|Year : 2019 | Volume
| Issue : 1 | Page : 112-118
Intrathecal nalbuphine versus fentanyl as an adjuvant to bupivacaine in spinal anesthesia for elective cesarean section: a randomized double-blind study
Farahat I Ahmed
Department of Anesthesia and Surgical Intensive Care, Zagazig University, Zagazig, Egypt
|Date of Submission||24-Dec-2017|
|Date of Acceptance||03-Dec-2018|
|Date of Web Publication||27-Feb-2019|
Farahat I Ahmed
41 Elssehabah Street, Hadayek Alkobbah, Cairo
Source of Support: None, Conflict of Interest: None
Background Opioids have been used as an adjunct to bupivacaine in spinal blockade to enhance the onset of action, to improve the quality of intraoperative and postoperative analgesia, and to increase the duration of block. Fentanyl is a synthetic opioid agonist and nalbuphine is a synthetic opioid agonist-antagonist. The present study aimed to compare the effects of adding nalbuphine or fentanyl as an adjunct to bupivacaine on the characteristics of spinal blockade, quality of postoperative analgesia, and on fetomaternal outcome after elective cesarean section.
Participants and methods A total of 80 full-term parturients scheduled for elective cesarean section were randomly allocated into two groups. Nalbuphine group (BN group) included parturients who received 12.5 mg of 0.5% hyperbaric bupivacaine with 800 μg nalbuphine intrathecally. Fentanyl group (BF group) included parturients who received the same dose of hyperbaric bupivacaine with 25 μg fentanyl intrathecally. Subarachnoid blockade characteristics, duration of postoperative analgesia, the amount of postoperative analgesic requirements, maternal adverse effects, and neonatal outcome were compared.
Results Onset of sensory and complete motor block, maximum height of sensory block, and time to two-segment sensory regression were significantly faster in BF group than in BN group. Maximum dermatomal block level was significantly higher in BF group than in BN group. The duration of motor block and the quality of anesthesia of both groups were comparable. Durations of postoperative complete and effective analgesia were highly significantly longer in BN group than the corresponding durations in BF group (P<0.001 and 0.002, respectively). The postoperative 24-h analgesic doses of ketorolac and pethidine were less in BN group than in BF group (P=0.03, 0.005, respectively). There was no pruritus in BN group (0%), but it occurred in five (12.5%) parturient in BF group, which was mild. The incidence of shivering was significantly lower in BN group (7.5%) than in BF group (27.5%) (P=0.01). Neonatal APGAR (Airway, Pulse, Grimace, Activity, Respiration) score and neurologic and adaptive capacity score were comparable between the two groups.
Conclusion As an adjunct to hyperbaric bupivacaine in spinal block, fentanyl was superior to nalbuphine in enhancing the onset of both sensory and motor block. Nalbuphine is superior to fentanyl in increasing the duration of postoperative complete and effective analgesia and in decreasing incidences of pruritus and shivering, and both drugs have similar effects on neonatal APGAR score and neurologic and adaptive capacity score.
Keywords: cesarean section, fentanyl, nalbuphine, spinal anesthesia
|How to cite this article:|
Ahmed FI. Intrathecal nalbuphine versus fentanyl as an adjuvant to bupivacaine in spinal anesthesia for elective cesarean section: a randomized double-blind study. Res Opin Anesth Intensive Care 2019;6:112-8
|How to cite this URL:|
Ahmed FI. Intrathecal nalbuphine versus fentanyl as an adjuvant to bupivacaine in spinal anesthesia for elective cesarean section: a randomized double-blind study. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2022 Dec 2];6:112-8. Available from: http://www.roaic.eg.net/text.asp?2019/6/1/112/253114
| Introduction|| |
Most anesthetists prefer spinal anesthesia over general anesthesia (GA) in cases of cesarean section (CS) delivery, as it avoids the risk of aspiration that may occur with GA, avoids the neonatal depressant effect of GA, and provides postoperative analgesia. However, it also has disadvantages, as it provides a relatively fixed short duration of anesthesia, causes sympathetic block with subsequent hypotension and bradycardia, lesser control on the level of blockade, may give insufficient visceral block with visceral pain, and the possible occurrence of nausea and vomiting especially during uterine manipulation and peritoneal closure .
Bupivacaine, which is the most commonly used drug for spinal anesthesia, has slow onset, high potency, and relatively short postoperative analgesia. The intrathecal (IT) dose of hyperbaric bupivacaine for CS ranges from 12 to 15 mg . Peritoneal traction and handling of intraperitoneal organs during cesarean delivery lead to intraoperative visceral pain. Increasing the dose of hyperbaric bupivacaine leads to reduction of the incidence of intraoperative visceral pain  but on the expense of the possibility of the risk of higher blockade and its adverse effects.
To avoid these drawbacks, a number of adjuvants have been used. The commonly used adjuvants include opioids such as fentanyl  and nalbuphine ; α2 stimulants such as clonidine  and dexmedetomidine ; NMDA receptor antagonist such as ketamine ; GABA receptor agonists such as midazolam ; etc.
Opioids are the most popular used adjuvants added to bupivacaine in spinal blockade to obtain a sufficient intraoperative visceral analgesia and increase the duration and quality of postoperative analgesia, with less sympathetic block and hemodynamic effect .
Because there are relatively limited published data on the comparison between the effects of addition of nalbuphine (opioid agonist-antagonist) and fentanyl (opioid agonist) as adjuvant to bupivacaine in spinal blocked for CS, so the aim of the present study was comparing the effect of nalbuphine or fentanyl as an adjunct to hyperbaric bupivacaine on the characteristics of spinal blockade, postoperative analgesia, and effects on the mothers and newborns after elective CS delivery.
| Participants and methods|| |
The study was conducted at Zagazig University Hospital between November 2015 and August 2016. After approval from Institutional Review Board (IRB) and obtaining a written informed consent from all parturients, 80 full-term singleton parturients aged 20–40 years old with American Society of Anesthesiologists physical status I and II enrolled for elective cesarean delivery were included in the study. They were randomly allocated into two equal groups, with 40 parturients each, using a computer-generated randomization schedule and sealed opaque envelope method. The nature of anesthetic technique, clinical study, and the drugs used in the study were explained to all parturients.
The following were the exclusion criteria:
- Age below 20 or above 40 years.
- Contraindications to spinal blockade, such as patient refusal, cardiorespiratory problems, coagulopathy, neurological disease, psychological troubles, endocrinal disease, and allergy to the used drugs.
- Morbid obesity.
- Failure of spinal blockade.
- Emergency CS.
- Complicated pregnancy.
- Intrauterine fetal compromise.
During the preoperative evaluation and clinical assessment, all parturients were educated about the use of 10 cm visual analog scale (VAS) for pain assessment, where 0 scale points at no pain and 10 to the worst pain.
The first group was the nalbuphine group (BN group) in which the parturient received 2.5 ml of 0.5% hyperbaric bupivacaine (12.5 mg) (Marcaine spinal heavy 0.5% by Astra Zeneca, Buyukdere Cad. Yapi Kredi Plaza B Blok Kat: 3-4 Levent, Istanbul, turkey) plus preservative-free 800 μg nalbuphine hydrochloride (Nalufin, 1 ml ampoule 20 mg, product of Amoun Pharmaceutical Co. (El Obour city, Cairo, Egypt), SAE) in 0.5 ml sterile water (total volume 3 ml) IT.
The second group was the fentanyl group (BF group) in which the parturients received the same dose of bupivacaine plus 25 μg fentanyl (0.5 ml) IT (Fentanyl Hameln 0.1 mg/2 ml manufactured by Sunny Pharmaceutical (100 Acre Industrial zone, Badr City, Egypt) under license of Hameln Pharmaceutical, Germany).
To facilitate blinding, both groups and observers were blinded to the tested drug. The night before surgery, all parturients were given an oral 150-mg ranitidine and fasted six hours before surgery. On arrival to the operating room, an 18-G intravenous cannula was fixed and then 10 ml/kg lactated Ringer’s solution was administered over 15 min. Standard monitoring was applied included ECG, pulse oximetry, and noninvasive blood pressure.
Under septic precaution, spinal anesthesia was performed with parturient in sitting position. At the level of L3-4 or L4-5 interspinous space, paramedian space was identified, and then infiltrated with 2 ml of 1% lidocaine. Then a 25-G Quinqe spinal needle was inserted via paramedian approach. After verification of free CSF flow, the local anesthetic mixture was administered over 15 s. Immediately after the injection of the anesthetic mixture, all the parturients were put in supine position with a wedge under the right hip to keep left uterine displacement. Maternal heart rate, pulse oximetry (SpO2), respiratory rate, and noninvasive blood pressure were recorded every 5 min until the end of surgery.
The data recorded
Characteristics of spinal blockade were as follows:
- Time pre min to T5 dermatomal block level.
- Maximum dermatomal block height.
- Time per min to maximum dermatomal block height.
- Time per min to two-segment regression from the highest level.
- Onset of complete motor blockade: it is the time per min from local anesthetic mixture injection until Bromage scale to be 3.
- Duration of motor block: it is the time per min from local anesthetic mixture injection until Bromage score 0.
- Quality of anesthesia: after surgery, the maternal satisfaction was evaluated by using a four-point scale, where 1 was poor; 2, satisfactory; 3, good; and 4, excellent.
After IT injection of LA mixture, the sensory blockade was assessed by using loss of pin-prick sensation at the med-clavicular lines on both sides every 2 min for ten minutes, every 5 min for the next 20 min, and then every 15 min until two-segment regression from the highest dermatomal block level. The motor blockade was assessed every 2 min for 10 min and then every 15 min till Bromage scale returned to 1. Assessment of motor blockade was done by using Bromage scale  as follows:
0=can flex an extended leg at the hip joint.
1=can flex knee but cannot flex extended leg.
2=can move foot only.
3=cannot move foot.
Durations of postoperative analgesia and the consumed analgesic dose in the first 24 h postoperatively in the two studied groups:
- Duration of complete analgesia, which was defined as the time interval from the subarachnoid block to the first sensation of pain (VAS >0).
- Duration of effective analgesia: it is the time interval from the subarachnoid block to the first analgesic intervention (VAS >3) where intravenous 30 mg keterolac was administered and can be repeated after 6 h if needed. If the mother was still complaining of pain or the VAS was still greater than 3 after 20 min from ketorolac injection, she was given intravenous pethidine in a dose of 0.5 mg/kg.
Maternal adverse effects
All mothers were monitored for the associated adverse effects such as postoperative nausea and vomiting (PONV), sedation, pruritus, hypotension, bradycardia, shivering, and respiratory depression:
- PONV was treated with intravenously 10 mg metoclopramide.
- Sedation was assessed by using a six-point Ramsay sedation scale :
- 1=restless or agitated.
- 2=oriented, calm, and cooperative.
- 3=obey commands.
- 4=Brisk response to loud voice stimulus or light glabellar tap.
- 5=Sluggish response to loud voice or light glabellar tap.
- 6=no response to loud voice stimulus or light glabellar tap.
- Pruritus was treated by intravenously 25 mg diphenhydramine (antihistaminic) but if the pruritus was still persistent or severe, intravenous infusion of naloxone at 1 μg/kg/h was used.
- Hypotension: fall in SBP greater than 25% from baseline measurements and was treated with intravenous incremental doses of 5 mg ephedrine.
- Bradycardia: heart rate less than 60 beats/min that was treated with intravenous atropine in a dose of 0.01 mg/kg.
- Shivering was treated by intravenous 25 mg pethidine.
After delivery, the neonate was evaluated by a pediatrician, who was blinded about the study, using both APGAR (Airway, Pulse, Grimace, Activity, Respiration) score  at one and five minutes and neurologic and adaptive capacity score (NACS)  at 15 min and 2 h after delivery.
Based on a previous study by Culebras et al. , the postoperative complete analgesia was considered as the primary outcome that enables primary endpoint verification with test power 0.8 and significance level 0.05. The required sample size was 33 parturients in each group. A total of 80 parturients were included in this study to compensate for possible dropouts. Moreover, choice of 800 μg of IT nalbuphine was the best among three different doses, which provided improved postoperative analgesia without adverse effects.
All statistics were performed using SPSS version 20.0 for windows (SPSS Inc., Chicago, Illinois, USA). Continuous variables were analyzed and compared by using independent Student’s t-test. Categorical variables were analyzed and compared using the Pearson’s χ2-test or Fisher exact test when appropriate. All tests were two sided. P value less than 0.05 was considered significant and less than 0.01 was considered highly significant.
| Results|| |
Parturient demographic data and duration of surgery of the two studied groups
The study was conducted on 80 parturients, with 40 in each group. The demographic data and duration of surgery in both groups were statistically comparable ([Table 1]).
|Table 1 Parturient demographic variables and the duration of surgery of the two studied groups|
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Characteristics of spinal blockade
The level of spinal needle insertion was comparable in both groups. Time to T5 sensory block was significantly faster in BF group than in BN group. Maximum sensory block height was highly significantly higher in BF group than in BN group. Time to maximum sensory block was significantly shorter in BF group than in BN group. Time to two-segment regression from the highest level was longer in BN group than in BF group. Onset of complete motor block was highly significantly faster in BF group than in BN group. The duration of motor block and the quality of anesthesia were comparable in both groups ([Table 2]).
Durations of postoperative analgesia and the consumed analgesic dose in the first 24 h postoperatively in the two studied groups
Durations of complete postoperative analgesia was highly significantly longer in BN group than in BF group (Р<0.001). Durations of effective postoperative analgesia was significant longer in BN group than in BF group (Р=0.002). The consumed analgesic dose in the first 24 h postoperatively was significantly lower (Р=0.003 for total ketorolac dose and 0.005 in total intravenous pethidine) in BN group than the corresponding values in BF group ([Table 3]).
|Table 3 Durations of postoperative analgesia and the consumed analgesic dose in the first 24 h postoperatively in the two studied groups|
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Maternal adverse effects
The incidences of pruritus and shivering were significantly higher in BF group than the corresponding incidences in BN group (Р=0.02, 0.01, respectively), but the incidence of PONV, sedation, hypotension, and bradycardia of both groups were comparable (Р>0.05). Respiratory depression was not detected in both groups ([Table 4]).
|Table 4 The incidences of maternal adverse effects in the two studied groups|
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Neonatal APGAR score at 1 and 5 min and NACS score at 15 min and 2 h after delivery of both groups were comparable ([Table 5]).
| Discussion|| |
The use of opioids as an adjunct to local anesthetics for neuraxial blockade has increased over the past decades. The combination of local anesthetics and opioids reduces the doses of both drugs with subsequent decrease in the incidences of the associated adverse effects of each one, improves the quality of anesthesia, and increases the duration of postoperative analgesia. Neuraxial opioids appear to act principally on μ-receptor in the substantia gelatinosa of the dorsal horn of spinal cord by inhibition of excitatory neuropeptide release from c-fibers .
Fentanyl is a strong µ-opioid receptor agonist. It is a lipophilic opioid, has fast onset of action after IT administration, provides better intraoperative analgesia, and is more safe than morphine for management of early postoperative pain as it does not spread to the fourth ventricle in sufficient concentration to cause delayed depression of the respiratory center after IT administration . Nalbuphine is a κ-opioid receptor agonist and μ-opioid receptor antagonist. It provides a potent analgesic effect in some cases of visceral pain . It has also complicated interactions with μ-opioid receptor agonists with a possible dose-dependent synergistic action and also a significant antagonizing effect when given at higher doses . If given systematically, the κ receptor agonist drugs have the advantage of a decreased incidence of respiratory depression. Moreover, they antagonize the adverse effects of spinal opiates (e.g. morphine and fentanyl) that have μ-receptor agonist actions such as pruritus, respiratory depression, and urine retention ,,. Moreover, it was observed that the κ-agonists may produce an unexpected action in female patients, suggesting the significant effect of sex on the response to such drugs .
In the present study, it was found that, as an adjunct to 12.5 mg hyperbaric bupivacaine in subarachnoid block, fentanyl (25 μg) was superior to nalbuphine in enhancing the onset of both sensory and motor blockade. However, nalbuphine (800 μg/mg) was superior to fentanyl in increasing the duration of postoperative complete and effective analgesia with decreased incidences of pruritus and shivering. Both drugs have similar effects on neonatal outcome as assessed by using both APGAR and NACS.
There are some published papers in agreement and others in partial agreement with the present study findings. Gupta et al.  compared 2-mg nalbuphine with 25-μg fentanyl IT as adjuvant to 17.5-mg hyperbaric bupivacaine in spinal anesthesia for lower limb orthopedic surgery. They noticed prolonged duration of both sensory and motor blockade, more enhanced postoperative analgesia, and less adverse effects in patients who received nalbuphine than in those who received fentanyl. Srivastava et al.  used IT fentanyl with heavy lidocaine and noticed that fentanyl not only enhanced the onset and increased the duration of sensory block but also prolonged the postoperative analgesic duration without affecting the recovery of motor block. Zeng et al.  performed a meta-analysis study including analysis of 15 trials (820 patients) to compare nalbuphine with morphine regarding the safety profile and quality of analgesia. They reported that both drugs provided a similar analgesic effect, but nalbuphine was safer than morphine owing to absence of respiratory depressant effect and deceased incidences of other adverse effects as such nausea, vomiting, and pruritus, which were currently observed with morphine. On the contrary, Vashishth et al.  compared the effects of adding nalbuphine or fentanyl as an adjuvant to bupivacaine in subarachnoid block in patients scheduled for lower abdominal and lower limb surgeries, and they noticed that fentanyl is better than nalbuphine in terms of onset of block and duration of analgesia without any significant hemodynamic disturbances and adverse effects. The higher incidences of pruritus and shivering in fentanyl group that were detected in present study but were not detected in the study by Vashishth et al.  study may be attributed to the different fentanyl doses that were used in each study and different patient group. Fentanyl dose was 25 μg in the present study and was 10 μg in the study by Vashishth et al. .
In the present study, the selected 800 μg nalbuphine as adjuvant dose to bupivacaine (12.5 mg) in spinal anesthesia for CS was according to the finding of Culebras et al. . They compared the efficacy for postoperative pain relief and adverse effects of three different doses (200, 800, and 1600 μg) of IT nalbuphine with 200 μg of IT morphine for cases of cesarean deliveries. Among the nalbuphine-treated groups, 800-μg dose gave the longest durations of both complete and effective postoperative analgesia. Increasing the nalbuphine dose to 1600 μg did not have further analgesic effect which may be attributed to nalbuphine ceiling effect above 800-μg dose. Neither pruritus nor PONV was noticed with 200 μg or 800 μg nalbuphine. The authors concluded that IT 800-μg nalbuphine was considered the optimum dose that produces a similar analgesic effect as 200-μg morphine with minimal adverse effects.
In their prospective study, Moustafa and Saleh  have reported that the addition of 1-mg nalbuphine to 0.2-mg morphine during subarachnoid blockade anesthesia antagonizes the morphine-induced adverse effects such as nausea-vomiting and pruritus without any effect on the duration of postoperative analgesia, analgesia quality, or the degree of postoperative rescue analgesic requirement dose.
Recently, Raghuraman  studied the effects of IT nalbuphine in the few available literatures and reported that nalbuphine when added to the LA for subarachnoid block anesthesia provided a good quality and prolonged duration of postoperative analgesia with a valuable antishivering and antipruritic effect, with decreased incidence of nausea-vomiting.
This study found no limitations except for the refusal of spinal anesthesia by a considerable number of parturients.
| Conclusion|| |
As an adjunct to hyperbaric bupivacaine in subarachnoid block anesthesia, fentanyl is better than nalbuphine in enhancing the onset of both sensory and motor block. However, nalbuphine is better than fentanyl in increasing the duration of postoperative complete and effective analgesia, decreasing the postoperative rescue analgesic requirement, and in decreasing maternal adverse effects such as pruritus and shivering. Therefore, IT nalbuphine is a safe and a valuable alternative to IT fentanyl for spinal anesthesia in CS.
Financial support and sponsorship
Conflicts of Interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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