathecal nalbuphine enhances the duration of sensory and motor blockade, extends postoperative analgesia, and reduces opioid-related side effects compared to traditional opioids such as morphine and fentanyl [5,6].

Pain management in the postoperative period is crucial in ensuring patient satisfaction and reducing morbidity. The Visual Analogue Scale (VAS) is a well-established tool for assessing pain intensity in clinical research and has been utilized in various studies evaluating intrathecal adjuvants [7]. Additionally, postoperative analgesia quality directly impacts hospital stay duration and overall patient recovery [8].

The efficacy and safety of nalbuphine as an intrathecal adjuvant have been explored in various clinical trials, but findings have been inconsistent. Some studies have demonstrated that nalbuphine significantly prolongs sensory and motor block duration without causing significant hemodynamic disturbances [9], while others have raised concerns about its hemodynamic effects and potential side effects such as pruritus and nausea [10]. Hence, further investigation is warranted to establish its role in spinal anaesthesia.

This study aims to evaluate the efficacy and safety of intrathecal nalbuphine as an adjuvant to bupivacaine in lower limb surgeries. Specifically, it compares the duration of sensory and motor blockade, hemodynamic parameters, duration of postoperative analgesia, VAS scores, and incidence of side effects between two groups receiving bupivacaine with or without nalbuphine. The aim of the study was to evaluate the efficacy and safety of intrathecal nalbuphine as an adjuvant to bupivacaine in spinal anaesthesia.Theobjectives are to compare the onset and duration of sensory and motor blockade, hemodynamic parameters, two segment regression time, time of rescue analgesia, post operativeVAS score and side effects between two groups.

After approval from institutional ethical committee, Rajkot (Outward No. PDUMCR/IEC/4509/2020 dated 20/3/2020) written informed consent was obtained from all the patients. This prospective, randomized, double blind study was conducted in department of orthopaedics, PDU Medical College, Rajkot during the period from March 2020 to November 2021.Both groups consist of genders belonging to ASA I to IVposted for lower limb surgeries. Infection at the site, bleeding disorder, allergic reaction to any anaesthetic drug, patients on tranquilizers, hypnotics, sedatives and other psychotropic drugs are excluded from study. Patients wererandomly allocated into two groups of 30 patients each. In Group BN (study group) patients were given spinal anaesthesia with Inj. Bupivacaine heavy 0.5% + Inj. Nalbuphine 2mg (0.2ml) and in Group B (control group) patients were given spinal anaesthesia with Inj. Bupivacaine heavy 0.5% + Inj. Normal Saline 0.2ml. Dose of Bupivacaine was according to height of the patient:- 2.8 ml for Height < 150 cm - 3 ml for Height 150-160 cm- 3.2 ml for Height > 160 cm.

For randomization, computerized randomization method was used, where a computer-generated random sequence was concealed in consecutively numbered sealed envelopes, which were opened on the morning of the surgery. This was a double-blinded study where the study medication was prepared by a person not involved in the study to ensure blinding of the anaesthetist.Preoperative anaesthetic check-ups, including detailed history and investigations were conducted and fitness was determined under ASA I-IV. Patients were explained the VAS score for pain assessment and all patients were kept nil per oral (NBM) for 6 hours.Data was collected using a structured, pre-prepared case proforma to enter patient details, detailed clinical history including presenting complaints, past history, family history and systemic examination.

Sub arachnoid block was given under strict aseptic precautions in sitting position preferably in L3-L4 interspinous space with 23G quinke’s spinal needle. Respective agents were injected according to the group.

Intra operatively haemodynamic parameters (pulse, BP, SPO2) were noted to compare between the groups and parameters were also collected as follows:- Time of onset of sensory block (from time of injection of drug till no pin prick felt in L1) and motor block (time of injection of drug till bromage grade 1), two segment regression of the block (time of injection of the drug to 2 segments regression from the peak sensory dermatome level achieved ), duration of sensory block(sensory level will be assessed by pin prick method) –time interval from onset of sensory block to regression of sensory level to L1 dermatome, duration of motor block (time interval from onset of motor block to regression of motor block to bromage grade 0).Modified Bromage scalewas mentioned below: [Modified bromage scale 0-no motor block with full flexion of knees and feet 1-just able to flex knees, full flexion of feet 2- unable to flex knees, but some flexion of feet possible. 3-unable to move legs/feet.]

Post operatively we have assessed two segment regression of block (time of injection of the drug to 2 segments regression from the peak sensory dermatome level achieved), Duration of post-operative analgesia(time of onset of sensory block to the first request of rescue analgesia by using VAS score), VAS (visual analogue scale) score at every 30mins for first 2 hours, every 60mins for next 6 hours and at 12 hours and 24 hours in recovery room. When VAS>3, rescue analgesia given with inj. diclofenac sodium.

Statistical Analysis

Results were expressed as mean ± standard deviation or number (%). The statistical analysis was conducted using the chi-square test for demographic data and an unpaired t-test for intergroup comparisons using the 2018 GraphPad Software. Results were considered significant if p-value ≤ 0.05 and highly significant if p < 0.01.Sample size was decided in consultation with the statistician and was based on initial pilot study observations, indicating that approximately 30 patients were included in each group in order to ensure a power of 0.80. Assuming a 5% drop out rate, the final sample size was set at 30 patients in each group, which would permit a type 1 alpha error =0.05, with a type 2 error of beta=0.2.

The demographic characteristics of patients in both groups, including age, gender distribution, ASA grading, and duration of surgery, were analyzed to ensure comparability. As shown in Table 1, there were no statistically significant differences between Group B and Group BN in terms of these baseline variables (p > 0.05). This confirms that the two groups were well-matched, minimizing potential confounding factors and ensuring a fair comparison of outcome.

Table 1: Demographic Characteristics

A-chi-square-test, P value <0.05 – statistically significant, M: F-male female, ASA-American society of anaesthesiologist

As illustrated in Table 2 and Figure 1, the onset of sensory and motor blockade was comparable between Group B and Group BN, with no statistically significant difference (p > 0.05). The duration of both sensory and motor blockadewas significantly prolonged in Group BN compared to Group B (p < 0.05), indicating an enhanced anaesthetic effect with nalbuphine. The time to first rescue analgesic requirement was significantly prolonged in Group BN (284.4 ± 31.33 min) compared to Group B (162.56 ± 8.12 min) (p < 0.0001), indicating enhanced analgesic duration with nalbuphine. Two segment regression time is prolonged in Group BN and statistically significant (p < 0.05). Postoperative analgesia was assessed based on the time to first rescue analgesia and postoperative pain scores using the Visual Analogue Scale (VAS). As shown in Figure 2 (VAS Score Graph), postoperative pain scores were significantly lower in Group BN at all time points, particularly in the early postoperative period (p < 0.0001)which shows that nalbuphine as an intrathecal adjuvant significantly improved postoperative analgesia and reduced pain intensity.

Table 2: Perioperative Parameters

Unpaired t-test, P value <0.05 – statistically significant, min- minute

Figure 1: Perioperative Parameters

The above bar graph shows various parameters between two groups. Here we show that onset of sensory and motor block mean values remains equal in both groups with no significant difference. Duration of sensory and motor block, two segment regression of block and time of 1^st rescue analgesia were significant between two groupsindicating an enhanced anaesthetic effect with nalbuphine.

Figure 2: Postoperative VAS Score

This line graph showsthe comparison of postoperative VAS score of group BN and group B which is non-significant until the first 1hour of arrival in the PACU (p>0.05).Statistical difference in post-operative VAS score between Group BN (0.30 + 0.53) and group B(1.1 + 0.54)appeared in the 1st hour postop (p<0.05) and continued throughout postoperative observation.

As shown in Figure 3 and 4 (Box Plot), hemodynamic parametersincluding pulse rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure, were recorded at multiple time points intraoperatively and postoperatively to assess the impact of nalbuphine on cardiovascular stability. In both groups demonstrated hemodynamic stability throughout the study, with no significant deviations in heart rate or blood pressure (p > 0.05). The variability in these parametersremained within the expected physiological range, further confirming the safety of nalbuphine in spinal anaesthesia.

Figure 3: Box Plot of Intraoperative Hemodynamic Variability in Group B and Group BN

The above box plot represents the distribution and variability of intraoperative Pulse Rate, Systolic Blood Pressure, Diastolic Blood Pressure, and Mean Blood Pressure in Group B and Group BN. The median values and interquartile ranges indicate that hemodynamic parameters remained stable in both groups, with no significant outliers or abnormal fluctuations. This further confirms that the addition of nalbuphine did not introduce hemodynamic instability.

Figure 4: Box Plot of Postoperative Hemodynamic Variability in Group B and Group BN

This box plot illustrates the distribution and variability of postoperative Pulse Rate, Systolic Blood Pressure, Diastolic Blood Pressure, and Mean Blood Pressure in Group B and Group BN over a 24-hour period. The median values and interquartile ranges indicate stable haemodynamics in both groups, with no significant outliers or unexpected fluctuations. These findings confirm that the addition of nalbuphine did not cause postoperative hemodynamic instability.

Table 3showsthat GroupBNhad3% (1 patient) incidence of bradycardia which was treated with inj.glycopyrrolate 0.2mg IV.Theincidence of hypotension was 6% (2 patients) which was treated with inj.mephenteramine5 m g iv.

Table3: Perioperative Complications

The use of intrathecal opioids as adjuncts to local anesthetics has been widely explored in regional anesthesia. Opioids selectively inhibit nociceptive input from A-delta and C fibers while preserving sensory function, thus providing effective postoperative analgesia [11,12]. Nalbuphine, a mixed μ-antagonist and κ-agonist, has gained attention as an intrathecal adjuvant due to its ability to prolong sensory and motor blockade with minimal respiratory depression [13,14]. This study aimed to assess the efficacy and safety of intrathecal nalbuphine as an adjuvant to bupivacaine in lower limb surgeries.

Demographic and baseline characteristics suggest both groups were comparable in terms of age, gender distribution, ASA grading, and duration of surgery. There were no statistically significant differences between the groups (p > 0.05), ensuring a well-balanced comparison without demographic bias. These findings align with prior studies that demonstrated effective randomization in intrathecal nalbuphine trials [15].

The onset of sensory and motor blockade was comparable between the two groups, with no statistically significant difference (p > 0.05). Group BN exhibited a sensory onset of 1.54 ± 0.20 min and motor onset of 3.20 ± 0.35 min, while Group B had similar values of 1.50 ± 0.20 min and3.17 ± 0.56 min, respectively. Similar findings have been reported by Fareed Ahmed et al. (2016) [16] and Jyothi B et al. (2014) [17], where different doses of nalbuphine showed no significant effect on the onset of sensory and motor blockade. The duration of sensory and motor blockade was significantly prolonged in Group BN compared to Group B sensory block: 182 ± 34.65 min (Group BN) vs. 144.76 ± 7.19 min (Group B), p < 0.05, motor block: 232.93 ± 31.27 min (Group BN) vs. 179.83 ± 7.06 min (Group B), p < 0.05.Two-segment regression: 282.4 ± 31.33 min (Group BN) vs. 162.56 ± 8.12 min (Group B), p < 0.05. These findings align with research conducted by Kumkum Gupta et al. (2016) [18], Swati Bisht et al. (2017) [19], and Amin et al. (2020) [20], which reported prolonged sensory and motor blockade durations with nalbuphine as an intrathecal adjuvant. The mechanism behind this effect is attributed to nalbuphine’s action on spinal κ-opioid receptors, which enhances local anesthetic effects without significant hemodynamic disturbances [21].

Postoperative analgesia, assessed via time to first rescue analgesia, was significantly prolonged in Group BN (284.4 ± 31.33 min) compared to Group B (162.56 ± 8.12 min, p < 0.001). Similarly, postoperative pain scores (VAS) were consistently lower in Group BN at all recorded intervals (p < 0.001). Studies by Pratibha Deshmukh et al. (2014) [22], Bindra TK et al. (2018) [23], and Parvin et al. (2019) [24] corroborate our findings, showing that nalbuphine significantly improves postoperative analgesia when used intrathecally.

Hemodynamic parameters, including HR, SBP, DBP, and SpO2, remained stable in both groups throughout the intraoperative and postoperative periods. No significant differences were observed (p > 0.05), suggesting that nalbuphine does not adversely affect cardiovascular stability. Previous studies by Tiwari et al. (2013) [25] and Fareed Ahmed et al. (2016) [16] also found no significant hemodynamic variability associated with nalbuphine, reinforcing its safety profile.

The incidence of adverse effects was minimal in both groupsGroup BN: Bradycardia (3%, n=1), hypotension (6%, n=2) Group B: Hypotension (13%, n=4), nausea (6%, n=2). These findings are in agreement with studies by Culebras et al. (2000) [26] and Shehla Shakooh et al. (2014) [27], which demonstrated that nalbuphine has a favorable safety profile with a lower incidence of adverse effects compared to other opioids such as morphine or fentanyl[28].

Our study confirms that intrathecal nalbuphine (2 mg) as an adjuvant to 0.5% heavy bupivacaine does not affect the onset of sensory and motor blockade, significantly prolongs  the duration of sensory and motor blockade., enhances postoperative analgesia and reduces pain intensity, maintains stable perioperative haemodynamics and has a favourable safety profile with minimal adverse effects hence supporting the use of nalbuphine as a safe and effective adjuvant in spinal anaesthesia for lower limb surgeries.

Conflict of interest

Nil

Source of Income

Nil

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