"Comparison of Nalbuphine Hydrochloride and Fentanyl as an Adjuvant to Bupivacaine for Spinal Anesthesia in Lower Abdominal Surgeries:" A Randomized, Double-blind Study.

BACKGROUND AND AIMS: Opioids have been favored as adjuvants to local anesthetics during spinal anesthesia. Nalbuphine, a μ-receptor antagonist and ĸ-receptor agonist, seems to be a suitable adjuvant to local anesthetics. The aim of this study was to compare postoperative analgesia and adverse effects of nalbuphine and fentanyl when used as an adjuvant to hyperbaric bupivacaine during spinal anesthesia.
MATERIALS AND METHODS: Sixty patients belonging to the American Society of Anesthesiologists Physical Status I and II were randomly allocated into two groups of thirty each. Patients in bupivacaine nalbuphine group (Group BN) received 0.8 mg (0.3 ml) of nalbuphine with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine diluted to 3 ml and bupivacaine-fentanyl group (Group BF) received 25 μg (0.5 ml) of fentanyl with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine. Patients were assessed for hemodynamic changes, sensory and motor block, early postoperative analgesia, and adverse effects.
RESULTS: Onset, duration of sensory and motor block, and duration of effective analgesia were comparable between both groups. Postoperative visual analog scale score was 4.8 ± 1.12 in Group BN, and in Group BF, it was 3.86 ± 1.04 which was statistically highly significant (P = 0.0007). The number of patients demanding rescue analgesia in early postoperative period was 18 (60.0%) in Group BN and 7 (23.33%) in Group BF which was statistically significant (P = 0.004).
CONCLUSION: Fentanyl was more efficient than nalbuphine in providing early postoperative analgesia when used as an adjuvant to hyperbaric bupivacaine.

INTRODUCTION

Pain is one of the primary concerns for patients after surgery. It can cause distress to patients, hamper their well-being, and finally prolong their hospital stay. While for surgeons, it can result in a poor clinical outcome. There are myriad choices of pharmacological agents and techniques to choose for postoperative pain management. The use of opioid as adjuvants in regional analgesia techniques has been one of the cornerstones in postoperative pain management in recent decades.[1]

Fentanyl and morphine have been the most preferred opioids. When used intrathecally along with local anesthetics, they prolong postoperative analgesic-sparing sympathetic action. Fentanyl is more lipid soluble than morphine which is more rapidly eliminated from cerebrospinal fluid. It provides dense blockade with complete intra- and postoperative analgesia without causing hemodynamic instability. It has relatively fewer side effects which are manageable and very well tolerated by the patients.

Recently, nalbuphine has been added to the anesthetic armamentarium as an adjuvant to local anesthetics. Nalbuphine is opioids μ-receptor antagonist and ĸ-receptor agonist.[23] It has the potential to provide good intra- and postoperative analgesia with decreased incidence and severity of μ-receptor side effects.[45] In contrast to other centrally acting opioid analgesics, nalbuphine has a minimal respiratory depressant effect and low potential abuse.

Most of the studies involving nalbuphine as an adjuvant are being investigated in cesarean section patients. Very few studies have compared intrathecal nalbuphine with fentanyl in lower abdominal surgeries. Hence, we designed this prospective, double-blind, randomized control study to compare the efficacy of early postoperative analgesia and adverse effects of intrathecal nalbuphine and fentanyl with hyperbaric bupivacaine.

MATERIALS AND METHODS

After obtaining clearance from the Institutional Ethical Committee, sixty patients of either gender undergoing elective lower abdominal surgeries, aged between 18 and 60 years, and patients’ physical status American Society of Anesthesiologists (ASA) Classes I and II were enrolled in this prospective, double-blind, randomized control study. The study was carried out from April to November 2016. Patients with known history of allergy to the study drugs, who had infection at the site of subarachnoid block (SAB), bleeding disorder, patients on tranquilizers, hypnotics, sedatives, and other psychotropic drugs, and patients who fall under physical status ASA Grade III and above were excluded from the study. They were randomly divided into two groups of thirty each using computer-generated randomized number. Bupivacaine nalbuphine group (Group BN) received 0.8 mg (0.3 ml) of nalbuphine with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine diluted to 3 ml, and bupivacaine-fentanyl group (Group BF) received 25 μg (0.5 ml) of fentanyl with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine. The drug was prepared by one of our technicians who was not involved further with the study.

Standard preanesthetic evaluation was performed, and informed consent was taken before the surgery. Patients were allowed to fast for 8 h. They were premedicated with tablet alprazolam and tablet ranitidine on the night before surgery. On arrival to the operation theater, 18 g intravenous (IV) line was secured, and patients were preloaded with Ringer's lactate solution at 10–15 ml/kg.

Patients were monitored for oxygen saturation, electrocardiogram, heart rate (HR), blood pressure, and mean arterial pressure using multiparameter monitoring system. They were premedicated with IV midazolam 1 mg and ranitidine 50 mg IV. SAB was performed in left lateral position under aseptic precautions using 25-gauge Quincke needle. Study drug was administered at a rate of 0.2 ml/s after free flow of cerebrospinal fluid. Patients were immediately positioned in supine position. Observation was carried out by one of our anesthesiologists who was blinded to the study drug. Patients were evaluated for sensory and motor block, intra- and postoperative hemodynamics, and side effects. Sensory block was assessed using pinprick method using 25 g hypodermic needle every 2 min until highest dermatomal level was reached and every 30 min till regression to S2 dermatome. Onset of sensory block, time to reach the highest dermatome, and time to regress to S2 level (duration of sensory block) were noted. Motor block was assessed using modified Bromage scale (0: no motor block, 1: inability to raise extended legs; able to move knees and feet, 2: inability to raise extended leg and move knee; able to move feet, and 3: complete block of motor limb) every 2 min and 30 min until regression of complete motor block. Onset of motor block (Bromage 2), time to reach maximum motor block (Bromage 2 or 3), and duration of motor block (Bromage 0) were noted. All the parameters were assessed from the time of intrathecal injection. Pain was assessed using visual analog scale (VAS) (0–10 cm where 0 = no pain and 10 = worst pain ever felt). Sedation was assessed using Ramsay sedation score. Side effects such as hypotension, bradycardia, shivering, respiratory depression, nausea and vomiting, and pruritus were noted during intra- and postoperative period. Patients were treated with injection fentanyl 25–50 μg intraoperatively if they complained of pain. In postoperative period, VAS score was assessed every 30 min for 6 h, and if the score was found to be more than 3, all patients were treated with rescue analgesics, injection diclofenac sodium; this was taken as the duration of effective analgesia and the number of patients receiving rescue analgesia was noted. Hypotension, defined as a decrease in systolic blood pressure by >20% from baseline or <90 mmHg, was treated with incremental IV doses of mephentermine 6 mg and further IV fluid as required. Bradycardia defined as HR <50 beats/min was treated with IV atropine 0.6 mg IV.

From previous studies, 30 min difference of mean duration of analgesia between two groups would be statistically significant. Using these data and assuming a study power of 80% and probability of type I error of 5%, a sample size of 55 patients was found to be required for obtaining statistically significant mean difference of mean duration of analgesia in two groups. Hence, assuming equal distribution of patients in both groups, a total number of sixty patients were incorporated in the study with thirty patients in each group.

RESULTS

All sixty patients who were enrolled successfully completed the study. There were no significant differences with respect to demographic characteristics and duration and type of surgeries [Table 1]. Baseline vitals were comparable between both the groups [Table 2].

Table 1

Demographic characteristics between two groups

Table 2

Baseline vitals between two groups

Onset of sensory block in Group BN was 3.07 ± 1.14 min, whereas in Group BF, it was 3.00 ± 1.26 with P = 0.822, and maximum sensory block was achieved in 8.27 ± 2.91 min in Group BN, whereas it took 7.40 ± 2.58 min for Group BF patients with P = 0.225. These differences were found to be statistically nonsignificant. Regression to S1 level was 219.33 ± 35.01 in Group BN and 210.93 ± 46.70 in Group BF with P = 0.434, whereas duration of analgesia was 180.50 ± 34.58 in Group BN and 198.67 ± 45.67 in Group BF with P = 0.0876. These differences were found to be comparable between both the groups [Table 3].

Table 3

Block characteristics and postoperative analgesia

Onset of motor block in Group BN was 2.53 ± 1.28 min, whereas in Group BF, it was 2.40 ± 1.22 min which was found to be statistically nonsignificant (P = 0.688). Similarly, there was no significant difference with regard to maximum motor block achieved and duration of motor block between both the groups; maximum motor block in Group BN was achieved in 5.80 ± 2.48, whereas in Group BF, it was 5.40 ± 2.42 min with P = 0.529, and duration of motor block was 222.50 ± 37.50 in Group BN and in Group BF was 227.50 ± 50.94 with P = 0.667 [Table 3].

Postoperative VAS score was higher in Group BN which was found to be 4.8 ± 1.12 and lower in Group BF which was found to be 3.866 ± 1.04. This difference was found to highly significant with P = 0.0007 [Table 3]. Two patients in Group BN received rescue analgesia intraoperatively while none of them in Group BF. Eighteen patients received rescue analgesia in Group BN within 6 h postoperatively, whereas seven patients received in Group BF which was found to be highly significant (P = 0.0043) [Table 4].

Table 4

Intra- and postoperative incidence of adverse effects and rescue analgesics use

Intraoperative hemodynamics were comparable between both the groups [Figures 1–3]. Hypotension was found in four patients in Group BN and seven patients in Group BF which was statistically nonsignificant. Similarly, pruritus was found in four patients in Group BF and none in Group BN. However, the difference was nonsignificant [Table 4].

Figure 1

Intraoperative heart rate

Figure 3

Intraoperative mean arterial pressure

Intraoperative systolic blood pressure

DISCUSSION

Spinal anesthesia is the preferred technique for the lower abdominal surgeries. Opioids as adjuvants to local anesthetics provide better perioperative sensory and motor blockade with prolongation of postoperative analgesia. By reducing the local anesthetic dosage, they decrease their toxicity and the side effects associated with higher level of blockade. Use of opioid adjuvants such as morphine, fentanyl, and nalbuphine along with bupivacaine has been very well established.[567]

In the present study, we compared fentanyl and nalbuphine as adjuvants to bupivacaine in spinal anesthesia. The results of our study showed that onset of sensory and motor block, duration of sensory and motor block, and effective analgesia were similar in both groups. However, fentanyl had lower VAS scores and was more efficient in providing better quality of analgesia in the early postoperative period than compared to nalbuphine.

Fentanyl in a dose range of 10–30 μg and nalbuphine of 0.8 mg have shown to provide better perioperative analgesia with less hemodynamic changes.[891011] Henceforth, we choose 25 μg of fentanyl and 0.8 mg of nalbuphine for our present study.

In our study, sensory and motor block onset was comparable between fentanyl and nalbuphine group. This can be explained that both fentanyl and nalbuphine are lipophilic which can result in rapid uptake of the drugs resulting in similar onset.[910]

Our result was in agreement with the studies performed by Thote et al., where onset of sensory and motor block with 25 μg of fentanyl and 0.5 mg of nalbuphine were similar.[12] While study done by Gomaa et al. in cesarean section patients showed the faster onset of motor block in fentanyl group when compared to nalbuphine group which contradicted our study results.[13] This can be explained that the study population was different.

Duration of sensory and motor block was comparable between both the groups. Although duration of effective analgesia was shorter in nalbuphine group, it was not statistically significant when compared to fentanyl.

Similar results were seen by the studies done by Gomaa et al. The study showed that fentanyl 25 μg and nalbuphine 0.8 mg as an adjuvant to 10 mg of 0.5% bupivacaine in cesarean section patients produced similar block characteristics.[13] Although duration of analgesia was prolonged when compared to fentanyl, the results were not statistically significant. Contradict to our study, the study done by Thote et al. in patients undergoing lower abdominal surgeries using 25 μg of fentanyl and 0.5 mg of nalbuphine with 12.5 mg of 0.5% bupivacaine observed longer duration of analgesia with nalbuphine group when compared to fentanyl group.[12] The study also showed the greater intensity of analgesia with nalbuphine group. Similarly, a study done by Fournier et al. comparing morphine and nalbuphine in patients undergoing total hip replacement using continuous spinal anesthesia showed that duration of analgesia was shorter in nalbuphine group when compared to morphine group. This shows nalbuphine though has a similar potency to morphine, the duration of analgesia is much shorter.[14]

We observed in our study that the early postoperative VAS was quite higher, and there was also a greater percentage of patients requiring rescue analgesia in early postoperative period in nalbuphine group than compared to fentanyl group. This showed that intensity and quality of analgesia provided by the nalbuphine were inferior to fentanyl. None of the studies done in the past have shown poor VAS with intrathecal nalbuphine. Studies done by Jyothi et al., Culebras et al., and Gomaa et al. have shown lesser VAS scores with prolongation of analgesia with nalbuphine group.[41113] Lesser potency of nalbuphine and its agonist and antagonist property might be the cause for its poor efficacy when compared to fentanyl. This pharmacodynamic property of nalbuphine needs further study involving larger sample group.

Incidence of hypotension and bradycardia was not statistically significant between the groups in our study. This shows that both the opioids did not have any significant sympatholytic activity and rather enhanced the antinociception in the spinal cord. A study done by Tiwari et al., where combination of bupivacaine with nalbuphine was compared with plain bupivacaine and a study done by Singh et al., where fentanyl was compared to plain bupivacaine group. Both these studies have shown that the incidence of hypotension and bradycardia were lesser in adjuvant groups than compared to plain bupivacaine.[1516]

Sedation was comparable in both the groups; none of the patients in both the groups had sedation score more than two. It has been seen in previous studies that nalbuphine produces more sedation than fentanyl or morphine which contradicted our study.[17]

Pruritus was seen in four patients in fentanyl group, whereas none in nalbuphine group. Respiratory depression was not seen in both the groups.

The limitations of our study were we did not have control group and the sample size was less. There is conflicting pharmacodynamic property exhibited by nalbuphine which needs to be further researched.

CONCLUSION

Although nalbuphine of 0.8 mg was equally efficacious in providing intraoperative surgical anesthesia, hemodynamic stability with fewer side effects. It was not as efficient as 25 μg of fentanyl in providing postoperative analgesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.