Karl August Bier introduced spinal anesthesia in clinical practice in 1898 [1]. It still remains the “golden” technique in most developing countries. The advantages of spinal anesthesia are rapid onset, dense blockade, ease and simplicity of administration , good safety profile , no airway instrumentation, minimal adverse effects and less resources. The major drawback is the onset of pain with regression of block and short duration of post operative analgesia [2]. Hence the need for intrathecal adjuvants to potentiate the neuraxial blockade with prolonged post operative analgesia [3]. Bupivacaine, the long acting, amino-amide local anaesthetic has a spinal block duration of one to three hours [4] . Higher doses cause hypotension, bradycardia and high level due to sympathetic blockade [2]. Bupivacaine blocks the voltage gated sodium channels of motor fibres Aβ , pain transmitting Aδ and C fibers with onset of action by 5-10 minutes [4]. Opioids cause more sensory block than motor , hemodynamic stability and longer analgesia without sympathetic block5. Opioids block substance P at the dorsal horn and local anaesthetics block the impulse transmission at the axon [6] to synergistically produce analgesia making opioids ideal intrathecal adjuvants. The difficulty in availability, procurement and stringent Narcotics license regulations for Morphine and Fentanyl in our place, prompted us to explore alternative opioids with accessible regulations and easy procurement process like Buprenorphine. Buprenorphine, a synthetic mixed agonist-antagonist opioid [7] also blocks voltage-gated sodium channels like a local anesthetic [8] and reduces the spinal anesthesiadose requirement[9,10]. Lanz et al [11] demonstrated that buprenorphine being lipophilic is compatible with CSF with no adverse reactions when administered. Though chemically similar to morphine, Buprenorphine is 33 times more potent with additional supra-spinal component of action [10]. Longer analgesia, ceiling effect on respiratory depression, anti-hyperalgesia preventing central sensitisation make it a good adjuvant for post-operative pain[11]. Intrathecal buprenorphine used varies from 30-300μg, but optimal dose essential to balance analgesia and adverse effects has not been described yet [6]. Earlier studies used 30μg to 150μg for caeserean sections and lower limb surgeries and 100μg to 300μg for abdominal surgeries. The drawback was adverse effects with higher doses and lesser analgesia at lower doses. The highest dose we chose was 150μg as there were major side-effects with 300μg noted by Sen M[12] . Capogna et al [13] demonstrated a significant prolongation in analgesia with 15μg increase without major side-effects, so 75μg was chosen as the lower dose which is 15μg more than the 60μg dose[3,17] of previous studies. Paucity of literature comparing 75μg and 150μg of Buprenorphine for infra-umbilical and lower limb surgeries prompted us to undertake this study to determine a dose, effective for analgesia with fewer adverse effects.

The aim of our study was to evaluate and compare the spinal block characteristics and side effects in adult patients undergoing infra-umbilical and lower limb surgeries under for spinal anesthesia with Hyperbaric bupivacaine with varying dose of buprenorphine of 75μg and 150μg to prolong postoperative analgesia in three groups, Group A-Buprenorphine 75μg, Group B-Buprenorphine 150μg and Group C-Control group, no adjuvant. The primary objectives were to compare the onset of block, sedation, regression of sensory level and total duration of analgesia. Secondary objectives were to compare hemodynamic parameters and adverse effects. Approval was obtained from the Institutional Ethics committee (IEC) for this prospective, double-blinded, randomized study. (IEC/RIMS/82/2024) Inclusion criteria Ninety (90) adult consenting patients with American Society of Anesthesiologists (ASA) physical status I and II, aged 18-75 years scheduled for infra-umbilical and lower limb surgeries were enrolled for the study, performed at a tertiary care academic institution. Exclusion criteria Patients with a history of pre-existing cardiac or pulmonary disease, renal or hepatic derangements, metabolic or neurological disorders and those who consumed opioids in the previous 2 weeks or with opioid dependance were excluded. Written informed consent was taken, pre-anesthetic evaluation done with airway and spine assessment. Ninety (90) patients were randomized into three groups of 30 each by computer-generated number table. Total dose of drug was 15mg of 0.5% hyperbaric Bupivacaine in all three groups with respective adjuvant - Group A Buprenorphine 75μg, Group B Buprenorphine 150μg and Group C - no adjuvant. Method of blinding The study drug was prepared by the anaesthetist who administered the spinal anesthesia. The principal investigator, blinded to the study group allocation monitored, managed the patients and collected the data. Both the patient and the investigator were blinded to the drug given. Subarachnoid blockade technique Selected patients were fasted for minimum six hours. On the day of surgery, all patients were assessed, informed consent taken and shifted into the Operation theatre. Pre-loading was done with 10-20 ml/kg of Ringer lactate solution before surgery to replenish the overnight fasting. Monitoring of heart rate, blood pressure, electrocardiography and pulse oximetry was commenced using multipara monitor. Under aseptic conditions, spinal anesthesia was administered using a 25 G Quincke’s spinal needle at the L3-4 or L4-5 interspaces through a midline approach in sitting position. Free flow of cerebrospinal fluid was ascertained and the drug injected at the rate of 0.2 ml/sec. Immediately after, patients were made to lie supine. All patients were supplemented with oxygen with a face mask at 4 liter/minute. The sensory block characteristics assessed by the pinprick method were i. The time of onset of sensory blockade at T10 level - loss of sensation to pinprick , checked every 30 sec after the patient is supine. ii. The peak level of sensory block was checked every 2min after spinal block till highest level attained. iii. The sensory level was checked every 30 minutes during and after the surgery till regression by two dermatome levels from the highest level and time taken for sensory level to regress till T10 dermatome was noted. . iv. The total duration of analgesia- i.e, from the time of onset of the block to the time of first analgesic was noted. The mean time of regression to T10 level was chosen as uniform parameter for all groups in order to avoid bias as abdominal surgeries had infra-umbilical incisions at T10 level whereas it was at lower levels for limb surgeries. The motor block characteristics assessed by the Bromage scale were a. The time of onset of motor blockade every one minute interval until Bromage score 3 b. Bromage score checked at end of surgery A minimum sensory block Grade 4 at T10 dermatomal level with motor block of Bromage score 3 was considered acceptable for lower limb surgeries to proceed and T6 level for lower abdominal surgeries. Intra-operatively, patients were monitored for hemodynamic changes in blood pressure, heart rate, respiratory rate, oxygen saturation (SpO2), level of block and Ramsay sedation scores. Grades of shivering and episodes of hypotension, bradycardia, vomiting or nausea were noted. A reduction of ≥ 20% from the initial mean arterial pressure (MAP) considered as hypotension was corrected with Inj. Ephedrine 6mg intravenously. Heart rate < 50 beats / min was considered as bradycardia and treated with Inj. Atropine 0.6mg iv. During the surgical procedure, all patients received intravenous fluids and blood transfusion was given if the maximum allowable volume of blood loss was exceeded. Post operative analgesia was assessed by a. Pain score using Visual analog scale at end of surgery and in the recovery room b. The time to first request for analgesia. c. The total duration of analgesia was noted from the time of onset of sensory block at T10 level upto the first request of analgesic or VAS ≥4 postoperatively. Numerical rating scale (NRS) / VAS - VISUAL ANALOG SCALE Instruct the patient to choose a number from 0 to 10 that best describes their current pain. 0 - No pain 1-3 - Mild pain 4-6 - Moderate pain 7-9 - Severe pain 10 - Worst possible pain Ramsay Sedation Scale - RSS 1. Patient is anxious and agitated or restless, or both 2. Patient is co-operative, oriented, and tranquil 3. Patient responds to commands only 4. Patient exhibits brisk response to light glabellar tap / loud auditory stimulus 5. Patient exhibits a sluggish response to light glabellar tap / loud auditory stimulus 6. Patient exhibits no response Bromage Score for Spinal Anesthesia 0 = Flexion at knees, ankle and able to raise the straight leg. 1 = Flexion at knees, ankle but unable to raise the extended leg at the hip 2 = Flexion at ankle but unable to flex the knee 3 = The patient is unable to move hip, knee, or ankle Crossley And Mahajan Intraoperative Shivering Score Grade 0 - No shivering Grade 1 - No visible muscle activity but piloerection, peripheral vasoconstriction or both Grade 2 - Muscular activity in only one muscle group Grade 3 - Moderate muscular activity in more than one muscle groups Statistical analysis : Power analysis was done for sample size calculation to detect a minimum of 10% difference in degree of sensory blockade between the groups with confidence limits - 95%, power of study - 80%. 26 patients were required in each group, so the sample size was chosen as 30 per group [14]. All data were entered in Microsoft Excel and analyzed using SPSS version 31 software (SSPS Inc., Chicago, IL, USA). Student t-test (two-tailed, independent) was used to find the significance of continuous parameters between the two groups like MAP, HR and RR. Analysis of variance ANOVA was used for three groups comparison on quantitative parameters. Pearson’s Chi-square test was used for categorical parameters. Kruskal-Wallis test was used for non-parametric data. P < 0.05 was considered to be statistically significant.

Table 1: Demographic variables S.NO VARIABLES BUPRENORPHINE 75μg GROUP A ( N = 30 ) BUPRENORPHINE 150μg GROUP B ( N = 30 ) CONTROL GROUP C ( N = 30 ) P VALUE 1 AGE 44.4 ± 15.9 53.8 ± 15.3 48.2 ± 17.4 0.082 2 GENDER 0.12 Males 19 13 19 Females 11 17 11 3 AMERICAN SOCIETY OF ANESTHESIOLOGISTS (ASA) PHYSICAL STATUS 0.262 CLASS 1 16 11 19 CLASS 2 14 19 11 4 SURGERY DURATION 115 ± 38.5 120.16 ± 32.7 105.6 ± 36.2 0.148 5 SITE OF SURGICAL PROCEDURE 0.692 LOWER ABDOMEN 15 19 14 LOWER LIMB 15 11 16 6 SURGERIES DONE TIBIA 11 6 6 0.39 FEMUR 5 5 10 HERNIA 4 9 9 HYSTERECTOMY 10 10 5 Demographics like Age, Gender, ASA physical status grading, duration of surgery, site of surgical procedures and type of surgeries done were comparable in all the three groups and statistically insignificant ( P > 0.05 ) . Table 2: SPINAL BLOCKADE CHARACTERISTICS SPINAL BLOCKADE PARAMETERS MONITORED COMPARISON OF THREE GROUPS USING ONE-WAY ANOVA COMPARISON OF 2 GROUPS BY STUDENT’S INDEPENDENT T-TEST CONTROL GROUP C MEAN ± SD ‘P’ VALUE BUPRENORPHINE 75μg GROUP A MEAN ± SD BUPRENORPHINE 150μg GROUP B MEAN ± SD ‘P’ VALUE Time Of Onset Of Sensory blockade at T10 level (in minutes) 2.78 ± 0.9 2.43 ± 0.5 0.04 3.16 ± 0.8 <0.001 Time Of Onset Of Motor Blockade (in minutes) 4.23 ± 1.3 3.43 ± 0.6 0.0428 4.6 ± 1.1 <0.001 Time Taken To Attain Highest Sensory Level (in minutes) 5.47 ± 1.3 5 ± 1.1 0.164 5.7 ± 1.4 0.076 Peak sensory dermatomal level attained 0.145 0.114 T 4 - 5 5 6 2 T 6 - 7 13 15 12 T 8 - 10 12 9 16 Time taken for Onset of sedation (in minutes) 9.4 ± 5.7 5.77 ± 2 0.0223 16.8 ± 4.7 <0.001 Two-Segment Regression Time Of Sensory Blockade from peak level (in minutes) 111.1 ± 16.9 124 ± 18.6 0.004 86 ± 8 <0.001 Regression Time Of Sensory Blockade to T10 level (in minutes) 140.16 ± 21.2 182.3 ± 25.4 <0.001 113.4 ±15.3 <0.001 Time of first analgesic request after surgery (in hours) 3.27 ± 0.9 4.45 ± 1.4 <0.001 1.33 ± 0.5 <0.001 Total duration of sensory analgesia after spinal (in hours) 4.8 ± 0.4 6.65 ± 1.2 <0.001 3.32 ± 0.3 <0.001 Pain Scores by VAS at end of surgery 0 - 1 23 26 0.0328 0 <0.001 2 - 3 6 3 11 >= 4 1 1 19 Bromage Scores at end of surgery 1 2 0 0.0604 5 <0.001 2 9 6 14 3 19 24 11 A. Comparison of Group A-75μg and Group B-150μg Buprenorphine by Student’s independent t-test. In our study we observed that between Groups A and B, most of the parameters determining the quality of spinal blockade were statistically significant (P<0.05) and better in Group B with 150μg Buprenorphine like i. Onset of sensory blockade at T10 level (2.78 vs 2.43min, P =0.04) ii. Onset of motor blockade of Bromage score 3 (4.23 vs 3.43min, P=0.0428) iii. Onset of Ramsay sedation score of 3 (9.4 vs 5.7min, P=0.0223 ) were all significantly earlier in Group B. iv. Regression of sensory blockade by two segments from the peak level (111 vs 124 min, P=0.004) v. Time for regression of sensory blockade till T10 dermatome level (140 vs 182min, P<0.001) vi. Time of the first rescue analgesic given after surgery (3.2 vs 4.45 hrs) vii. Total duration of sensory analgesia (4.8 vs 6.6 hrs) were all significantly longer in Group B. viii. VAS scores at the end of surgery (P=0.0145) ix. Hypotension episodes (Table3) were significantly more with Group B with 150μg Buprenorphine and was statistically significant (P = 0.033). B. Comparison of all three groups A, B and C by ANOVA These parameters were statistically significant P<0.05 i. All the parameters determining the quality of spinal blockade ( Table 2) and the duration of analgesia were statistically significant at all intervals with a P<0.001 among all the three groups, with best values in Group B with 150μg Buprenorphine. ii. The number of patients with Ramsay sedation score of 3 or more (Table 3) at all time intervals was significantly more in the Buprenorphine groups A and B than the control group C, P <0.05 at all intervals was statistically significant. iii. The mean Ramsay sedation score of 3 (Figure 4) at most time intervals was in Group B than A and C. Whereas all the below parameters were comparable and statistically insignificant in the three groups comparison (P>0.05) a. The time taken to attain peak sensory level (P=0.076 ) b. The peak sensory level of block attained (P=0.114) c. Hemodynamic parameters - the mean heart rate (Figure 1) and mean arterial pressure (Figure 3) calculated at various intervals were comparable in all three groups at almost all intervals and P<0.05 was statistically insignificant among the groups. d. The mean respiratory rate in all the three groups was comparable (Figure 2) at all intervals and statistically insignificant. Among all the patients in all the three groups none had respiratory depression at any point. e. Adverse effects (Table 3) like Shivering (P=0.16) Hypotension (P=0.422) Bradycardia (P=0.356) Nausea and vomiting (P=0.69) were all comparable between the three groups. PARAMETERS MONITORED BUPRENORPHINE 75μg GROUP A ( N = 30 ) BUPRENORPHINE 150μg GROUP B ( N = 30 ) P VALUE CONTROL GROUP C ( N = 30 ) P VALUE Grades of Shivering 0 22 19 0.359 15 0.16 1 1 5 8 2 5 5 4 3 2 1 3 Total number of patients with shivering 8 (27%) 11 (37%) 15 (50%) Patients with Hypotension 6 (20%) 14 (47%) 0.033 6 (20%) 0.422 Patients with Bradycardia 4 (13%) 7 (23%) 0.158 2 (7%) 0.356 Patients with Nausea, Vomiting 2 (7%) 7 (23% ) 0.073 3 (10%) 0.69 Table 3: ADVERSE EFFECTS Table 4: NUMBER OF PATIENTS WITH RAMSAY SEDATION SCORE 3 AT VARIOUS TIME INTERVALS NUMBER OF PATIENTS WITH RAMSAY SEDATION SCORE 3 BUPRENORPHINE 75μg GROUP A (N = 30) BUPRENORPHINE 150μg GROUP B (N = 30) CONTROL GROUP C (N = 30) P VALUE 5 MIN POST SPINAL - SCORE 3 6 9 3 0.018 10 MIN POST SPINAL - SCORE 3 14 21 3 0.047 20 MIN POST SPINAL - SCORE 3 20 22 4 <0.001 30 MIN POST SPINAL - SCORE 3 22 19 3 <0.001 45 MIN POST SPINAL - SCORE 3 18 20 3 0.02 60 MIN POST SPINAL - SCORE 3 24 21 3 <0.001 75 MIN POST SPINAL - SCORE 3 16 16 2 0.016 90 MIN POST SPINAL - SCORE 3 18 17 2 <0.001

Post operative analgesia, a crucial part of post-operative care is an ongoing research in finding the right balance of drugs with adequate alleviation of pain, stable hemodynamics, less adverse effects, earlier mobilization of the patient to ensure earlier recovery and shorter hospital stay which is the main objective of (ERAS) Early Recovery After Surgery Protocols. The aim of our study was to compare the efficacy of 75μg and 150μg of Buprenorphine as Intrathecal adjuvants with Hyperbaric bupivacaine in lower abdominal and lower limb surgeries for anesthesia and post operative analgesia in three groups of 30 patients each, Group A-Buprenorphine 75μg , Group B- Buprenorphine 150μg and Group C- Control group, no adjuvant. The demographic characteristics were comparable in all the groups, thereby eliminating selection bias. Primary outcomes - Spinal blockade characteristics The onset of sensory block in our study (Table 2) was significantly earlier in group B (P=0.04) than group A and group C (P<0.001) which correlate with studies by Dixit et al[15] , Thomas et al[16] (2.37 min) and Ravindran et al[17] but only with doses above 60μg. Our findings support Borkotoky et al [3] in that the median time for onset of sensory block at different doses was 6 min, but the dispersion with respect to the median value was the lowest in higher dose of buprenorphine, owing to significant difference when compared to lower doses. The rapid onset may be due to its high lipid solubility and high affinity for opioid receptors [9,16] . The onset of motor block in our study (Table 2) was significantly earlier in group B (P=0.0428) than group A and C (P<0.001) which correlates with the observations of Borkotoky et al [3] , Dhawale et al[14] , Pal et al[18] with 75μg while Irfan et al 19 and Borse et al [20] observed the same at 120μg and 150μg Buprenorphine only. We observed that the height of block or the time taken to reach the peak level of T4 was comparable among the three groups which corresponds with the results of Ravindran et al [17] and Borse et al[20] . This may be due to the same dose of 15mg bupivacaine with similar drug volume used in all the three groups. We observed that the mean time of regression of sensory block by 2 segments from the peak level (Table 2) was significantly longer in group B (P=0.004) than group A and C (P<0.001) . The mean time of regression to T10 level was significantly longer in group B at 182.3±25.4min (P<0.001) and group A at 140.16±21.2min versus 113.4 ±15.3min in group C (P<0.001) . This duration of sensory regression with 150μg buprenorphine was 215.4 ±26.2min for Borse et al[20], 209±33.8min for Arora et al[21] , 189.23±7.42min for Irfan et al[19] and 180 min for Khan et al [22]. which were consistent with our study findings. The duration of analgesia was considered from the time of onset of sensory block upto the time of first analgesic demand which was significantly longest in group B at 6.65±1.2hours (P<0.001) versus 4.8±0.4hrs in group A and 3.32 ±0.3hrs in group C (P<0.001). The analgesic duration with 75μg Buprenorphine was 5hrs for Pal et al [18] , 6hrs with 150μg for Ipe et al[23] , 6.5 hrs with 90μg and 8hrs with 120μg for Irfan et al [19] which support our findings. These observations demonstrate prolonged duration of bupivacaine‑induced sensory blockade, suggesting a potential synergism between buprenorphine and bupivacaine [22].This action is attributed to the time taken by the opioid to penetrate the deeper substantia gelatinosa from the CSF, where opioid receptors are present[24]. Hence sensory analgesia of opioid persists long after the local anesthetic action has weaned off. The pain scores by VAS were significantly low (0 and 1) at the end of surgery and remained so for 3-4 hrs postoperatively in both Buprenorphine groups (P<0.001) . Mean time of first analgesic demand was 3.2 and 4.45 hrs in the postoperative period for 75μg and 150μg Buprenorphine respectively which are consistent with that of Nelamangala et al [25] with 100μg at 4.20±0.81 hrs and Irfan et al [19] at 5-8hrs with 90μg and 7-10hrs with 120μg. Thus, Buprenorphine potentiates the spinal blockade and prolongs analgesia, due to its local anesthetic properties by blocking voltage-gated sodium channels [8]. Secondary outcomes - Hemodynamics and side-effects There was no statistically significant change attributable to intrathecal buprenorphine during peri-operative period in heart rate, mean arterial pressure and respiratory rate (Figures 1 and 2) which correlate with the studies of Chansoriya et al[26] and Thomas et al[17] . The onset of sedation (Table 2) was significantly earlier (P=0.0223) in Group B (5.77min) than Group A (9.3min) and group C (16min) (P<0.001) . Dixit S[15] noted drowsiness with easy arousability, as sedation is advantageous in the peri-operative period. More patients had Ramsay sedation scores of 3 at most intervals (Table 4) with 150μg Buprenorphine. Similar findings were observed with 60μg by Ravindran et al[17] and Dixit S[15] and Irfan et al[19] with 90μg and 120μg. Sedation after intrathecal buprenorphine may be due to its systemic absorption and vascular redistribution to higher centers or cephalad migration in CSF [4,19] . In our study, none of the patients had respiratory depression. Mean respiratory rate was above 13 breaths/minute (Figure 2) which was consistent with the studies of Ipe et al[24] and Borkotoky et al[3] with 150μg Buprenorphine. Being lipophilic, Buprenorphine intrathecally is rapidly soaked up in the lipid tissue of spinal cord and lesser concentration of drug remains in CSF so that less respiratory depression occurs [27]. Buprenorphine has a ceiling effect on respiratory depression and is 25 to 50 times more potent than morphine[27]. Dahan et al[11] compared the effect of buprenorphine 0.2 and 0.4 mg and observed that doubling the dose of buprenorphine prolonged the analgesic effect, but the magnitude of respiratory depression remained unchanged suggesting that Buprenorphine displays a plateau for respiratory depression over a dose range but not for analgesia [3,11] . Our study findings on shivering, nausea and vomiting were comparable between all the three groups as seen in Table 4 (P > 0.05, statistically insignificant). These correlate with studies by Thomas et al[16] , Irfan et al[19] and Sen M[12] who observed higher incidence of nausea and vomiting with 120μg and 300μg buprenorphine, which was easily treated and statistically insignificant. Rostral spread of buprenorphine is prevented by high lipophilicity and larger molecular weight, so nausea, vomiting, somnolence, pruritus are lesser [18]. In our study, incidence of hypotension (Table 3) was significantly higher in Group B at 47% (P = 0.033) than 20% in Groups A and C (P=0.422) with the mean fall in blood pressure comparable in all groups (Figure 3) and hypotension easily treated with vasopressors. This was similar to Dhawale et al[14] and Ipe et al [24] who reported a significant change in mean arterial pressure with higher doses of buprenorphine but easily treatable. Bradycardia observed in all the three groups was statistically insignificant correlating with Dhawale et al[14], Ipe et al[24] and Borkotoky et al[3] who observed it only with 150μg intrathecal buprenorphine. Implications of this study on patient care 150mcg Buprenorphine intrathecally potentiated spinal blockade, prolonged analgesia, with optimal sedation, patient comfort and minimal adverse effects. The remarkable surgical anesthesia enabled surgeons to perform hysterectomy, incisional hernia repairs, gynecologic laparoscopy surgeries with ease. Limitations of the study Peri‑operative period hemodynamics also depends on the amount of blood loss in the surgery which was not considered in our study which may affect the results.

In conclusion, 75μg of Buprenorphine as intrathecal adjuvant with hyperbaric Bupivacaine provides significant peri-operative analgesia with hemodynamic stability. Higher dose of 150μg Buprenorphine provides faster onset, dense spinal block, longer sensory block than motor, prolonged analgesia with optimal sedation, patient comfort and minimal adverse effects in a dose-dependent manner.

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