Caudal Nalbuphine versus Fentanyl with Bupivacaine for Postoperative
Analgesia in Children Undergoing Lower Abdominal Surgeries: A
Randomized Controlled Double Blind Non –Inferiority Study
Gangur B. Sumalatha1 and Ravichandra R. Dodawad2* 1,2Department of Anaesthesiology, ESIC Medical College,
Received date: April 21, 2018; Accepted date: : May 29, 2018; Published date:
June 05, 2018.
*Corresponding author: Dr. Ravichandra R Dodawad, Assistant Professor,
Department of Anaesthesiology, ESIC Medical College, Gulbarga, #3, 1st floor,
Yamunadeep apartments, opposite HKE dental college, jayanagar, Gulbarga,
Kartnataka, India, 565105, Tel,: 9986514152, E-mail: firstname.lastname@example.org
Background and Aims: Nalbuphine is an agonist -antagonist opioid having analgesic and sedative effects and ceiling effect to respiratory depression. The aim of this study is to compare the effect of caudal nalbuphine and fentanyl as adjuvant in providing post-operative analgesia.
Methods: One hundred and ninety two patients with the American society of anesthesiologists’ physical status I–II, aged 2–7 years enrolled
in this study were randomly assigned in to two groups as (n=96), Group BF(bupivacaine – fentanyl) and BN(bupivacaine -nalbuphine). Both
groups received caudal bupivacaine (0.125%) 1ml/kg. Pain was evaluated using Wong -Baker FACES scale post-operatively at the time of
first rescue analgesia (FACES-R) and at 24hr (FACES-24h). The frequency of rescue analgesics was also noted along with side effects 24
Results: Comparison of pain scores in both groups did not differ significantly. FACES –R and FACES-24h score in Group BN and Group
BF was 1.7±1.1 versus 1.8±1.06 and 0.6±1.3versus 0.3±1.0 respectively which was statistically not significant. The frequency of rescue
analgesics received was comparable in both groups. Two children had vomiting in group BF whereas none of the children in group BN
complained nausea and vomiting. No other side effects were noted in either group.
Conclusion: Caudal nalbuphine 0.2mg/kg added to bupivacaine provides effective post-operative analgesia and is non-inferior to 1μg/kg
of fentanyl with no significant side effects.
Keywords: Analgesia; Bupivacaine; Caudal block; Fentanyl; Nalbuphine;
Caudal block is useful as an adjunct during general anaesthesia and
for providing post-operative analgesia after infraumblical operations
. Fentanyl has been widely used as an analgesic adjuvant to epidural
analgesia. However it has undesirable side effects as respiratory depression,
itching and vomiting [2,3]. Nalbuphine has relatively potent μ-antagonist
and κ-agonist activity. The respiratory depression induced by opioids is
primarily mediated by the μ-receptor agonist activity. The μ-antagonist
properties of the nalbuphine produce fewer μ-mediated side effects such as
respiratory depression, pruritus, nausea and vomiting [4-6]. In addition,
presently there are no studies reporting the efficacy of caudal nalbuphine
versus fentanyl. The aim of this prospective, randomized, double-blind
study, therefore, was to investigate the non-inferiority of nalbuphine to
fentanyl and to assess efficacy and side-effects of caudal nalbuphine as an
adjuvant by single shot technique in children.
committee clearance as well as informed consent from all parents.
One hundred and ninety two children in the age group of 2-7 years,
American society of anaesthesiologists physical status I-II, posted for
elective paediatric short surgical procedures below the umbilicus were
included in the study The study was conducted from May 2016 to October
2017. Children with co-existing medical illness, coagulation disorders,
anatomical abnormalities of the spine, metabolic and endocrine disorders,
infection at the local site, known allergy to local anaesthetics and with
anticipated difficult intubation were excluded. Thorough pre-anaesthetic
evaluation and required investigations were done the day before surgery.
General pre-operative fasting guidelines were followed. One hundred
and ninety two children were randomly divided into two groups:
Bupivacaine-Fentanyl (BF) and Bupivacaine-Nalbuphine (BN) of 96 each
as shown in figure 1. Group BF received 1ml/kg of 0.125% bupivacaine
(Anawin 0.25%, Neon laboratories, Andheri East Mumbai) plus fentanyl
(Fent 50μg/ml, Neon laboratories, Andheri East, Mumbai) 1μg/kg and
Group BN received 1ml/kg of 0.125% bupivacaine plus nalbuphine
(Nacphin, 10mg/ml, Neon Laboratories, Andheri East, Mumbai) 0.2mg/
kg for caudal block. Randomization was done using computer generated
random numbers inserted into opaque-concealed envelopes; inside these
envelopes was a number, which indicates the group to which the patient
was assigned. The drug was prepared by one anaesthesiologist who gave
unlabelled syringes to the anaesthesiologist performing the block who
was blinded to the solution of bupivacaine and adjuvant, thus ensuring
double blindness of the study. After securing intravenous (IV) access with
appropriate- sized IV cannula, all children were pre-medicated before
induction. Pre-operative heart rate (HR), blood pressure (BP), oxygen
saturation (SPO2) and Respiratory Rate (RR) were recorded using routine
monitors. After pre-oxygenation with 100% O2 for 3 min, anaesthesia
was induced with injection - Propofol 2mg/kg IV, and tracheal intubation
(with appropriate-sized endotracheal tube) was facilitated by injection
succinylcholine 1.5 mg/kg iv followed by Intermittent Positive Pressure
Ventilation (IPPV). Anaesthesia was maintained with sevoflurane, N2O
and oxygen and injection atracurium 0.3 mg/kg was given for maintenance
of neuromuscular blockade. IPPV was continued with Jackson Rees
modification of Ayre’s T-piece. IV fluid administration was done using
Holliday and Segar formula. Thereafter, patients were positioned in a
lateral decubitus and caudal space was identified under aseptic technique
with 25-gauge needle. After negative aspiration for blood or cerebrospinal
fluid, appropriate drugs were injected depending on the group to which
they were assigned. The patient was handed over to surgeon after 20 min
of caudal block. Any increase in the HR or mean arterial pressure within
15 min of skin incision indicated failure of caudal analgesia. If the readings
increased by more than 15%, the child received a rescue opioid and the
caudal analgesia was considered failure and the patient was excluded from
the study. Hypotension (Systolic pressure; mmHg 70+2× age in years)
and bradycardia (HR 20% decrease from baseline for that specific age)
 if any, were noted and treated appropriately. At the end of surgery,
neuromuscular blockade was reversed with injection neostigmine 0.05
mg/kg and injection atropine 0.02 mg/kg. Extubation was done once the
extubation criteria were fulfilled. Assessment of pain was done by using
Wong-Baker FACES scale . It consists of six Cartoon faces ranging
from smiling face for “no pain” to tearful face “worst pain”. The score
is given from 0-5 indicating as: 0 – no hurt; 1 – hurts little bit; 2-hurts
little more; 3- hurts even more; 4-hurts whole lot; 5- hurts worst. Rescue
analgesic was given if FACES scale score was ≥ 3 with iv tramadol 1mg/kg
Since, the aim of the study was to test the non-inferiority of nalbuphine
to fentanyl; FACES score at the time of rescue analgesia was taken as
primary end point. To assess the efficacy of nalbuphine, the mean time
for rescue analgesia and the total number of rescue analgesics received in
24h was noted down. The two groups were assessed in the post-operative
room for sedation, nausea and vomiting and residual motor block for 15
min for the 1st h and then hourly for 6h. HR, BP, RR and SPO2 were also
recorded. After 6h, the children were observed and monitored 6 hourly
for 24h using the same parameters. Assessment of sedation was done
by Ramsay sedation . Side effects such as post-operative nausea and
vomiting, pruritis, urinary retention, and respiratory depression (RR < 10
or SPO2< 90%) were recorded.
The required number of subjects per group was calculated from the
where μ1 was 2.1 (mean FACES score of fentanyl
group in a pilot study), μ2 was 2.5, (mean FACES score of nalbuphine
group in a pilot study), the non-inferiority margin was 1.5 and α was
0.05, β was fixed at 0.2. The pilot study included 16 patients and based
on this calculation and assuming a 10% dropout rate, the study required
100 patients per group. We assessed 200 patients for eligibility, of which
8 did not meet the inclusion criteria, and 192 were recruited. Figure 1
Figure 1: Consort Flow Diagram showing the study phases
depicts the flow diagram of patient progress through the study. All
enrolled patients were randomized (group: BN = 96; group BF = 96) and
completed the study, and their data were analyzed. All the values were
expressed as Mean±SD or percentage. Qualitative data (ASA grade,
residual motor block and complications) were compared using Chisquare
test incorporating Fishers exact test and quantitative data (age,
weight, heart rate, blood pressure, duration of analgesia) were compared
using unpaired and paired t-test. A linear mixed model was used to
compare simultaneous FACES score, to account for correlations between
repeated observations The non inferiority of nalbuphine to fentanyl was
analysed using 95% Confidence Intervals (CI) for the difference in FACES
score (μ2−μ1, as above). Noninferiority was confirmed when the upper
95% CI was less than the no inferiority margin i.e 1.5(the largest change
from the reference value considered to be trivial). All statistical analyses
were performed with SPSS® version 17.0 (SPSS Inc., Chicago, IL, USA) for
Windows®. P-values < 0.05 were considered statistically significant.
The demographic data and types of surgeries between the two groups
were comparable as shown in table 1 and figure 2 respectively. There was
no statistically significant difference among the two groups as regards
to HR, BP and SPO2. The mean FACES score at the time of first rescue
analgesia and at 24hr was comparable in both groups and the analgesic
effect of nalbuphine was not significantly inferior to that of fentanyl at
24 h after surgery as shown in table 2. Post-operative pain as assessed by
FACES scale was comparable in both groups as shown in table 3. In group
BF, 92(95.8%) children and in group BN ,90(93.7%) children received 2-
times rescue analgesia whereas 4(4.1%) and 6(6.2%) children in group BF
and group BN respectively, received 3-times rescue analgesia which was
statistically not significant as depicted in table 4. Anaesthetic recovery was
not delayed in any child in both the groups. There was no incidence of
residual motor block observed in both the groups. The patients in Group
BF were significantly more sedated than the ones in Group BN, till 1h
postoperatively. The median values of sedation score at 30 min and 60
min are shown in table 5. Beyond this time, the sedation scores were
not significantly different amongst the two groups. All the children in
the study groups were wide awake and alert by 2h postoperatively. Two
children had nausea and vomiting in group BF whereas none of the
children in group BN complained nausea and vomiting. No other side
effects were observed in either of the group.
Figure 2: Types of surgeries among the two groups
Table 1: Demographic data
Duration of surgery (min)
BN – Bupivacaine nalbuphine; BF – Bupivacaine fentanyl; SD – Standard
deviation; NS – Not significant
Table 2: Test of non-inferiority between nalbuphine and fentanyl
Group BN n-96
Group BF n-96
TIME OF 1ST Rq Analgesia
FACES – 24h
Data presented as mean±SD, FACES-R – FACES score at the time of first
rescue analgesia; Rq – rescue analgesia; min-minutes;FACES -24h- FACES
score at 24 h postoperatively; BN – Bupivacaine –nalbuphine, BFBupivacaine-
fentanyl, NS- not significant
Table 4: Frequency of rescue analgesics in 24 hour
Number of rescue analgesics
Group BF Group BN
Group BF- Bupivacaine fentanyl;BN-Bupivacaine –nalbuphine; NS – not
Table 5: Median (interquartile range) of sedation score
After 30 min
After 60 min
After 120 min
Group BN – Bupivacaine-nalbuphine; Group BF – Bupivacaine-fentanyl; * -
significant ;NS-not significant
The result of our study showed that addition of 0.2mg/kg as adjuvant
to bupivacaine for postoperative analgesia in children undergoing elective
lower abdominal surgeries is effective and non-inferior to fentanyl
with reduced postoperative FACES pain scores. Nalbuphine is a mixed
K-agonist and μ-antagonist opioid of the phenanthrene group and its
structure is similar to those of naloxone and oxymorphone. The drug
is used for managing slight and moderate pain. Its affinity to K-opioid
receptors results in analgesia, sedation and cardiovascular stability with
minimal respiratory depression. The analgesic effect of nalbuphine has
been found to be equal to the analgesic effect of morphine but unlike it
has a ceiling effect on respiration . The drug used in recommended
doses is believed not to induce respiratory depression in children. Many
authors consider that the profile of its action is safe . The safety and
efficacy of nalbuphine is established through the epidural route . The
pharmacokinetic profile of epidural nalbuphine was similar to that seen
with rapid intravenous injection. The dose of maximum analgesic action
of nalbuphine is 0.3-0.4mg/kg. Higher doses neither increase the analgesic
effects nor substantially increase the risk of respiratory failure Nalbuphine
for post-operative management in children can be used in boluses at a
dose of 0.2mg/kg .
In one of their study by Salama et al, compared 0.2 mg/kg caudal
nalbuphine added to levo-bupivacaine in pediatric infraumblical surgeries
and concluded that 0.2mg/kg nalbuphine as an adjuvant was associated
with prolonged duration of analgesia and reduced analgesic requirements
with no side effects when compared to levo-bupivacaine alone . In
another study, caudal nalbuphine at a dose of 0.1mg/kg was compared
with caudal dexmedetomidine in which the authors concluded that
dexmedetomidine prolonged the duration of analgesia when compared
to nalbuphine . Based on these references we decided the dose of
nalbuphine as 0.2mg/kg in our study. The dose of the fentanyl 1μg/kg was
based on our routine institutional practice. The current study compared
the caudal nalbuphine 0.2mg/kg and fentanyl1μg/kg in paediatric
population who underwent lower abdominal surgeries in terms of, post
operative pain score, sedation score and side effects. As regards to the
primary outcome, post-operative pain FACES score caudal nalbuphine
and fentanyl did not show statistically significant difference. The mean post
–operative FACES score at the time of first rescue analgesic (Group BN
1.7±1.1 versus Group BF 1.8±1.06) and at 24 hr (0.6±1.3 versus 0.3±1.0)
were comparable in both groups. Similarly there was no statistically
significant difference in the Faces scale. The mean duration of analgesia
in nalbuphine and fentanyl groups was comparable. In a study assessing
nalbuphine at a dose of 0.2 mg/ kg as adjuvant to levo-bupivacaine,
nalbuphine delayed the time for the first analgesic requirement .
Similar observation was reported in another study with 0.1mg/kg of
caudal nalbuphine [19,20]. These results were consistent with the results
of the current study in the effectiveness of nalbuphine in post-operative
analgesia but differ in using the concentration of bupivacaine. A study by
shin et al, evaluated the postoperative analgesic efficacy of different doses
of caudal nalbuphine (3,5 and10mg ) with 1.5% lidocaine, in which10 mg
of nalbuphine significantly reduced the use of systemic analgesics in the
first 24h . Similarly two other studies showed that 10mg of epidural
nalbuphine compared to morphine and tramadol provided better quality
of analgesia with lesser incidence of side effects and complications with
better patient satisfaction score [22,23]. In contrast to these studies,
another study compared epidural butorphanol, nalbuphine and fentanyl
for postoperative analgesia in lower limb surgeries and the authors
concluded that butarphanol has longer duration of analgesia compared to
nalbuphine and fentanyl .
On note in our study the sedation score was significantly higher in
fentanyl group (4 children) and children responded for stimuli till 30 min
postoperatively. However at 2h postoperatively, all children were awake
and alert. Taking into account the incidence of nausea and vomiting, two
children in fentanyl group had nausea and vomiting. However none of
the children in nalbuphine group had nausea and vomiting. Compared
with other opioids, the nalbuphine-induced incidence of nausea and
vomiting is lower [16,21]. The side effects are observed in our study may
not reflect the accurate results as our study sample is intended only to find
the analgesic efficacy of nalbuphine.
Limitation of this study is the dose of nalbuphine which was
comparable to those used for IV analgesic therapy based on various
references. Thus our results may reflect systemic effects which needs
estimation of blood levels of nalbuphine in future studies. The other
limitation includes the small follow up duration of the patients and the
lack of important outcomes such as length of hospital stay. Till date no
studies have compared the efficacy of caudal fentanyl and nalbuphine in
post-operative analgesia especially in paediatric population; therefore
further studies are recommended on this aspect.
Nalbuphine 0.2mg/kg in caudal block is non-inferior to 1μg/kg fentanyl
in providing efficient analgesia with no significant side effects in the postoperative
pain management of children undergoing lower abdominal
Johr M, Berger TM. Caudal blocks. Paediatr Anaesth. 2012;22(1):44-50. doi: 10.1111/j.1460-9592.2011.03669.x
Ahuja S, Yadav S, Joshi N, Chaudhary S, Madhu SV. Efficacy of Caudal Fentanyl and Ketamine on Postoperative Pain and Neuroendocrine Stress Response in Children Undergoing Infraumblical and Perineal Surgery –A Pilot Study. J Anaesthesiol Clin Pharmacol. 2015;31;104-109. doi: 10.4103/0970-9185.150558
Cousins M. J. & Mather L. E. Intrathecal and epidural administration of opioids. Anesthesiology. 1984;61(3):276–310.
J Fioramonti, L Bueno . Centrally acting agents and visceral sensitivity. Gut. 2002;51 Suppl 1:i91-5.
Tkacz J, Pesa J, Vo L, Kardel P, Un H, Volpicelli J, et al. Opioid analgesic treated chronic pain patients at risk for problematic use. Am J Manag Care. 2013;19:871-880.
Gunion M, MarchionneA, Corrie T. Use of the mixed agonist-antagonist nalbuphine in opioid based analgesia. Acute Pain. 2004;6(1):29-39.
Elham M. El-Feky, Ahmed A.abd El Aziz. Fentanyl, dexmedetomidine, dexamethasone as adjuvant to local anesthetics in caudal analgesia in pediatrics: A comparative study. Egyptian journal of anaesthesia. 2015;31(2):175-180.
Aldrete JA, Kroulik DA. Post Anaesthetic recovery score. Anesth Analg. 1970;49:924-934.
International association for study of pain, Subcommittee on Taxonomy. Pain terms: a list with definitions and notes on usage. Pain. 1979;6:249-252.
Chambers CT, Giesbercht K, Craig KD, Bennett SM, Huntsman E. A comparison of facies scales for the measurement of paediatric Children’s and parents’ ratings. Pain. 1999;83:25-35.
Gehdoo RP. Postoperative pain management in paediatric patients. Indian Journal of Anaesthesia. 2004;48:406-414.
Mason KP, Lubisch BN, Robinson F, Roskos R. Intramuscular Dexmedetomidine Sedation for Pediatric MRI and CT. American Journal of Roentgenology. 2011;197:720-725. doi: 10.2214/AJR.10.6134.
Gear R.W, Miaskowski, C. and Gorden, N.C. The Kappa Opioid Nalbuphine Produces Gender and Dose Dependent Analgesia and Antianalgesia in Patients with Postoperative Pain. Pain. 1999;83(2):339-45.
Berg AA ,Honjol NM, Prabhu NV , Datta S, Rozario J, Muraleedaran R, et al. Analgesics and ENT surgery. A clinical comparison of the intraoperative, recovery and postoperative effects of buprenorphine, diclofenac, fentanyl, morphine, nalbuphine, pethidine and placebo given intravenously with induction of anaesthesia. Br J Clin Pharmacol. 1994;38:533−543.
Baxter AD, LaganièreS, Samson B, Hull K. A dose-response study of nalbuphine for post-thoracotomy epidural analgesia. Canadian Journal of Anaesthesia. 1991;38(2):175-182.
Anna Kubica-Cielińska, Marzena Zielińska. The use of nalbuphine in paediatric anaesthesia. Anaesthesiology Intensive Therapy. 2015:47(3);252–256. doi: 10.5603/AIT.2015.0036
Salama AK. Comparison between caudal levobupivacaine versus levobupivacaine–nalbuphine for postoperative analgesia in children undergoing hernia repair: A randomized controlled double blind study. Egyptian Journal of Anaesthesia. 2016;32:83–87.
Salama AK, Galante D, Abdallah NM. Comparison between caudal dexmedetomidine and nalbuphine in children undergoing hypospadias surgery: a prospective randomized double blind controlled study. Pediatric Anesthesia and Critical Care Journal. 2016;4(1):48-54. doi:10.14587/paccj.2016.10
Mohamed MF, Husein RM, El Sonbaty MI, Khattab SM. A comparative study of caudal epidural bupivacaine and bupivacaine plus nalbuphine in postoperative analgesia in children. Ain-Shams J Anaesthesiol. 2015;8:628-633.
Saleh RH, Mohammad FY, Heba Mohammad Nassar, Tamer Fathy Younes. Effect of nalbuphine as an adjuvant on levobupivacaine induced caudal analgesia in children undergoing surgical procedures, controlled randomized double blinded study. Egyptian Journal of Anaesthesia. 2016;32:97-102.
Shin JS, Yoon DM, Lee KM, Oh HK. Postoperative analgesia by caudal nalbuphine HCL. J Kor Pain Soc. 1990;3(1):44–50.
Mok MS, Lippmann M, Wang JJ, Chan KH, Lee TY. Efficacy of epidural nalbuphine in postoperative pain control. Anesthesiology. 1984;61(3A).
Chatrath V, Attri J P, Bala A, Ranjana Khetarpal, DeeptiAhuja, and Sawinder Kaur. Epidural nalbuphine for postoperative analgesia in orthopedic surgery. Anesth Essays Res. 2015;9(3):326–330. doi: 10.4103/0259-1162.158004
Banerjee S, Pattnaik SK. A Comparative study between epidural butorphanol, nalbuphine and fentanyl for post-operative analgesia in lower abdominal susrgeries. Asian J Pharm Clin Res. 2017;10(5):383-388.