1. INTRODUCTION:

Cesarean section is usually done under subarachnoid block as it is economical, effective and easy to administer. Risks associated with general anesthesia such as aspiration of gastric contents, difficulty with airway management, infant respiratory distress can be avoided with spinal anaesthesia.^1,2.

Limitations of spinal anesthesia include shorter duration of action and non-provision of prolonged postoperative analgesia with a local anesthetic.³Lack of adequate postoperative analgesia results in delayed recovery, compromised pulmonary functions, thromboembolic complications and a significant amount of physical and mental stress.^4-6 To improve the quality of spinal anesthesia and to prolong the postoperative analgesia, several adjuvants such as opioids (fentanyl, buprenorphine), benzodiazepines, alpha-2 agonist (clonidine, dexmedetomidine), neostigmine and adrenaline have been added to local anaesthetic.⁷

Buprenorphine is a mixed agonist-antagonist narcotic with high affinity at both Mu (μ) and kappa (k) opiate receptors.⁸ A study demonstrated that buprenorphine is compatible with CSF and produces no adverse reactions when administered intrathecally. Buprenorphine has a high molecular weight (481), is highly lipophilic and has a high affinity for opiate receptors.⁹ Various studies have demonstrated the efficacy of buprenorphine with variable doses such as 15μg, 60μg, 75μg, 150μg but safety and efficacy of low dose buprenorphine in lower segment cesarean has not been studied much. This study aimed to evaluate the safety and efficacy of buprenorphine (45ug) as an adjuvant to hyperbaric bupivacaine for postoperative analgesia in the lower segment cesarean section. The primary objective was to compare postoperative analgesia in two groups with respect to the onset and duration of analgesia and the secondary objective was to compare the incidence of side effects in the two groups with respect to the mother and fetus.

2. MATERIALS AND METHODS:

After approval from the institutional ethical review board, this prospective, randomized, double-blinded study was conducted at a rural tertiary care center named Acharya Vinoba Bhave Rural Hospital, Sawangi (Meghe) Wardha, during the study period of 2 years. Written informed consent was obtained from all the patients who participated in the study.

Sixty ASA physical status class I and class II parturients posted for the elective cesarean section between the age of 20 and 35yrs, with the height of 145-170cm and bodyweight 45kg-75kg were selected for this study. Computer-generated simple random sampling with a sealed envelope technique was used to allocate the subjects into two groups of 30 parturients each.

Group B (Bupivacaine + Buprenorphine) receiving 2ml (10mg) of 0.5% hyperbaric bupivacaine with 45ug buprenorphine.

Group C (Bupivacaine) receiving 2ml (10mg) of 0.5% hyperbaric bupivacaine with 1.5ml normal saline.

The volume of the solutions was made equal to avoid bias.

A thorough preoperative evaluation was done a day before surgery. Vitals, body weight and height of the patients were noted. The procedure and visual analogue scale were explained to the patients. Aspiration prophylaxis was given to the patients with oral ranitidine 150mg a night before surgery and on the day of surgery along with metoclopramide 10mg. Patients were shifted to operation theatre and monitors (blood pressure cuff, pulse oximeter, electrocardiograph leads) were attached. Intravenous access was secured with an 18gauge cannula and preloading was done with 20ml/kg crystalloid.

Study drugs were prepared by an anesthesiologist not involved in patient care. The parturients, as well as the attending anesthesiologist, were not aware of the study drug solution.

After confirming the fasting status and with the patient in the left lateral position, under strict aseptic precautions, the subarachnoid block was performed at L3-L4 interspace using a 25gauge spinal needle using the midline approach. After the confirmation of dural puncture by aspiration of CSF, the drug was injected into the subarachnoid space. The time of injection of the drug was noted.

After the subarachnoid injection, patients were turned to supine position with a 15̊ wedge under the right hip for left uterine displacement, a pillow was placed below the shoulders and eyes were covered. Oxygen (3 lit/min) was supplemented via face mask throughout the procedure.

Loss of pinprick sensation determined the onset of the cephalad spread of analgesia. Onset time was defined from the time of injection of the drug into the intrathecal space to the achievement of the T10 dermatomal level. The time between the injection of intrathecal drug and onset of unbearable pain was taken as the effective analgesia time. Modified Bromage scoring system was used to assess the degree of motor block. Motor block was assessed every 5 minutes until the achievement of the maximum block (Bromage 3) and then every 30 minutes till the normal motor functions returned (Bromage 0).

Cardiorespiratory parameters were monitored at every 2min interval for the first 10min and then every 10min for rest of the surgical procedure. Hypotension (systolic blood pressure less than 90mmHg or > 20% fall from the baseline) was treated with an increase in the rate of intravenous fluid administration, left uterine displacement and injection mephentermine (3-6mg iv), bradycardia (heart rate < 50 /min) was treated with atropine i.v 0.02mg/kg and any fall in the respiratory rate (< 10/min) was also noted.

10 units of injection oxytocin was given i.v in a running infusion bottle after delivery of the baby and clamping of the umbilical cord.

Apgar scores of all the babies at 1 and 5 minutes were recorded. The total duration of surgery was noted

Postoperatively, pulse rate, blood pressure, respiratory rate, and oxygen saturation were monitored every 30mins for the first 4hrs and then hourly for 24hrs. Patients were monitored for any neurological deficits/ symptoms and respiratory depression till 24hr after surgery.

Injection Diclofenac sodium was given intramuscularly as a rescue analgesic at the VAS score of > 4. Analgesia duration was defined as the interval between the injection of the intrathecal drug and the time injection diclofenac was injected.

Side effects such as nausea, vomiting, pruritus, respiratory depression were noted.

Statistical analysis:

Rationality for sample size was based on a study conducted by Samal et al.¹⁰ which revealed that time to first request for postoperative analgesia was 17.63 ± 2.28 hours in the buprenorphine group. Hence assuming the duration of analgesia to be 17.63 hours with a standard deviation of 2.28 hours, keeping power at 80% and confidence interval of 95% (α error at 0.05), it was estimated that a minimum of 30 patients need to be recruited in each group. (Sample size was calculated using Open epi software).

Data was analyzed using SPSS version 17.0 for Windows. Using this software, means and standard deviations were calculated for quantitative variables and percentages for qualitative variables. Student’s ‘t’ test was used to test the significance of the difference between quantitative variables and Chi-square test for qualitative variables. A ‘p’ value less than 0.05 was considered to be significant.

3. RESULTS

Table 1: Demographic data and duration of surgery

Variables	Group C (n=30)	Group B (n=30)	p value
Age (years)*	27.8 ± 3.31	28.9 ± 2.44	0.1488, NS
Height (cm)*	157.7 ± 5.81	159.8 ± 7.17	0.2180, NS
Weight (kg)*	58.06 ± 5.15	57.93 ± 7.47	0.9360, NS
ASA (I:II)	12:18	14:16	x²= 0.26 p = 0.60, NS
Gravida (1:2)	16:14	15:15	x²= 0.065 p = 0.798, NS
Duration of surgery(minutes)*	43.56 ± 8.10	42.8 ± 10.07	0.7468, NS

[*Data: Mean±SD, SD= Standard deviation, NS= Non significant]

A total of 60 parturients were recruited in the study. Parturients in both groups were hemodynamically stable throughout the study. The mean age, height, weight, duration of surgery were comparable and the difference was statistically insignificant between the two groups. Similarly, the proportion of cases belonging to ASA class I and II, gravida 1 and 2 was not statistically different in two groups. (Table 1)

Table 2: Spinal block characteristics

Variables	Group C (n=30)	Group B (n=30)	p value
Onset of sensory block (min)*	4.33 ± 1.44	2.76 ± 0.30	p < 0.00001, S
Onset of motor block (min)*	4.98 ± 1.20	3.32 ± 1.45	p < 0.0001, S
Duration of analgesia (min)*	294 ± 76.13	795.33 ± 261.49	p < 0.00001, S
Duration of motor block (min)*	188.4 ± 53.4	182.5±25.2	p = 0.5863, NS
Mean number of rescue analgesic doses	1.36	1.0	p = 0.0004, S

[*Data: Mean±SD, SD= Standard deviation, NS= Non significant, S= Significant]

Before the start of surgery, an adequate surgical block was achieved. The onset time of sensory block to reach the T10 level was 4.33 ± 1.44 min in group C and 2.76 ± 0.30 min in group B. The difference between the mean onset time of sensory block between the two groups was statistically significant (p < 0.00001). The mean duration of analgesia was significantly longer in group B (795.33 ± 261.49 min) than group C (294 ± 76.13 min) (p < 0.00001). The onset of motor blockade was faster in group B (3.32 ± 1.45 min) as compared to group C (4.98 ± 1.20 min). The difference between the two groups was statistically significant (p < 0.0001). The difference between the mean duration of motor blockade between group B (188.4 ± 53.4min) and group C (182.5±25.2 min) was not statistically significant (p = 0.5863). Mean number of rescue analgesic doses required was higher in group C as compared to group B and the difference was statistically significant (p = 0.0004). (Table 2)

Table 3: Complications

Complications	Group C (n=30)	Group B (n=30)
Nausea and vomiting	02 (6.66%)	02 (6.66%)
Respiratory depression	0	0
Hypotension	0	0
Bradycardia	0	0
Drowsiness	0	0
Pruritus	0	01 (3.33%)
Urinary retention	0	0
Headache	0	0

2 (6.66%) patients in both the groups experienced nausea and vomiting which was treated by administering injection ondansetron 4mg i.v. Only 1 (3.33%) patient in the buprenorphine group experienced pruritis. It was relieved by giving injection pheniramine maleate 1ml intravenously. Injection naloxone was not needed. Respiratory depression, hypotension, bradycardia, and drowsiness were not seen in any patient. (Table 5)

For all the babies in both the groups Apgar score was more than 7.

4. DISCUSSION:

A great challenge that awaits an anesthesiologist after the cesarean section is postoperative pain management. Adequate postoperative analgesia helps to decrease the physical and mental stress of the mother and allow early ambulation of the patient thereby decreasing the incidence of thromboembolic complication and ensures maternal and fetal bonding. The idea of intraoperative and postoperative pain relief greatly changed with the introduction of the intrathecal administration of opioids.

The density of opioid receptors is high in spinal cord lamina I and II. Opioid when applied directly to these receptors, produce intense analgesia.¹¹ Opioids when administered intrathecally, act by inhibiting the release of substance P, thereby inhibiting the relay of nociceptive impulses.¹² Buprenorphine being a mixed agonist-antagonist narcotic with high affinity to opioid receptors, high lipid solubility and longer duration of action serves as an attractive option as an adjuvant to local anesthetic for postoperative pain relief.^13-15

Various studies have been carried out with different doses of buprenorphine but none states an ideal dose with the least possible complications. An increased dose of buprenorphine (3μg/kg) was associated with a greater amount of side effects in patients undergoing a cesarean section.¹⁶ We chose the dose to be 45μg as it is in the middle range of the doses quoted in literature.

This study was done to evaluate the safety and efficacy of 45μg of buprenorphine as an adjuvant to hyperbaric bupivacaine for postoperative analgesia in lower segment cesarean section and it involved a total of 60 patients divided into 2 groups of 30 each. Both these groups were comparable with respect to demographic data and the duration of surgery.

The onset of sensory block was significantly faster in the buprenorphine group (2.76 ± 0.30 minutes) as compared to the control group (4.33 ± 1.44 minutes) in our study (p<0.00001). In a study conducted by Letha. et al ¹⁷, the onset of sensory block in the control group was within 4.8±1.16 minutes and that in buprenorphine (1μg/kg) group was 2.84± 0.75minutes. The results are parallel to our study. Similarly in a study by Dubey et al.¹⁸ onset of sensory block in the buprenorphine group was within 2.28±1.31 minutes, which is comparable to our study.

Duration of analgesia was found to be significantly prolonged in the buprenorphine group [795.33 ± 261.49 minutes (13.2±4.22 hrs)] with respect to the control group [294 ± 76.13 minutes (4.9±1.26 hrs)]. A study by Letha et al¹⁷ also shows the duration of analgesia with buprenorphine to be 14 ±3.55 hrs which is parallel to our study. Thomas et al.¹⁹administered 1μg/kg up to a maximum of 50μg buprenorphine intrathecally for postoperative pain relief. They found that the duration of analgesia was longer with the addition of buprenorphine. (15.25 hrs). These observations are similar to our study.

The onset of motor block was found to be within 3.32 ± 1.45 minutes in group B and within 4.98 ± 1.20 minutes in group C in our study. The difference between the two groups is statistically significant. And the difference between the mean duration of motor blockade between the two groups was statistically insignificant. A study by Dubey et al.¹⁸ runs parallel to our study and shows similar results.

A study by Thomas et al.¹⁹showed vomiting in 13.3% of the patients, nausea in 10% of the patients and urinary retention in 26.7% of the patients. These results are parallel to our results. Nausea and vomiting were seen in only 2 patients (6.66%) in our study and pruritis was seen in only one patient (3.33%) in the buprenorphine group.

Hence 45μg buprenorphine, when added to bupivacaine, provided prolonged analgesia with lesser side effects.

5. CONCLUSION:

The present study thus proves that low dose buprenorphine (45μg), when added to bupivacaine as an adjuvant for subarachnoid block in lower segment cesarean section provides prolonged postoperative analgesia with decreased rescue analgesic requirement and decreased incidence of maternal and neonatal side effects.

6. LIMITATIONS OF THE STUDY:

1) We did not compare different doses of buprenorphine

2) Neonatal effects due to the use of buprenorphine as an adjuvant to bupivacaine for cesarean section were studied only using Apgar scores though umbilical cord blood gas analysis could have been used.

7. ACKNOWLEDGEMENTS:

The authors would like to thank Department of Anaesthesiology, Jawaharlal Nehru Medical College, Sawangi (Meghe), Wardha for their support and co-operation.

Funding: No funding sources

Conflict of interest: None

Ethical approval: Approved by the institutional ethics committee

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Received on 13.07.2019 Modified on 12.08.2019

Research J. Pharm. and Tech. 2019; 12(12): 6062-6066.

DOI: 10.5958/0974-360X.2019.01052.7