Synergistic Interaction between Fentanyl and

Bupivacaine Given Intrathecally for Labor Analgesia

Warwick D. Ngan Kee, M.B., Ch.B., M.D., F.A.N.Z.C.A., F.H.K.A.M.,
Kim S. Khaw, M.B.B.S., M.D., F.R.C.A., F.H.K.A.M., Floria F. Ng, R.N., B.A.Sc.,
Karman K. L. Ng, M.B., Ch.B., F.A.N.Z.C.A., F.H.K.A.M.,
Rita So, M.B., Ch.B., F.A.N.Z.C.A., F.H.K.A.M., Anna Lee, M.P.H., Ph.D.

ABSTRACT
Background: Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. How-
ever, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans.
Methods: Three hundred nulliparous women randomly received 1 of 30 different combinations of fentanyl and bupivacaine
intrathecally using a combined spinal-epidural technique for analgesia in the first stage of labor. Visual analogue scale pain
scores were recorded for 30min. Response was defined by percentage decrease in pain score from baseline at 15 and 30min.
Doseresponse curves for individual drugs were fitted to a hyperbolic doseresponse model using nonlinear regression. The
nature of the drug interaction was determined using dose equivalence methodology to compare observed effects of drug com-
binations with effects predicted by additivity.
Results: The derived doseresponse models for individual drugs (doses in micrograms) at 15min were: Effect = 100 dose /
(13.82 + dose) for fentanyl, and Effect = 100 dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine
produced greater effects than those predicted by additivity at 15min (P < 0.001) and 30min (P = 0.015) (mean differences,
9.1 [95% CI, 4.114.1] and 6.4 [95% CI, 1.211.5] units of the normalized response, respectively), indicating a synergistic
interaction.
Conclusions: The pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization
and quantification of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal
opioids and local anesthetics. (Anesthesiology 2014; 120:1126-36)

L IPOPHILIC opioids are commonly coadministered

with local anesthetics for spinal and epidural analgesia
in obstetrics and other subspecialties.13 Combining drugs has
What We Already Know about This Topic
Quantitative analysis of drug interactions is commonplace for
general anesthetics and sedatives, but has been little applied
the advantage of reducing the dose that would be necessary if to intrathecal drugs in clinical practice
either drug were used alone, thus potentially decreasing the Addition of fentanyl enhances the analgesic effect of intrathe-
incidence and severity of associated side effects such as hypo- cal bupivacaine for labor, but quantitative analysis of this inter-
tension and motor block.1 However, the nature of the phar- action has not been adequately described
macologic interaction between opioids and local anesthetics
given neuraxially has not been clearly elucidated in a clinical
context. Several studies in animals have reported a synergistic What This Article Tells Us That Is New
interaction.4,5 However, few experimental data examining the In a study of 300 parturients receiving intrathecal fentanyl and
interaction of neuraxial drugs in humans are available. bupivacaine for labor analgesia, these drugs interacted in a
The aim of this randomized, double-blinded study was to clearly synergistic fashion
describe the pharmacologic interaction between fentanyl and
bupivacaine when administered intrathecally in combina- Ethics Committee, Shatin, Hong Kong, China, and the pro-
tion for labor analgesia. We hypothesized that combinations tocol was registered in the Centre of Clinical Trials Clinical
of fentanyl and bupivacaine would produce greater analgesia Registry of the Chinese University of Hong Kong (reference
than that predicted by simple additivity between drugs. no. CUHK_CCT00124).
We recruited 300 women with American Society of Anes-
Materials and Methods thesiologists physical status 1 to 2 who matched the follow-
The study was approved by the Joint Chinese University of ing criteria: nulliparous, singleton pregnancy, gestation of
Hong Kong New Territories East Cluster Clinical Research 36 weeks or greater, in active labor with cervical dilatation
Presented in part as a free article at Obstetric Anaesthesia 2013, Bournemouth, United Kingdom, May 23, 2013.
Submitted for publication August 26, 2013. Accepted for publication November 27, 2013. From the Department of Anaesthesia and Inten-
sive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China (W.D.N.K., K.S.K., F.F.N., K.K.L.N.,
R.S., and A.L.).
Copyright 2014, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2014; 120:1126-36

Anesthesiology, V 120 No 5 1126 May 2014

Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017

 PERIOPERATIVE MEDICINE

5cm or less, visual analogue scale pain score 50mm or
greater (scale, 0100mm), and requesting neuraxial analge-
sia. Patients were excluded if they had a known fetal abnor-
mality, hypertension, a medical contraindication to regional
anesthesia, or received parenteral opioid within the preced-
ing 2h. Informed consent was obtained from all participants
in two stages. Initially, a research nurse approached patients
who were potentially suitable soon after admission to the
labor ward; an explanation of the study was given, and pre-
liminary verbal consent was obtained. Subsequently, if the
patient requested neuraxial analgesia, willingness to partici-
pate and patient eligibility were confirmed, written consent
was obtained, and the patient was entered into the study.
Patients were only recruited during office hours when mem-
bers of the investigating team were available.
Upon entering the study, patients were instructed on the
use of a 100-mm visual analogue scale ruler (0mm = no pain
and 100mm = worst pain imaginable) for assessment of pain
scores, a baseline measurement of pain score was recorded,
and intravenous prehydration of 500ml lactated Ringers
solution was given. Combined spinal-epidural (CSE) analge-
sia was then administered by using a needle-through-needle
system. The anesthesiologist was free to choose the patient
position. Under full aseptic precautions, an 18- or 16-gauge
Tuohy needle was inserted into the epidural space at what
was estimated to be the L3-4 or L4-5 vertebral interspace
using a loss-of-resistance technique with either air or saline
according to the anesthesiologists preference. A pencil-
point spinal needle was then inserted through the epidural
needle with intrathecal placement confirmed by free-flow
of cerebrospinal fluid. The study solution was then injected
intrathecally followed by removal of the spinal needle and
placement and fixation of an epidural catheter.
The study solution was 1 of 30 different combinations
of fentanyl and bupivacaine (table1). Drug combinations
were divided into five groups (n = 60 per group), each of
which contained fentanyl and bupivacaine in a fixed ratio.
Each group was subdivided into six subgroups (n = 10 per
subgroup) in which the ratio of fentanyl to bupivacaine was
constant, but the mass of drug varied on an approximately
log-based scale. Randomization was performed in blocks
of 30 (one code for each subgroup per block); a member
of the secretarial staff who had no patient contact inserted
coded instruction forms for each of the 30 different solu-
tions into individual opaque envelopes and then sealed,
thoroughly shuffled, and consecutively numbered them. An
envelope was opened for each patient after confirmation of
consent and participation but before commencement of the
CSE procedure. The solutions were prepared by one of the
investigators who was not involved with subsequent patient
assessment. All drugs were freshly prepared by careful serial
dilution with aseptic precautions, diluted to a total volume
of 2.5ml with saline in identical syringes, and maintained
under sterile conditions until use. In the event that the CSE
procedure was unsuccessful (failure to correctly place epi-
dural needle, failure to correctly place spinal needle, or acci-
dental dural puncture with epidural needle), the patient was
withdrawn from the study, and the randomization envelope
was reused for the subsequent patient recruited.
After completion of the CSE procedure, visual analogue
scale pain scores were assessed by a research nurse (F.F.N.),
who was blinded to the patients group, at the peak of the
uterine contraction nearest to consecutive 5-min intervals,
for 30min. At the same times, the upper level of sensory
block was recorded by assessing changes in sensitivity to
ice, and motor block was assessed using a modified Brom-
age scale (0 = able to lift extended leg at the hip, 1 = able
to flex the knee but not lift extended leg, 2 = able to move
the foot only, and 3 = unable to move even the foot). If the
level of sensory block differed between the left and right
sides of the body, the highest level was recorded and used for
analysis. During the study period, standard monitoring of

Table 1. Combinations of Fentanyl and Bupivacaine in Study Groups

Subgroup

Group A (n = 60) A1 A2 A3 A4 A5 A6
Fentanyl dose, g 2 5 10 15 25 40
Bupivacaine dose, g 0 0 0 0 0 0
Group B (n = 60) B1 B2 B3 B4 B5 B6
Fentanyl dose, g 1.5 3.75 7.5 11.25 18.75 30
Bupivacaine dose, g 50 125 250 375 625 1,000
Group C (n = 60) C1 C2 C3 C4 C5 C6
Fentanyl dose, g 1 2.5 5 7.5 12.5 20
Bupivacaine dose g 100 250 500 750 1,250 2,000
Group D (n = 60) D1 D2 D3 D4 D5 D6
Fentanyl dose, g 0.5 1.25 2.5 3.75 6.25 10
Bupivacaine dose, g 150 375 750 1,125 1,875 3,000
Group E (n = 60) E1 E2 E3 E4 E5 E6
Fentanyl dose, g 0 0 0 0 0 0
Bupivacaine dose, g 200 500 1,000 1,500 2,500 4,000

All drug combinations were diluted to a total volume of 2.5ml with saline. There were 10 patients in each subgroup.

Anesthesiology 2014; 120:1126-36 1127 Ngan Kee et al.

Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017


arterial pressure, pulse rate, oxyhemoglobin saturation, and
cardiotocography was continued. Any occurrences of hypo-
tension (defined by systolic arterial pressure <90 mmHg),
nausea or vomiting, pruritus, and new nonreassuring fetal
heart rate tracing were noted; these were managed according
to the standard practice.
After 30min, the study was terminated, further analge-
sia was provided if required by epidural bolus, and patient-
controlled epidural analgesia was provided for maintenance
of analgesia according to usual clinical practice.
Statistical Analysis
Sample size was determined using the previous recommen-
dation by Tallarida et al.6 who suggested that for efficient
design of studies designed to compare interactions of drug
combinations, six doses be administered with a minimum of
10 subjects per dose; in our study, we regarded each of the
five doseratio groups as equivalent to a single drug, there-
fore a total sample size of 300 patients were chosen.
Univariate intergroup comparisons were made using
ANOVA or the KruskallWallis test. Categorical data were
compared using the chi-square test and the chi-square test
for trend. Data for pain scores were analyzed in several steps,
repeated for the two main assessment times of 15 and 30 min:
1. Doseresponse curves were first determined for the indi-
vidual drugs using the data for patients who received
fentanyl only (group A) or bupivacaine only (group E).
As previously described,7 normalized response (effect)
was calculated according to the following formula:
Initial VAS Measured VAS
pain score pain score
Response = 100% (1)
Initial VAS pain score
Data were then fitted to a standard rectangular hyperbolic
model according to the following formula:
E max Dose
Y = (2)
Dose + D50
where Y = normalized response, Emax = maximum response
which was constrained to equal 100, and D50 = dose giving a
half-maximal response.
This analysis was performed using nonlinear regression
using GraphPad Prism 5.01 (GraphPad Software, Inc., La
Jolla, CA).
2. Using the doseresponse models for fentanyl and bupi-
vacaine determined above, the predicted additive effects
of combinations of fentanyl and bupivacaine were cal-
culated by using the principle of dose equivalence, using
previously described methods.813 First, the predicted
effect from the dose of fentanyl in each combination
was calculated using the doseresponse equation for
fentanyl. This effect magnitude was then substituted
into the doseresponse equation for bupivacaine to
Anesthesiology 2014; 120:1126-36 1128 Ngan Kee et al.
Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017
Intrathecal Fentanyl and Bupivacaine Synergism
determine the equivalent dose of bupivacaine. The sum
of this equivalent dose and the actual dose of bupivacaine
given in the combination was then substituted into the
doseresponse equation for bupivacaine to determine
the predicted effect from the combination. This proce-
dure is summarized by the following equation12:
E max ( fD50 B + bD50 F )
E( f + b ) = (3)
fD50 B + bD50 F + D50 B D50 F
where E(f + b) is the predicted additive effect from a com-
bined mixture of fentanyl and bupivacaine in doses f and b,
respectively, and D50F and D50B are the respective doses of
fentanyl and bupivacaine giving half-maximal effects, from
equation (2).
Because E(f+b) is derived from experimental data, it has
a variance; this was estimated by the delta method,14 using
the following equation, as described by Tallarida and Raffa12:
4
D50 F
( )
Var E( f +b ) = (bE max )
2
T
Var ( D50 B )
4 (4)
2 D
+ ( fE max ) 50 B Var ( D50 F )
T
where Var(E(f + b)) is the variance of E(f+b), Var(D50F) and
Var(D50B) are the respective variances of the estimates of D50F
and D50B derived from nonlinear regression, and T = fD50B+
bD50F + D50FD50B.
3. Predicted additive effects for a full range of combina-
tions of fentanyl and bupivacaine were calculated using
equation (3) and a three-dimensional response surface
plot was constructed with axes X = bupivacaine dose, Y
= fentanyl dose, and Z = predicted additive effect, using
Sigmaplot 2001 for Windows 7.0 (Systat Software Inc.,
Chicago, IL).
4. Observed (measured) effects were graphically compared
with predicted effects by superimposing the means of
the observed effects from each experimental fentanyl
bupivacaine combination group upon the predictive
additive response surface graph. Points above the surface
indicate responses that are greater than that predicted
by simple additivity and are indicative of synergism.
5. Observed and predicted effects were compared statis-
tically. For this analysis, because predicted values were
derived from curve-fitting procedures rather than
enumerated data, simulated datasets for compari-
son were generated based on the derived parameters.
This was achieved by programming syntax using the
RV.NORMAL function in IBM SPSS Statistics ver-
sion 20 (IBM SPSS Inc., Chicago, IL);15 for each
fentanylbupivacaine combination group, a dataset
of 10 was generated from a normal distribution based
on the individual parameters (mean and SD) for that
group. Observed effect data were then compared with
 PERIOPERATIVE MEDICINE

predicted effect data using two-way ANOVA. For the The doseresponse curves are shown in figures2 and 3.
latter analysis, the dependent variable was effect and the The predicted effect surfaces as functions of fentanyl
independent variables included were (1) dose group, (2) bupivacaine combinations, with superimposed mean
observed or predicted, and (3) the interaction of factors values of observed experimental effects for 15- and
(1) and (2). If the interaction between independent vari- 30-min data, are shown in figures4 and 5, respectively.
ables was not significant on initial analysis, the analysis Analysis of 15-min data showed that the observed effects
was repeated with interactions excluded. Bootstrapping were greater than the predicted effects (P < 0.001),
was applied with 1,000 replications to derive two-way with a mean difference averaged across all dose com-
ANOVA final results. bination groups of 9.1 units (95% CI, 4.114.1) of
6. For illustrative purposes, response surfaces for the the normalized response. The interaction between the
observed effects were derived by modeling using meth- independent variables was not significant (P = 0.74).
ods described in appendix. Analysis of 30-min data also showed that the observed
effects were greater than the predicted effects (P =
Analyses were performed using Microsoft Excel 2010
0.015), with a mean difference averaged across all dose
(Microsoft Corporation, Redmond, WA), GraphPad Prism
combination groups of 6.4 units (95% CI, 1.211.5)
5.01 (GraphPad Software, Inc.), IBM SPSS Statistics version
of the normalized response. The interaction between the
20 (IBM SPSS Inc.), and Stata 12.1 (STATA; StataCorp LP,
independent variables was not significant (P = 0.15).
College Station, TX). P values less than 0.05 were consid-
These results indicate that the interaction between fen-
ered significant.
tanyl and bupivacaine is synergistic.
The response surface derived from modeling of observed
Results effect data is shown in figure6. Details of the model are
Patient recruitment and flow are summarized in figure1. provided in appendix.
Twenty-one patients were excluded after entry into the study Upper levels of sensory changes and side effects that
(unsuccessful CSE procedure [n = 19], protocol violation occurred during the study period are summarized in table3.
[n= 2]) and were replaced. Patient characteristics were simi- Two patients had hypotension, both of whom were in group
lar among groups (table2). E6 (largest dose of bupivacaine: 4,000 g, without fentanyl);
The derived doseresponse models for individual drugs both patients responded to standard treatment without
were: sequelae. Two patients (one in group B1 and one in group
15 min: E6) had nausea or vomiting. Four patients had motor block,
100 Dose
Fentanyl: Y = (5) all of whom were in group E6 (three with Bromage scale 1
Dose 13.82 and one with Bromage scale 2); one of these patients also
D50: 13.82 g had hypotension. Pruritus occurred in 46 patients (15.3%)
Standard error of D50: 3.10 and was significantly associated with increasing dose of fen-
95% CI of D50: 7.61 to 20.00 g tanyl in the combination (P < 0.0001, chi-square test for
trend). New nonreassuring fetal heart rate tracings occurred
100 Dose in three patients (one in group B2, one in group B4, and one
Bupivacaine: Y = (6)
Dose + 1590 in group E5); these were all transient decreases in fetal heart
rate of duration of 1min or less that resolved spontaneously
D50: 1,590 g without sequelae.
Standard error of D50: 299
95% CI of D50: 993 to 2,188 g
30 min: Discussion
The results of our study provide evidence for a synergistic
100 Dose
Fentanyl: Y = (7) interaction between fentanyl and bupivacaine given intra-
Dose 19.83 thecally in combination for labor analgesia. These find-
D50: 9.83 g ings are consistent with the results of previous studies in
Standard error of D50: 2.11 animals. For example, Maves et al.16 used isobolographic
95% CI of D50: 5.61 to 14.10 g analysis to demonstrate antinociceptive synergism between
morphine and lidocaine given as intrathecal boluses to
100 Dose rats that were tested with both somatic and visceral nox-
Bupivacaine: Y = (8)
Dose + 2184 ious stimuli. Saito et al.5 also confirmed synergism when
D50: 2,184 g the same drugs were given intrathecally by infusion to rats
Standard error of D50: 421 g over 6 days. Synergism has also been shown for epidural
95% CI of D50: 95% CI 1,341 to coadministration of opioids and local anesthetics in ani-
3,026 g mals. Kaneko et al.4 administered morphine and lidocaine

Anesthesiology 2014; 120:1126-36 1129 Ngan Kee et al.

Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017

 Intrathecal Fentanyl and Bupivacaine Synergism

Fig. 1. Patient recruitment and flow.

Table 2. Patient Characteristics

Group A (n = 60) Group B (n = 60) Group C (n = 60) Group D (n = 60) Group E (n = 60) P Value

Age, yr 29.3 (4.7) 28.9 (4.6) 30.1 (4.3) 29.5 (4.8) 29.2 (4.2) 0.70
Weight, kg 68.4 (4.7) 66.8 (8.1) 67.4 (7.5) 70.0 (14.8) 66.4 (12.3) 0.49
Height, cm 156 (12) 159 (6) 157 (5) 157 (14) 159 (6) 0.32
Cervical dilatation, cm 2 [12] 2 [12] 2 [12.8] 2 [1.2] 2 [12] 0.90
Induction of labor, n 37 (62%) 42 (70%) 42 (70%) 36 (60%) 42 (70%) 0.60
Oxytocin use, n 27 (45%) 27 (45%) 25 (42%) 26(43%) 25 (42%) 0.99

Values are mean (SD), median [interquartile range], or number (%).

Anesthesiology 2014; 120:1126-36 1130 Ngan Kee et al.

Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017

 PERIOPERATIVE MEDICINE
Fig. 2. Doseresponse curves at 15min for (A) fentanyl and
(B) bupivacaine derived by nonlinear regression using a
hyperbolic model. The derived doseresponse models for
individual drugs (doses in micrograms) were: Effect = 100
dose / (13.82 + dose) for fentanyl, and Effect = 100 dose /
(1,590 + dose) for bupivacaine.
epidurally to rats and, also using isobolographic analy-
sis, showed a synergistic interaction for both visceral and
somatic antinociception.
Several previous studies have reported on the inter-
action of neuraxial opioids and local anesthetics in
humans with equivocal results. Some studies have sug-
gested the presence of a synergistic interaction but
without supporting experimental evidence.17,18 In
obstetrics, Camann et al.19 investigated the combina-
tion of intrathecal sufentanil and epidural bupivacaine
given together for labor analgesia. Isobolographic analy-
sis based on ED50 doses was performed, and although
this was suggestive of synergism, the 95% CIs for the
estimate of ED50 of the combined dose overlapped the
line of additivity, and therefore an additive interaction
could not be excluded. McLeod et al.20 used updown
sequential methodology to determine the median effec-
tive concentrations of levobupivacaine and diamorphine
given epidurally for labor analgesia followed by investi-
gation of the interaction of combinations of the drugs.
By using isobolographic analysis, they concluded that
the interaction was additive. The reason for difference
between the findings of the latter study and our results
Anesthesiology 2014; 120:1126-36 1131 Ngan Kee et al.
Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017
Fig. 3. Doseresponse curves at 30min for (A) fentanyl and
(B) bupivacaine derived by nonlinear regression using a
hyperbolic model. The derived doseresponse models for
individual drugs (doses in micrograms) were: Effect = 100
dose / (19.83 + dose) for fentanyl, and Effect = 100 dose /
(2,184 + dose) for bupivacaine.
is uncertain. It is possible that the interaction between
opioids and local anesthetic may differ between intra-
thecal and epidural administration. Alternatively, the
difference could be explained by methodological dis-
similarity between studies or by differences between the
specific opioids and local anesthetics studied.
The underlying mechanism by which intrathecally
administered fentanyl and bupivacaine interact to pro-
duce synergism remains to be determined. Previously, it
has been suggested that the interaction between drugs that
are agonists at the same receptor is expected to be addi-
tive, whereas drugs that act at different receptors are more
likely to show a synergistic interaction.21 Our results are
consistent with this, because the primary site and mode
of action of intrathecally administered opioids and local
anesthetics are different. It is also possible that phar-
macokinetic factors might also have contributed to our
observed results.4 For example, changes to pH or other
characteristics of cerebrospinal fluid induced by intrathe-
cal injection of one drug might influence the disposition
of the other drug. Further investigation is required to
determine whether this possible mechanism is important
in the context of our study.

Fig. 4. Predicted and observed effects at 15min for combi-
nations of fentanyl and bupivacaine. The surface plot shows
predicted effect as a function of drug combinations when the
interaction between drugs is additive. Superimposed points
show mean values of observed effects for experimental drug
combinations. Points above the surface are shown as black
circles. (A) Standard representation. (B) Graph rotated 80
counterclockwise to reveal points under the surface.
In our study, we investigated the interaction between
drugs by comparing observed experimental effect mag-
nitude with predicted additive effect magnitude. This
method of analysis based on comparisons on the effect
scale is an alternative to traditional isobolographic analy-
sis and has been described previously in the pharmacology
literature.813 The method is based on the same principle
of dose equivalence which is used with isobolographic
analysis. However, it has the added advantage of allowing
analysis at multiple effect levels, it provides a useful visual
representation, and it is more suited to statistical analysis
than isobolographic analysis. When using the principle of
dose equivalence, a number of assumptions are made, for
example that both drugs are full agonists; modification of
Anesthesiology 2014; 120:1126-36 1132 Ngan Kee et al.
Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017
Intrathecal Fentanyl and Bupivacaine Synergism
Fig. 5. Predicted and observed effects at 30min for com-
binations of fentanyl and bupivacaine. The surface plot
shows predicted effect as a function of drug combinations
when the interaction between drugs is additive. Superim-
posed points show mean values of observed effects for
experimental drug combinations. Points above the surface
are shown as black circles. (A) Standard representation.
(B) Graph rotated 80 counterclockwise to reveal points
under the surface.
the analysis is required if one drug is a partial agonist.12
In our study, we considered both drugs to be full agonists,
as evidenced by the observation that some patients who
received either drug alone achieved a complete relief of
pain (normalized response of 100%). However, it should
be noted that fentanyl may not capable of producing a
full response in other clinical circumstances, for example,
when given for analgesia in advanced or second-stage
labor or when given as part of spinal anesthesia for sur-
gery. In these circumstances, the nature of the interac-
tion between opioids and local anesthetics remains to be
determined.
Our study specifically examined the interaction of fen-
tanyl and bupivacaine given in combination as single boluses
 PERIOPERATIVE MEDICINE
Fig 6. Modeled response surfaces for observed data, super-
imposed on predicted additive response surface, for data at
15min (A) and 30min (B). The modeled surfaces are shown
in color to differentiate them from the predicted additive sur-
faces, with color of shading changing according to vertical
height above horizontal plane.
using the CSE technique for labor analgesia. Although we
have demonstrated a synergistic interaction in this clini-
cal context, further investigation is required to delineate
the interaction in other circumstances, for example, when
the drugs are given in repeated doses, by infusion, by
the epidural route, and for other acute and chronic pain
indications.
In our study, the magnitude of the mean difference
between the observed and predicted effects was modest
(<10 units of the normalized response), and the clinical
significance of this might be questioned. However, our
results (figs. 1 and 2) show that the doses of fentanyl and
bupivacaine required to provide complete or near-com-
plete analgesia in this clinical context are relatively large.
Large doses of individual drugs are likely to be associated
with a greater risk of adverse effects, as evidenced in our
study by hypotension and motor block that was observed
Anesthesiology 2014; 120:1126-36 1133 Ngan Kee et al.
Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017
with the largest dose of bupivacaine and the dose-related
incidence of pruritus with fentanyl. Together, reduc-
tion of side effects and improvement in analgesic effect
seem compelling reasons to recommend combining the
drugs in routine clinical practice. Of note, this advan-
tage would also be present if the interaction between
fentanyl and bupivacaine were simply additive. None-
theless, our demonstration of a synergistic interaction
reinforces the practice and provides quantitative infor-
mation and a theoretic basis that informs the common
practice of combining opioids and local anesthetics for
neuraxial administration. In theory, the optimal combi-
nation dose of fentanyl and bupivacaine would balance
the relative risks of side effects from the local anesthetic
and opioid components; this is likely to vary according
to clinical circumstances and patient population and is
not addressed by our study.
Finally, we modeled the observed effects to generate
response surfaces for the data at 15 and 30min. These were
superimposed on the predictive additive surfaces for illus-
trative purposes as previously described.11,13 Of note, the
modeled response surfaces were irregular and not positioned
uniformly above the additive surfaces as shown in previous
examples of superimposed synergistic and additive response
surfaces.11,13 However, the latter depictions were made
with the assumption of a constant value of the interaction
index between experimental drugs. This may not be a valid
assumption, and furthermore, experimental and individual
variation in the clinical setting may explain the irregularity
of our modeled surfaces.
Acknowledgments
The authors thank the midwives of the Labour Ward,
Prince of Wales Hospital, Shatin, Hong Kong, China, for
their assistance and cooperation. The modeling of the
response surfaces detailed in appendix was performed
by Jack Lee, Ph.D., Division of Biostatistics, Jockey Club
School of Public Health and Primary Care, The Chinese
University of Hong Kong, Shatin, Hong Kong, China.
The work described in this article was substantially sup-
ported by a grant from the Research Grants Council of the
Hong Kong Special Administrative Region, China (Project
No. 473409).
Competing Interests
The authors declare no competing interests.
Correspondence
Address correspondence to Dr. Ngan Kee: Department of
Anaesthesia and Intensive Care, The Chinese University
of Hong Kong, Prince of Wales Hospital, Shatin, Hong
Kong, China. warwick@cuhk.edu.hk. Information on pur-
chasing reprints may be found at www.anesthesiology.org
or on the masthead page at the beginning of this issue.
Anesthesiologys articles are made freely accessible to all
readers, for personal use only, 6 months from the cover
date of the issue.
 Intrathecal Fentanyl and Bupivacaine Synergism

Table 3. Sensory Levels and Side Effects

Fentanyl Upper Sensory Upper Sensory New Fetal

Dose Bupivacaine Level at 15min Level at 30min Nausea or Motor Heart Rate
Group (g) Dose (g) (Dermatome) (Dermatome Hypotension Vomiting Block Pruritus Changes

A1 2 0 L2.5 [L5 to T10] L2 [L4 to T10] 0 0 0 0 0

A2 5 0 T11.5 [L5 to T6] T9 [L4 to T6] 0 0 0 0 0
A3 10 0 T7 [L4 to T6] T7 [L4 to T4.5] 0 0 0 3 (30%) 0
A4 15 0 T9 [T11.5 to T9] T8 [T11 to T4.5] 0 0 0 3 (30%) 0
A5 25 0 T8 [T10 to T7] T7.5 [T11 to T5] 0 0 0 3 (30%) 0
A6 40 0 T9 [L4 to T3.5] T6.5 [T11 to T1] 0 0 0 4 (40%) 0
B1 1.5 50 T10 [L5 to T8] T10 [L5 to T7] 0 1 (10%) 0 0 0
B2 3.75 125 L2 [L2 to T10] L2 [L3 to T11] 0 0 0 1 (10%) 1 (10%)
B3 7.5 250 T12 [L4 to T8] T10 [L3 to T7] 0 0 0 1 (10%) 0
B4 11.25 375 T11 [L2 to T8] T10.5 [L2 to T7.5] 0 0 0 1 (10%) 1 (10%)
B5 18.75 625 T6.5 [T8 to T4] T4.5 [T8 to T4] 0 0 0 5 (50%) 0
B6 30 1,000 T7 [T11 to T4] T6 [T12 to T4] 0 0 0 5 (50%) 0
C1 1 100 T12.5 [L3 to T8] T12 [L3.5 to T8] 0 0 0 2 (20%) 0
C2 2.5 250 T10 [L3 to T6] T10.5 [L3 to T6] 0 0 0 0 0
C3 5 500 T10.5 [L3 to T7.5] T11 [L3 to T7.5] 0 0 0 1 (10%) 0
C4 7.5 750 T7 [L2 to T5] T8 [L1 to T5] 0 0 0 4 (40%) 1 (10%)
C5 12.5 1,250 T8 [T10 to T5.5] T6.5 [T11 to T4] 0 0 0 3 (30%) 0
C6 20 2,000 T7 [T10 to T4] T6 [T9 to T2] 0 0 0 5 (50%) 0
D1 0.5 150 T10 [L1 to T6] T10 [L2 to T6.5] 0 0 0 0 0
D2 1.25 375 T12.5 [L3 to T12.5] T11 [L3 to T9] 0 0 0 0 0
D3 2.5 750 T12.5 [L2 to T6.5] T11.5 [L1 to T6.5] 0 0 0 1 (10%) 0
D4 3.75 1,125 T9 [L2 to T5] T10 [L5 to T5] 0 0 0 3 (30%) 0
D5 6.25 1,875 T7 [T10 to T5] T6 [T10 to T4] 0 0 0 0 0
D6 10 3,000 T6.6 [T11 to T5] T6 [T10 to T5] 0 0 0 1 (10%) 0
E1 0 200 L3 [L3 to T10] L1 [L3 to T10] 0 0 0 0 0
E2 0 500 L1 [L5 to T9] L2 [L4 to T9] 0 0 0 0 0
E3 0 1,000 L2 [L3 to T10.5] T12 [L2 to T10] 0 0 0 0 0
E4 0 1,500 T8.5 [T11.5 to T7] T8 [T12.5 to T7] 0 0 0 0 0
E5 0 2,500 T7.5 [T12 to T4.5] T6.5 [T10 to T4] 0 0 0 0 1 (10%)
E6 0 4,000 T4.5 [T10 to T2] T4.5 [T9 to T2] 2 (20%) 1 (10%) 4 (40%) 0 0

Data are presented as median (interquartile range) or number (%). Patients classified as having motor block are those with modified Bromage scale 1.

Appendix
To obtain estimated response surfaces for the observed data,
models were derived from the data using regression analy-
sis.22 Mathematical equations were fitted to the data, and
by substituting the full range of drug doses as independent
variables, the response surfaces were generated.
The response surfaces are represented by the generic sec-
ond-order polynomial equation as follows23:
Y = b0 + j =1 b j X j + i < j bij X i X j + j =1 b jj X 2j + (1)
m m
b22 are estimated coefficients, X1 and X2 are the coded inde-
pendent factors (bupivacaine dose and fentanyl dose, respec-
tively), and is the random error (noise).
The coefficients of the equation were estimated from
quadratic model fitting techniques with a generalized linear
model using the software Matlab R2013a (The MathWorks,
Inc., Natick, MA).
ANOVA was used to determine the interactions between
the process variables and the responses. The quality of the
fit of the polynomial model was expressed by the coefficient

of determination R2, and its statistical significance/model

For the current particular data, equation (1) transforms to
generic equation (2) below:
Y = b0 + b1 X 1 + b2 X 2 + b12 X 1 X 2 + b11 X 12 + b22 X 22(2)
Where Y is the predicted response (normalized reduction
in visual analogue scale pain score), b0, b1, b2, b12, b11, and
adequacy was checked by Fisher F test. Model terms were
evaluated by the P value (probability) with 95% confidence
level. Homogeneity of the variance and significance of the
polynomial coefficients were tested by the G-test and coef-
ficient significance index-test, respectively.
The estimated coefficients of the models are detailed
below:

Anesthesiology 2014; 120:1126-36 1134 Ngan Kee et al.

Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017

 PERIOPERATIVE MEDICINE

A. 5-min Data

Estimate Standard Error tStat P Value

b0 (intercept) 7.6237 0.9618 7.9265 3.7146e-08

b1 0.03324 0.0015483 21.469 3.5663e-17
b2 3.6766 0.15483 23.745 3.5238e-18
b12 0.00094189 7.0323e-05 13.394 1.2441e-12
b11 4.3561e-06 4.0016e-07 10.886 9.1356e-11
b22 0.050864 0.0040016 12.711 3.7634e-12

Number of observations: 30, error degrees of freedom: 24. Root mean squared error: 2.22. R-squared: 0.991, adjusted R-squared: 0.989. F-statistic vs.
constant model: 528, P value = 1.03e-23.

ANOVA Results for Model

SumSq DF MeanSq F P Value

Total 13,169 29 454.11

Model 13,050 5 2,610.1 527.56 1.034e-23
Linear 11,688 2 5,844.2 1,181.2 1.0702e-24
Nonlinear 1,362.1 3 454.04 91.772 2.7385e-13
Residual 118.74 24 4.9475

B. 30-min Data

Estimate Standard Error tStat P Value

b0 (intercept) 8.6429 1.2736 6.7861 5.1005e-07

b1 0.025376 0.0020503 12.377 6.576e-12
b2 4.5188 0.20503 22.04 1.9551e-17
b12 0.00090739 9.3122e-05 9.7441 8.1356e-10
b11 2.8519e-06 5.299e-07 5.3821 1.5846e-05
b22 0.069667 0.005299 13.147 1.8456e-12

Number of observations: 30, error degrees of freedom: 24. Root mean squared error: 2.95. R-squared: 0.985, adjusted R-squared: 0.982. F-statistic vs.
constant model: 319, P value = 4.04e-21.

ANOVA Results for Model

SumSq DF MeanSq F P Value

Total 14,033 29 483.9

Model 13,825 5 2,765 318.71 4.0434e-21
Linear 12,123 2 6,061.5 698.69 5.3708e-22
Nonlinear 1,701.9 3 567.32 65.393 1.0752e-11
Residual 208.21 24 8.6755

References of morphine and lidocaine in rats. Anesthesiology 1994;

1. Collis RE, Davies DW, Aveling W: Randomised comparison of
combined spinal-epidural and standard epidural analgesia in
labour. Lancet 1995; 345:14136
2. Comparative Obstetric Mobile Epidural Trial (COMET) Study
Group UK: Effect of low-dose mobile versus traditional epi-
dural techniques on mode of delivery: A randomised con-
trolled trial. Lancet 2001; 358:19233
3. Ppping DM, Elia N, Wenk M, Tramr MR: Combination of a
reduced dose of an intrathecal local anesthetic with a small
dose of an opioid: A meta-analysis of randomized trials. Pain
2013; 154:138390
4. Kaneko M, Saito Y, Kirihara Y, Collins JG, Kosaka Y: Synergistic
antinociceptive interaction after epidural coadministration
80:13750
5. Saito Y, Kaneko M, Kirihara Y, Sakura S, Kosaka Y: Interaction
of intrathecally infused morphine and lidocaine in rats (part
I): Synergistic antinociceptive effects. Anesthesiology 1998;
89:145563
6. Tallarida RJ, Stone DJ Jr, Raffa RB: Efficient designs for
studying synergistic drug combinations. Life Sci 1997; 61:PL
41725
7. Ngan Kee WD, Ng FF, Khaw KS, Lee A, Gin T: Determination
and comparison of graded dose-response curves for epidural
bupivacaine and ropivacaine for analgesia in laboring nul-
liparous women. Anesthesiology 2010; 113:44553
8. Berenbaum MC: The expected effect of a combination of
agents: The general solution. J Theor Biol 1985; 114:41331

Anesthesiology 2014; 120:1126-36 1135 Ngan Kee et al.

Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017


9. Greco WR, Bravo G, Parsons JC: The search for synergy:
A critical review from a response surface perspective.
Pharmacol Rev 1995; 47:33185
10. Lamarre NS, Tallarida RJ: A quantitative study to assess syn-
ergistic interactions between urotensin II and angiotensin II.
Eur J Pharmacol 2008; 586:3501
11. Tallarida RJ: Drug Synergism and Dose-Effect Data Analysis.
Boca Raton, Chapman & Hall/CRC, 2002, pp 5787
12. Tallarida RJ, Raffa RB: The application of drug dose equiva-
lence in the quantitative analysis of receptor occupation and
drug combinations. Pharmacol Ther 2010; 127:16574
13. Tallarida RJ, Stone DJ Jr, McCary JD, Raffa RB: Response sur-
face analysis of synergism between morphine and clonidine.
J Pharmacol Exp Ther 1999; 289:813
14. Casella G, Berger RL: Statistical Inference. Pacific Grove,
Thomson Learning, 2002, pp 2405
15. Boslaugh S: An Intermediate Guide to SPSS Programming:
Using Syntax for Data Management. Thousand Oaks, Sage
Publications, Inc., 2005, pp1336
16. Maves TJ, Gebhart GF: Antinociceptive synergy between
intrathecal morphine and lidocaine during visceral and
somatic nociception in the rat. Anesthesiology 1992;
76:919
Anesthesiology 2014; 120:1126-36 1136 Ngan Kee et al.
Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/930982/ on 07/08/2017
Intrathecal Fentanyl and Bupivacaine Synergism
17. Belzarena SD: Clinical effects of intrathecally administered
fentanyl in patients undergoing cesarean section. Anesth
Analg 1992; 74:6537
18. Bogra J, Arora N, Srivastava P: Synergistic effect of intrathe-
cal fentanyl and bupivacaine in spinal anesthesia for cesar-
ean section. BMC Anesthesiol 2005; 5:5
19. Camann W, Abouleish A, Eisenach J, Hood D, Datta S:
Intrathecal sufentanil and epidural bupivacaine for labor
analgesia: Dose-response of individual agents and in combi-
nation. Reg Anesth Pain Med 1998; 23:45762
20. McLeod GA, Munishankar B, Columb MO: An isobolographic
analysis of diamorphine and levobupivacaine for epidural
analgesia in early labour. Br J Anaesth 2007; 98:497502
21. Shafer SL, Hendrickx JF, Flood P, Sonner J, Eger EI II:
Additivity versus synergy: A theoretical analysis of impli-
cations for anesthetic mechanisms. Anesth Analg 2008;
107:50724
22. Montgomery DC: Design and Analysis of Experiments, 5th
edition. New York, John Wiley & Sons, 2001, pp 42710
23. Silva GF, Camargo FL, Ferreira ALO: Application of response
surface methodology for optimization of biodiesel produc-
tion by transesterification of soybean oil with ethanol. Fuel
Process Technol 2011; 92:40713