Effect of Different Doses of Buprenorphine in Combination with Bupivacaine in the Management of Postoperative Analgesia: A Comparative Study.

Background: Longer duration of analgesia, ceiling effect on respiratory depression, and the antihyperalgesia property make buprenorphine a good adjuvant for managing moderate-to-severe postoperative pain. Aims: The aim of this study is to evaluate the onset and duration of postoperative analgesia of three different doses of buprenorphine of 60, 100, and 150 μg given intrathecally along with hyperbaric bupivacaine in patients undergoing lower limb surgeries. Setting and Design: This prospective observational study was carried out in the anesthesia department of a tertiary care hospital. Materials and
Methods: The study included 90 patients of either sex, aged 18-60 years, scheduled for elective lower limb surgery under subarachnoid block. Patients were randomly allocated into three groups (30 each) receiving different doses of buprenorphine. In addition, all patients received 3 mL of 0.5% hyperbaric bupivacaine. Statistical Analysis Used: The Chi-square test or Fisher's exact test was used to find out the association between the categorical variables. The association of quantitative variables between the groups was assessed by Kruskal-Wallis test while within the groups was assessed by repeated-measures analysis of variance test.
Results: Baseline characteristics such as age, gender, and American Society of Anesthesiologist physical status classification were comparable among the three groups. Sensory block, motor block, and total duration of analgesia were significantly higher with higher doses of buprenorphine. The mean difference in the duration of analgesia was comparable in patients receiving 100 μg (720 min) and 150 μg (825 min) of buprenorphine. Bradycardia as a side effect was only in patients receiving 150 μg of buprenorphine.
Conclusion: Risk-benefit of different doses of buprenorphine suggests that 100 μg may be the ideal dose for a better quality of spinal block and maintaining hemodynamic stability. Copyright:

INTRODUCTION

Pain is defined as an unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage.[12] Pain following surgical trauma remains a major problem for anesthetists and management of pain warrants more evidence. The objective of postoperative management is to prolong the sensory block without affecting the rate of motor block recession.[3] Spinal anesthesia is extensively used for lower abdominal surgeries as it provides excellent anesthesia and analgesia compared to other methods. It provides pain relief in the entire distribution of the lumbar plexus along with the thigh and knee and even below the knee region. Along with spinal anesthesia, adjuvant drugs are being tried to prolong pain relief.

Bupivacaine, a local anesthetic agent, emerged as an alternative in spinal anesthesia after the use of lidocaine becomes obsolete because of the high incidence of transient neurologic symptoms. Bupivacaine is an amino-amide compound, highly lipid-soluble, and protein-bound compound. The possibility of adverse cardiac effect raised concern regarding its use. The s-enantiomer of bupivacaine (levobupivacaine) is recognized of having less cardiac and neurological toxicity. Currently, bupivacaine is available as a racemic mixture of both bupivacaine and levobupivacaine and preferred by anesthetists.[45]

Several studies mainly in lower doses of buprenorphine have demonstrated efficacy as adjuvant in spinal anesthesia. Although buprenorphine is chemically similar to morphine but it is 33 times more potent compared to morphine and act as partial mu-receptor agonist.[67] Longer duration of analgesia, ceiling effect on respiratory depression compared to morphine, antihyperalgesia property preventing central sensitisation make it a good adjuvant for managing moderate-to-severe postoperative pain. It also reduces the dose requirement for spinal anesthesia.[689] However, there is a paucity of literature with respect to its efficacy and effect of dose escalation in combination with bupivacaine. Hence, the present study was carried out to evaluate the onset and duration of postoperative analgesia of three different doses of buprenorphine 60, 100, and 150 μg given intrathecally along with hyperbaric bupivacaine in patients undergoing lower limb surgeries.

MATERIALS AND METHODS

This was a prospective observational study conducted after approval from the institutional ethics committee (ref.no./DMR/IMS.SH/SOA/180248 dated 07-06-2019). Written informed consent was obtained from the patients before enrollment into the study and the study was carried out according to the Declaration of Helsinki. Ninety patients of American Society of Anesthesiologist (ASA) physical status (PS) Class I and II of either sex, aged 18–60 years, scheduled for elective lower limb surgery under subarachnoid block, were included in the study. Patients with known contraindication for spinal anesthesia, allergy to local anesthetic drugs, having neurological disease, having block site infection, coagulopathy, and patient converted to general anesthesia intraoperatively for any reason, were excluded from the study.

All patients underwent a thorough preanesthetic checkup, and after obtaining written informed consent, patients were randomly allocated into three groups (Groups A, B, and C), 30 patients each using computer-generated random number chart. All the patients received 3 mL of 0.5% hyperbaric bupivacaine. In addition, Group A received 60 μg buprenorphine, Group B received 100 μg buprenorphine, and Group C received 150 μg buprenorphine. Total volume of drugs administered intrathecally was made up to 3.5 mL in transparent looking similar syringe by the addition of sterile isotonic normal saline in all three groups. The details of the study are described in Figure 1.

Figure 1

CONSORT diagram

After the routine preoperative assessment, patients were kept nil per oral from midnight, the day before surgery. After shifting to the preoperative room, baseline vital parameters were recorded. The intravenous line was secured by an 18 G or 20 G cannula. In the operating room, appropriate equipment for airway management and emergency drugs were kept ready. Noninvasive blood pressure monitor, pulse oximeter, and electrocardiogram (ECG) leads were used to monitor the patient's hemodynamics. Preoperative baseline systolic and diastolic blood pressure, mean arterial pressure, pulse rate, respiratory rate, and oxygen saturation were recorded. Patients were preloaded with 10 mL.kg− 1 of Ringer's lactate 15 min before the subarachnoid block. In the sitting position, the skin over the back was prepared with antiseptic solution and draped with sterile drape. After skin's infiltration with 2% lidocaine, 25 G Quincke's spinal needle was inserted at the L3-L4 interspace in the midline. After confirming free flow of cerebrospinal fluid, the prepared solution was injected. The patients were made to lie supine immediately after injection and the time at which the spinal anesthesia performed was noted.

The parameters such as time of onset of sensory block, time of onset of motor block, and duration of surgical procedure were noted. The onset of sensory block was defined as the time between the injection of anesthetic solution and the absence of pain at the T8 dermatome. Sensory block was assessed by loss of sensation to pinprick using 25 G sterile needle bilaterally along the midclavicular line. This assessment started immediately after turning the patient to the supine position and continued every minute till loss of sensation to pinprick at T8 level was noted.

Motor block was assessed bilaterally using modified Bromage Scale. The assessment of motor block was started immediately after turning the patient to the supine position and continued every minute till Bromage score of 3 was reached. The onset of motor block was defined as the time to achieve Bromage score of 3 from the time of intrathecal injection. Duration of motor block was taken as the time from intrathecal injection to return of Bromage score of zero (complete recovery). The duration of effective analgesia was defined as the period from spinal injection to the first time when the patient complained of pain in the postoperative period.

Systolic and diastolic blood pressure, pulse rate, and oxygen saturation were recorded at 0, 15, and 60 min of the procedure. Hypotension was considered to have occurred if there was fall in systolic blood pressure of more than 20% from baseline. They were treated with 100% oxygen, increasing the rate of intravenous fluids, and injected with ephedrine in incremental doses of 6 mg at interval of 2 min. Bradycardia was defined as heart rate <60 per minute and was planned to be managed with intravenous atropine in incremental doses. Respiratory depression was considered having SpO2 <90% and planned to be managed with mask ventilation or intubation and intermittent postive pressure ventilation. Other side effects such as nausea, vomiting, shivering, pruritus, and ECG changes were also noted. On completion of surgery, patients were shifted to postoperative recovery unit after hemodynamic stabilization. Tramadol (100 mg) was used as rescue analgesia for patients complaining of pain.

Statistical analysis

The data were entered into Microsoft excel (Version 2007, Redmond, WA: Microsoft corporation) and analyzed using Statistical Package for the Social Sciences (SPSS), version 27.0, Armonk, New York, IBM corporation. The categorical variables were described in number and proportions. The Chi-square test or Fisher's exact test was used to find out association between the categorical variables. Quantitative variable was described in median and interquartile range (IQR) and distribution was assessed using Shapiro–Wilks test. Kruskal–Wallis test was used to find out the difference between three groups followed by Bonferroni post hoc test. Repeated-measures analysis of variance test was used to measure the difference within the group. P < 0.05 was considered statistically significant.

RESULTS

The median age was 37.0 (IQR: 27.8–55.0), 43.5 (IQR: 37.0–52.8), and 50.0 (IQR: 38.8–52) in Groups A, B, and C, respectively. Majority of patients were male and belonged to ASA Grade I. Baseline characteristics such as age, gender, and ASA PS classification were comparable among the three groups. Body mass index was comparatively lower as compared to Group A and B (P = 0.026) [Table 1].

Table 1

Baseline characteristics of the study population

Parameters	Group A (n=30)	Group B (n=30)	Group C (n=30)	P
Age in years, median (IQR)	37.0 (27.8-55.0)	43.5 (37.0-52.8)	50.0 (38.8-52.8)	0.338
Gender, n (%)
Male	24 (80.0)	21 (70.0)	22 (73.3)	0.664
Female	6 (20.0)	9 (30.0)	8 (26.7)
BMI* in kg/m2, median (IQR)	24.2 (22.8-27.0)	23.0 (21.5-23.9)	24.0 (22.4-25.5)	0.026
ASA, n (%)
Grade I	20 (66.7)	20 (66.7)	21 (70.0)	0.950
Grade II	10 (33.3)	10 (33.3)	9 (30.0)

*BMI (Bonferroni post hoc analysis showed a significant difference for BMI between Group A and Group B [P=0.008] only), †ASA Physical Status Classification System. ASA=American Society of Anesthesiologist, BMI=Body mass index, IQR=Interquartile range

Proportions of disease for which patients underwent surgery between the groups were comparable (P = 0.172) [Figure 2]. Comparison of outcome variables such as onset of sensory block, onset of motor block, and total duration of analgesia between the three groups shows significant difference [Table 2]. Post hoc analysis showed that Group A and B are comparable for the onset of sensory and motor block but duration of analgesia was significantly higher in Group B. Group C significantly differs from Group A in all outcome parameters. Althogh patients in the Group C had significantly higher duartion of sensory and motor block comoared to Group B but were comparable with respect to duration of analgesia [Tables 2 and 3].

Figure 2

Type of disease condition for which participants undergone surgery

Table 2

Comparison of analgesia between the groups

Duration in min	Group A (n=30)	Group B (n=30)	Group C (n=30)	P
T8 analgesia	5.0 (5.0-5.0)	5.0 (5.0-6.0)	6.0 (6.0-6.0)	<0.001
Onset of sensory block	6.0 (5.0-6.0)	6.0 (5.0-6.0)	6.0 (6.0-6.0)	<0.001
Onset of motor block	5.0 (5.0-5.3)	6.0 (5.0-6.0)	6.0 (6.0-6.0)	<0.001
Total duration of analgesia	480 (360-660)	720 (660-780)	825 (720-900)	<0.001
Duration of surgery	127 (89-180)	130 (120-150)	135 (120-160)	0.637

*All values were shown in median (IQR). IQR=Interquartile range

Table 3

Post hoc analysis of duration of analgesia between the groups

Parameters	Group A versus B	Group A versus C	Group B versus C
T8 analgesia	0.110	<0.001	<0.001
Onset of sensory block	0.599	<0.001	<0.001
Onset of motor block	0.057	<0.001	<0.001
Total duration of analgesia	<0.001	<0.001	0.186

*Bonferroni correction was used for post hoc analysis

Pulse rate of three groups measured at different time interval showed no significant difference [Figure 3]. Bradycardia was seen in four patients (13%) in Group C while none of patient in Group A and B had bradycardia. Systolic and diastolic blood pressure was significantly higher in Group A compared to B and C at all-time intervals, while diastolic blood pressure was significantly higher for Group A at baseline and 60 min time intervals [Figures 4 and 5]. Within the group comparison revealed that all the hemodynamic parameter significantly reduced between baseline to 60 min measurements. None of the patients required supplementary oxygenation support intraoperatively and postoperatively till 24 h. The oxygen saturation was maintained above 94% in all patients irrespective of the groups and time intervals.

Figure 3

Comparison of pulse rate across group and at different time interval

Figure 4

Comparison of systolic blood pressure across group and at different time interval

Figure 5

Comparison of diastolic blood pressure across group and at different time interval

DISCUSSION

The current study evaluated the efficacy of different doses of buprenorphine in combination of bupivacaine. We found, 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. Our study findings were similar to a study by Sonya and Davies.[10] and Pal et al.[11] where sensory onset with 75 μg buprenorphine ranged between 4 and 8 min. Similarly, onset of motor block in our study was comparable to other studies who reported a onset duration between 4.5 and 9.3 min.[1112]

We observed that as the dose of buprenorphine increased from 60 μg to 150 μg, the effective duration of analgesia was also increased. Although the difference between 60 μg and 100 μg doses is significant, further increase in dose to 150 μg did not show a significant rise compared to 100 μg. Our study findings were substantiated by study conducted by Capogna et al.[13] where 30 μg had duration of analgesia for 8 h, while patients who received 45 μg had duration of analgesia 7–12 h. Few other studies at higher doses of buprenorphine also observed a higher duration of analgesia.[1415] Mishra and Maharana.[16] reported a much longer duration of analgesia (17 h) with 150 μg buprenorphine in vaginal hysterectomy patients and this difference may be due to study on different patient population as orthopedic procedures are more painful compared to soft-tissue surgeries.

The incidence of bradycardia was reported in higher doses of buprenorphine in our study which was similar to study other studies where the incidence of bradycardia ranged from as 10% to 16%.[121416] Lower or no bradycardia with lower doses of buprenorphine in our study was supported by studies elsewhere.[1315171819] Our observation of a higher incidence of hypotension in higher doses of buprenorphine (150 μg) compared to lower doses was similar to a study by Mishra and Maharana who reported a significant change in mean arterial pressure with higher doses of buprenorphine.[16] Other studies also supported our findings on incidences of hypotension with different doses of buprenorphine.[10121420]

Dahan et al.[21] observed that in increase in doses of morphine increases the duration of analgesia along with concentration-dependent respiratory depression without any plateau or ceiling as a side effect. However, increasing the dose of intrathecal buprenorphine prolonged the analgesic effect without change in timing and magnitude of respiratory depression. Our study finding also supports this observation as other studies.[1516]

There were few limitations to our study. The hemodynamic parameters were observed up to 60 min irrespective of the duration of surgery which may affect the outcome parameters in our study, so long-term observation may be required to evaluate efficacy at a longer time frame. Intra- and postoperative period is also depended on the amount of blood loss in the surgery which was not considered in our study which may affect the results.

CONCLUSION

The current study suggested that although the onset of sensory block, onset of motor block, and duration of analgesia were higher in higher doses of buprenorphine, the side-effects such as bradycardia and hypotension are also more likely. Risk–benefit of different doses of buprenorphine suggests that 100 μg may be the ideal dose for a better quality of spinal block and maintaining hemodynamic stability.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.