Pain Medicine

Section Editor: Spencer S. Liu

What Epidural Opioid Results in the Best Analgesia

Outcomes and Fewest Side Effects After Surgery?:
AMeta-Analysis of Randomized Controlled Trials
Nayer Youssef, MD,* David Orlov, MD, Tristan Alie, MSc, MD,* Matthew Chong, MD,
Ji Cheng, MSc, Lehana Thabane, PhD,* and James Paul, MD, MSc, FRCPC*
BACKGROUND: Epidural opioids are widely used for central neuraxial blockade and postoperative analgesia. However, differences in analgesic efficacy and side effect rates among individual
opioids remain controversial.
METHODS: We conducted a random-effects meta-analysis of randomized controlled trials that
compared at least 2 continuous epidural infusions for acute postoperative analgesia over at
least 24 hours. Individual study data were weighted by the inverse-variance method. Visual
analog scale (VAS) pain scores were the primary outcome. Secondary outcomes included opioid
side effects, such as pruritus, postoperative nausea and vomiting (PONV), sedation, hypotension, and respiratory depression.
RESULTS: Nineteen of the 24 trials included compared 2 of the following opioids: morphine,
fentanyl, or sufentanil. The total subjects studied were 1513. Pooled analysis by type of surgery
showed no clinically significant differences in VAS pain scores at any time after surgery. There
were more PONV (OR = 1.91; 95% CI, 1.143.18; P = 0.014) and perhaps pruritus (OR = 1.64;
95% CI, 0.982.76; P = 0.162) with morphine compared to fentanyl. Total opioid consumption
differed only in the trials comparing morphine and fentanyl, where patients in the morphine
group required 1.2 mg (of morphine equivalent) less (95% CI, 0.272.18). Use of analgesic
adjuncts was similar for all but 2 studies.
CONCLUSIONS: Analgesic outcome, in terms of VAS pain score, was similar between the epidural opioids studied. These similarities in analgesia may reflect the common practices of concurrently using epidural local anesthetics with the opioids and titrating infusion rates according
to a patients pain status. With respect to side effects, the incidence of PONV and possibly pruritus was higher with morphine compared with fentanyl, despite there being similar total opioid
consumption between those groups. (Anesth Analg 2014;119:96577)

pidural opioids have been widely used for facilitation

of central neuraxial blockade and postoperative analgesia. Although they may be used alone in this regard,
multiple studies have shown that analgesia is more effective when they are combined with local anesthetics.13 Such
mixtures minimize the risk of respiratory depression, somnolence, and pruritus associated with solitary narcotic use,
while also reducing incidence of motor block, and hypotension associated with local anesthetics. Even more importantly,
From the *Department of Anesthesia, McMaster University, Hamilton,
Ontario; Department of Anesthesia, University of Toronto, Toronto,
Ontario; Michael G. School of Medicine, McMaster University, Hamilton,
Ontario; Department of Clinical Epidemiology and Biostatistics, McMaster
University, Hamilton, Ontario; and Biostatistics Unit, St. Josephs Healthcare Hamilton, Hamilton, Ontario.
Accepted for publication June 3, 2014.

Funding: This study was supported by the Department of Anesthesia,

McMaster University.
The authors declare no conflicts of interest.
Parts of this report were presented at the 2013 ASA meeting in San Francisco.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journals website (www.anesthesia-analgesia.org).

this multimodal approach has been shown to provide superior postoperative analgesia to that of IV patient-controlled
analgesia with opioids.2 Despite the effectiveness of such epidural combinations, differences in analgesic efficacy and side
effect rates among opioids remain to be elucidated. This may
be a function of physician preference, hospital-specific policies, or the specific opioids available on formulary. Given the
unique pharmacologic properties of each opioid and studies
that show different rates of accumulation in the cerebrospinal fluid, there is biologic plausibility for differences in the
side effect profiles and analgesia among different opioids.47
No single large randomized controlled trial (RCT) has definitively identified the ideal opioid for a postoperative epidural
infusion, either with or without local anesthetic. This ideal
opioid should improve subjective postoperative analgesia
while minimizing the aforementioned side effects.
As such, we conducted a meta-analysis of all RCTs comparing perioperative epidural opioid infusions. Most of these
trials involved local anestheticopioid mixtures. Specifically,
we sought to determine which opioid offers the best epidural
analgesia in terms of postoperative visual analog scale (VAS)
pain scores while minimizing opioid side effects after surgery.

Reprints will not be available from the authors.

Address correspondence to James Paul, MD, MSc, FRCPC, Department of
Anesthesia, McMaster University, HSC-2U, 1280 Main St. West, Hamilton,
ON L8S 4K1. Address e-mail to james_paul@sympatico.ca.
Copyright 2014 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000377

October 2014 Volume 119 Number 4

METHODS
Ethics

The HIREB (Hamilton Integrated REB) does not require

ethics approval for systematic reviews, including network
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Meta-Analysis: Best Epidural Opioid with Least Side Effects

meta-analyses, because there are no data being collected

from patients. We only evaluated and synthesized data that
had been reported in published trials, and only used aggregate level data reported from the original trials.

Literature Search

Computerized searches of Ovid MEDLINE (from 1950 to

November 2013), EMBASE (from 1980 to December 2013),
and the Cochrane Controlled Trials Register (CCTR up to
November 2013) were conducted. While identifying clinical
trials, a sensitive search strategy developed by Haynes et
al.8 was used along with free text combinations and MeSH
terms (Appendix, Supplemental Digital Content 1, http://
links.lww.com/AA/A931). The searches were designed to
be sensitive and identify the maximum number of RCTs
that compared at least 2 different perioperative epidural
opioid infusions. The search was restricted to studies published or translated to the English language. Unpublished
studies were not sought.

Study Selection

Inclusion for data abstraction was determined by reviewing

each study abstract identified by the search. All abstracts
were read by 2 authors, and agreement was reached by consensus to either include or exclude a study. Full articles were
obtained so that reference lists could be reviewed to further
identify additionally relevant studies. The reviewers were
not blinded to the authors names, affiliated institutions, or
the journal of publication for any of the studies.
Population
Studies were included if they enrolled male or female participants of any age undergoing either elective or emergency
surgery. Studies involving epidural analgesia in parturients
during labor were excluded for many potential confounding factors, including differences between labor and postoperative pain, variability in epidural insertion site, and time
use during labor.9
Intervention
Studies must have compared at least 2 different continuous epidural opioid infusions ceteris paribus for at least 24
hours postoperatively. Studies were limited to opioids used
in common practice, which include morphine, fentanyl,
hydromorphone, oxycodone, or sufentanil. In most cases,
opioids were combined with local anesthetics. Studies were
excluded if comparisons involved only varying concentrations of the same opioid or various types of local anesthetics.
Outcomes
Analgesia in terms of VAS pain scores measured for at least
24 hours was the primary outcome. Secondary outcomes
included opioid side effects, such as nausea/vomiting, pruritus, and respiratory depression. No a priori definition was
set for the latter, although in the majority of studies it was
defined as administration of naloxone.
Study Design
Only RCTs were included in our review, regardless of the
quality of assessment or results. Crossover trials were
not included due to the potential for inadequate washout
period between compared opioids.

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Study Evaluation

Each study included in the analysis was assessed independently by each author, and any discrepancies were resolved
by consensus. The assessment was performed using a modified version of the 5-point methodological quality scale
designed by Jadad et al.10 To receive full points, a study had
to meet the following criteria: be randomized; be doubleblind; include appropriate follow-up for 24 hours at a minimum; use suitable techniques to create the randomization
sequence; and describe an acceptable blinding method. To
satisfy the follow-up criteria of the modified Jadad scale,
withdrawals/dropouts must be described or all study participants accounted for in the results.10 Funnel plots were
constructed of the primary outcome to evaluate for publication bias.

Data Extraction

The methodological data were extracted and later verified. The extracted methodological data included the type
of surgery and detail of the anesthetics. Medications used
at induction, maintenance, and emergence were recorded.
Descriptions of the epidural included the level of insertion,
initiation of the epidural within the delivery of anesthesia,
and time course for epidural administration. Additionally,
the number and baseline characteristics of subjects in each
treatment group were recorded. Numerical data were
extracted and also verified. These data included VAS pain
scores at rest (primary outcome) and incidence of opioidrelated side effects (secondary outcomes). Pain scores could
not be extracted from the study by Coppe and Willaert11
because poor graphical quality precluded differentiation
of the treatment arms. Numerous attempts to contact the
authors were unsuccessful, and only partial data (concerning opioid side effects) were included.

Statistical Analysis

The reporting of this review was done in accordance with

the PRISMA guideline.12 The selection process for articles
is summarized using a flow diagram. Due to interstudy
variability in the timing of pain assessment, pain scores
were grouped in 6- to 8-hour intervals where necessary. In
cases where the standard deviation (SD) was not reported,
it was derived from range or interquartile range. When
studies reported multiple infusion rates for the same opioid, data for the most equipotent dose (the one most similar to the comparison opioid in the trial) were retained for
analysis. Categorical outcomes (e.g., none, mild, and severe)
were converted into binary data by summing the number
of patients who experienced the outcome, regardless of
severity.
Due to the known dose dependency of opioid analgesia and side effects,13 we conducted subgroup analyses to
explore (1) whether equipotent infusion rates were used
within individual studies and (2) whether comparable doses
of the same opioid were used among studies. Equipotency
was determined by comparing the relative average rates of
infusion within a study to epidural equianalgesic tables.14
Total opioid consumption was also analyzed for studies
that administered opioids via equianalgesic infusions and a
non-fixed amount of opioid.

ANESTHESIA & ANALGESIA

Under each predefined clinical outcome, the eligible

studies with available data were pooled using the randomeffects model, which incorporated statistical heterogeneity.
The weight of each individual study was calculated using
the inverse-variance method. The overall pooled estimates
were reported as weighted mean difference and odds ratio
with the associated confidence intervals for continuous and
dichotomous outcomes, respectively. The statistical heterogeneity was quantified as the I2 statistic, which measures
the between-study variance as a percentage of total variance. The Q test was used to test heterogeneity. The criteria
used to define statistical significance were set at = 0.01 for
continuous data (because there were multiple comparisons
over time) and = 0.05 for dichotomous data. The overall pooled estimates and individual studies included were
graphically presented using forest plots. Bias was assessed
through funnel plots and Eggers regression. Stata 12.0
(StataCorp, College Station, TX) was used to conduct the
meta-analyses and assessment of bias.

A Priori Hypothesis for Sources of Heterogeneity

Before analyzing the results, potential sources of heterogeneity among studies were identified, and hypotheses were formulated to explain this heterogeneity. Much of the possible
heterogeneity from RCTs comparing opioids was thought to
depend on dose dependency of opioid analgesia and side
effects.13 First, inconsistent use of analgesic adjuncts (nonsteroidal antiinflammatory drugs or local anesthetics) among
studies may result in an opioid-sparing effect, which may
decrease rates of side effects and give rise to synergistic or
additive benefits.15 Second, deviation from equianalgesic
dosing within a study may inflate the number of side effects
in patients receiving inappropriately large amounts of opioid or increase pain in those receiving too little. Third, it is
important to consider the infusion rates of the same opioid
between each study, which in some cases varied by approximately 10-fold. Higher rates of infusion may lead to better
analgesia and a higher incidence of side effects.13
In addition to factors related to opioid dosage, additional anesthetic and surgical factors should be considered. Intraoperative factors include administration of any
antipruritic or antiemetic medication. Furthermore, certain
anesthetic drugs are associated with particular side effects,
such as nitrous oxide and postoperative nausea and vomiting (PONV).16 In addition, administration of opioids intraoperatively may raise the risk of side effects in 1 group if it
is unevenly distributed.13 With respect to the type of surgery, certain procedures are more invasive than others and
thus may give rise to more postoperative pain, leading to
increased opioid consumption and systemic side effects.13,17
Additionally, thoracic surgery has relatively higher rates
of postoperative respiratory complications compared with
other types of operations.18 With respect to data reporting,
continuous versus dichotomous outcome measures may
give rise to differences in side effect profiles among patients,
due to the higher sensitivity of a continuous scale to detect
a difference.
With regard to pediatric studies, the measurement of pain
in pediatric patients relies on assessing cues, such as crying or facial expression.19 These third-person methods may
differ in sensitivity from the standard VAS administered to

October 2014 Volume 119 Number 4

adult patients.19 Furthermore, pediatric patients as a group

are heterogeneous and experience different rates of side
effects based on age.20 Thus, for these reasons, pediatric
studies were analyzed separately.

RESULTS
Literature Search

The initial search retrieved 8219 articles. After title review,

113 studies were retained for abstract and/or full-text
review (Fig.1). Ultimately, 24 of these studies met the inclusion criteria (Table1).11,2143

Study Description

Nineteen studies obtained a Jadad quality score of 3/5 or

higher. The most common methodological shortcomings
were failure to fully describe the randomization or blinding
technique.
Abdominal, orthopedic, and cesarean delivery with nonlaboring epidural accounted for 10, 7, and 2 of the 24 studies, respectively. Five trials included a mix of abdominal
or thoracic surgery. Of the 24 studies, 2 included pediatric
patients.
Sufficient data were available to analyze the following
secondary outcomes: nausea and vomiting (24/24), pruritus
(22/24), respiratory depression (19/24), sedation (17/24),
and hypotension (9/24).
Most studies described confirmation of epidural catheter
placement (18/24) at a spinal level appropriate for the specific operations reported (16/24) (Table1).44 In addition, the
majority of trials made a binary comparison between two
different opioids, except the pediatric study by Goodarzi
that compared morphine, fentanyl, and hydromorphone
(Table1).43

Primary Outcome: VAS Pain Scores

Pain scores were compared for at least the first 24 hours

among various intervals of time, if pain was assessed during that interval. For trials comparing morphine to fentanyl,
pooled analysis revealed significant heterogeneity at the 0
to 6, 13 to 18, 19 to 24, and 48-hour time intervals. Given
the overall small number of studies, this heterogeneity
appeared to be primarily driven by certain individual studies that showed significant pain reduction in favor of either
opioid (Fig.2).2426,28,31 Subgroup analysis by type of surgery
significantly reduced the amount of heterogeneity at these
time points (Fig.3). Care was taken not to pool studies in
this subgroup analysis unless there were at least 3 studies
comparing the same type of surgery at that time interval,
in order to avoid presenting a misleading pooled estimate.
There was no significant difference between pain scores
for fentanyl versus sufentanil (Fig. 4). The significant heterogeneity at the 19- to 24-hour time interval was likely
driven by the single discordant study that favored sufentanil.37 Subgroup analysis was not feasible given the small
number of studies.
Other comparisons involving morphine versus either
sufentanil or oxycodone did not reveal any differences (data
not shown). There were also no differences detected by the
single adult study comparing morphine to hydromorphone
and 2 pediatric studies that compared the same opioids.4143

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Meta-Analysis: Best Epidural Opioid with Least Side Effects

Figure 1. PRISMA flow sheet describing the study

selection process.

Table 1. Description of Included Studies

Adult
patients

Comparison
Morphine vs sufentanil

Morphine vs fentanyl

Fentanyl vs sufentanil

Morphine vs oxycodone

Peds

968

Morphine vs hydromorphone
Fentanyl vs sufentanil
Morphine vs fentanyl vs
hydromorphone

Jadad
score
(out of 5)
5
3
4
4
2
3
5
3
5
2

Reference
Kim et al.21
Broekema et al.22
Dyer et al.23
Coppe et al.11
Valairucha et al.24
Vallejo et al.25
Berti et al.26
Gedney and Liu27
Tsueda et al.28
Saito et al.29

Data extraction
source
Tables and in-text
Tables, figures, and in-text
Tables, figures, and in-text
Tables and in-text
Tables and in-text
Tables, figures, and in-text
Tables, figures, and in-text
Tables, figures, and in-text
Tables and in-text
Tables, figures, and in-text

Type of
surgery
Abdominal
Abdominal
Abdominal
Abdominal
Abdominal and thoracic
Abdominal
Orthopedics
Orthopedics
Orthopedics
Abdominal and thoracic

Total
subjects
60
59
40
46
79
60
30
64
47
85

White et al.30
Tsui et al.31
Chrubasik et al.32
Fischer et al.33
Jeon et al.34
Lutti et al.35
Wilhelm and Dieleman36
Cohen et al.37
Geller et al.38
Yanagidate and Dohi39

Figures and in-text

Tables and in-text
Tables, figures, and
Figures and in-text
Tables, figures, and
Tables and in-text
Tables, figures, and
Tables, figures, and
Tables and in-text
Tables, figures, and

in-text

Orthopedics
Abdominal and thoracic
Abdominal
C-section
Orthopedics
Orthopedics
Abdominal and thoracic
C-section
Abdominal
Abdominal

66
35
40
105
37
70
53
250
30
50

3
2
3
4
2
2
4
4
5
4

Backlund et al.40
Chaplan et al.41
Cho et al.42
Goodarzi43

Figures and in-text

Figures and in-text
Tables and in-text
Tables, figures, and in-text

Abdominal
Abdominal and thoracic
Abdominal
Orthopedics

29
54
64
60

5
5
5
3

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in-text
in-text
in-text
in-text

ANESTHESIA & ANALGESIA

example, 1 trial reported sedation in 98 of all 105 patients33

and another reported sedation in 2 of 64 patients.27 The only
exception to this is the study by Chrubasik et al., where 0
and 9 of 20 patients receiving morphine and fentanyl were
sedated, respectively.32 Given the similarity in respiratory
depression, hypotension, and sedation among studies, it
is unsurprising that pooled and subgroup analyses did not
reveal any significant differences in these outcomes (data
not shown).

Secondary Outcomes
Postoperative Nausea and Vomiting
There was a higher incidence of PONV in patients receiving morphine compared with fentanyl (OR = 1.91; 95% CI,
1.143.18; Fig.5). The absolute risk reduction for this result
was 10.46%, which corresponds to a number needed-totreat (NNT) of 9.6 patients (95% CI, 5.926.2). No other differences in PONV for other opioids were detected in pooled
(Fig.5) and subgroup analyses.
Pruritus
Patients receiving morphine experienced more pruritus
than those receiving fentanyl, although the data were
not statistically significant (OR = 1.64; 95% CI, 0.982.76;
Fig. 6). Two studies in this group were not pooled. First,
we excluded the data from Tsui et al.31 because an antipruritic was randomly administered to all study subjects.
Second, the study by Vallejo et al.25 was the only trial to
report pruritus on a continuous scale, and no difference
between the groups was detected. With respect to other
opioids and subgroup analyses (data not shown), no further differences were detected.

Total Opioid Consumption

Total opioid consumption was only compared for studies
that used equipotent infusion rates and was standardized
per 24 hours. As a caveat, not all studies reported the SD
associated with the infusion rate, and in some cases it had to
be estimated. There was slightly lower opioid consumption
in the morphine group among trials comparing morphine
versus fentanyl (1.22 mg of morphine equivalent; 95% CI,
0.272.18; P = 0.012; Fig. 7). There were no differences in
opioid consumption in studies comparing fentanyl to sufentanil and insufficient data to perform this analysis for the
other groups.

Respiratory Depression, Hypotension, and Sedation

Regardless of the opioids being compared, the incidence
of respiratory depression and hypotension was low across
most trials, with 0 to 2 patients generally experiencing the
outcome in each group. In addition, the number of patients
experiencing sedation was generally similar between groups
in the same trial but varied markedly among trials. For

Pediatric Studies
Cho et al.42 showed a higher incidence of pruritus in the sufentanil group compared with the fentanyl group (P = 0.026).
Goodarzi43 showed a higher incidence of pruritus, urinary
retention, and respiratory depression in the morphine
group compared with both fentanyl and hydromorphone.

Table 1. Continued
Nausea and
Pruritus
vomiting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Respiratory
depression
X
X
X
X

X
X
X
X
X

X
X
X
X
X
X
X
X

X
X
X
X
X
X
X
X
X
X

X
X
X
X

X
X
X
X

X
X
X
X

X
X
X
X
X
X

Sedation
X
X

Hypotension
X
X
X
X

X
X
X
X

X
X

X
X
X
X
X
X
X

X
X
X

X
X

Equianalgesic
dosing
Yes
Yes
No
No
Yes
Yes
Yes
No
No
Yes
No
Yes
Yes
Yes
No
Yes
No
No
Yes
Yes
No
No
No
a

Postoperative
adjuncts to epidural
anesthesia
IM meperidine
Diclofenac suppository
IV morphine

IV bupivacaine
IV diclofenac
IV bupivacaine
IV pentazocine or
buprenorphine

IM meperidine

Diclofenac or
pentazocine PO
IV or IM ketorolac
Epidural fentanyl
Epidural ropivacaine

Epidural
level
T7-8
T7-9
L2-3
T7-8
T6-9
L2-3
L2-4
L2-4
L2-4
T5-9

Appropriate
epidural
insertion level
Yes
No
ND
No
Yes
Yes
Yes
Yes
Yes
Yes

Confirmed
epidural
placement
Yes
Yes
No
Yes
Yes
Yes
Yes
ND
Yes
Yes

L2-4
L2-3
T6-L3
T4-5
L3-5
ND
ND
L3-4
T11-L2
T12-L2

Yes
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes

Yes
Yes
Yes
ND
Yes
Yes
Yes
ND
Yes
Yes

T8-10
ND
L2-5
L3-4

No
No
Yes
No

Yes
Yes
ND
ND

ND = not described or could not be determined.

a
Dosing for morphine versus fentanyl was equipotent but not for hydromorphone.

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Meta-Analysis: Best Epidural Opioid with Least Side Effects

Figure 2. Visual analog scale (VAS) pain scores for trials comparing morphine to fentanyl grouped by time. SD = standard deviation;
CI = confidence interval.

Individual Studies
The single study that compared morphine versus hydromorphone found a higher incidence of pruritus in those
receiving morphine in the first 24 hours postoperatively
(44.4% vs 11.5%, respectively; P < 0.01) with no other differences detected.41
Adjuncts to Analgesia
Dyer et al.23 reported significantly higher use of supplementary IV morphine in the epidural sufentanil group
compared with the epidural morphine group. In addition,
despite detecting no difference in VAS pain scores, the
pediatric study by Cho et al.42 showed that patients in the
fentanyl group required more rescue analgesia than those
receiving sufentanil (6/32 subjects compared with 0/32
subjects; P=0.012). Otherwise, the use of analgesic adjuncts
was similar in the rest of the studies.

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Assessment of Publication Bias

Funnel plots were constructed for the analyses presented in Figures2 to 6 (Supplemental Digital Content2,
http://links.lww.com/AA/A932). Eggers regression
was nonsignificant (P > 0.05) for all these analyses, and
all the plots were symmetric with the exception of that
corresponding to Figure 3. The symmetry in these plots
suggests that there was no publication bias in this review.
This asymmetry in the plot for the studies in Figure 3
may have been due to the small number of studies
included in that analysis, given the nonsignificant Eggers
regression.

DISCUSSION
Summary of Key Findings

This novel meta-analysis identified 24 RCTs that compared various continuous infusions of epidural opioids

ANESTHESIA & ANALGESIA

Figure 3. Visual analog scale (VAS) pain scores for trials comparing morphine to fentanyl grouped by time and pooled by type of surgery.
SD = standard deviation; CI = confidence interval.

for postoperative analgesia and side effects. Most trials

(19/24) compared the clinically relevant opioids morphine, fentanyl, and sufentanil. Overall, there were no
clinically significant differences in analgesia. There was
an increased rate of PONV (OR = 1.91; 95% CI, 1.143.18;
and NNT 9.6; 95% CI, 5.926.2) and pruritus (OR = 1.64;
95% CI, 0.982.76) among patients receiving morphine
versus fentanyl. There were no other differences in opioid
side effects detected, including respiratory depression,
which had a low event rate. Limitations of our analysis
included the heterogeneity in surgical populations, differences in outcome reporting among studies, and overall
paucity of trials.

Analgesia

It was challenging to combine the data for analgesia in a manner that is both clinically meaningful and not misleading.

October 2014 Volume 119 Number 4

For instance, a pooled analysis ignoring the type of surgery

would have been better powered but at the cost of equating
the bony pain of orthopedics to the laboring pain of a parturient.9,45 Furthermore, by virtue of their interaction with
different parts of the body, certain surgical procedures give
rise to higher rates of side effects, such as the increased risk
of respiratory complications after thoracotomy.18 With this
rationale in mind, we opted to pool only data involving the
same type of surgery and at least 3 trials for adequate power.
Very few individual studies24,25 reported statistically
significant differences in analgesia that met the 20-mm
VAS threshold suggested by Farrar et al.46,47 for clinically
meaningful pain reduction. These isolated findings did not
persist when studies were pooled overall and in subgroup
analysis by type of surgery. Importantly, the use of analgesic
adjuncts was similar between groups (for all but 2 trials),23,42
as was overall total opioid consumption.

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Meta-Analysis: Best Epidural Opioid with Least Side Effects

Figure 4. Visual analog scale (VAS) pain scores for trials comparing fentanyl to sufentanil grouped by time. CI = confidence interval.

Several factors may account for this lack of difference

in analgesia. First, all studies reported epidural titration
according to the patients VAS pain scores using either a
bolus or increase in infusion rate of the study solution (by
patient-controlled analgesia or staff administration) or
analgesic adjunct pro re nata. Although the standard of
care, such protocols were problematic when interpreting
pain scores because they minimize any difference between
the opioids being compared. As an alternative to pain
scores, time to first rescue analgesia and total opioid consumption can be considered.48,49 Unfortunately, none of
the studies reported the former. With respect to the latter,
the small magnitude of the reduced morphine consumption (1.2 mg of morphine equivalent; 95% CI, 0.272.18)
from the morphine versus fentanyl analysis would not be
considered clinicallyrelevant.

Opioid Side Effects

With respect to secondary outcomes, our meta-analysis

revealed more similarities than differences among the
side effect profiles of opioids being compared. Notably,
morphine resulted in more PONV (OR = 1.91; 95% CI,

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1.143.18) and perhaps pruritus (OR = 1.64; 95% CI,

0.982.76) relative to fentanyl. The NNT for the former
is <10 patients, which is arguably clinically significant in
settings where epidural analgesia is performed in high
volume.
The general lack of differences in secondary outcomes is unsurprising given both the dose-dependent
nature of opioid side effects and the similarities in total
opioid consumption across all studies. 13 Nonetheless,
morphine still gave rise to more PONV and pruritus
than fentanyl, although the latter was not statistically significant. This higher rate of side effects may
reflect morphines propensity for cephalad migration
due to its higher hydrophilicity relative to fentanyl. 5
Furthermore, although both fentanyl and morphine
can give rise to pruritus directly via opioid receptor
stimulation, morphine and its derivatives have an
additional mechanism of doing so via inducing histamine release. 45
Similarly, the lack of difference in analgesic properties or side effects between sufentanil and fentanyl
may be accounted for by their closely shared lipophilic

ANESTHESIA & ANALGESIA

Figure 5. Odds ratios of postoperative nausea and vomiting. CI = confidence interval.

nature, which permits similar penetration of the blood

brain barrier and onset of central nervous system effects
(effect-site equilibration time of 6.2 minutes for sufentanil versus 6.8 minutes for fentanyl).50 In contrast, better powered analyses (in other clinical contexts) have
found differences in analgesia and side effects between
sufentanil and fentanyl that were not observed herein.51
Biologic plausibility for such a difference is suggested by
animal studies that show sufentanil has a much larger
spinal volume of distribution compared with fentanyl,
which instead preferentially distributes to the epidural
space and fat.52
A meta-analysis on intrathecal opioids (in combination
with local anesthetics) found similar results to the study
presented herein, with higher rates of PONV with intrathecal morphine compared with fentanyl.52 This study
addressed a different clinical question in that it assessed
epidural opioids that were given in combination with local
anesthetic and compared head to head with another opioid
in a randomized fashion.

October 2014 Volume 119 Number 4

Limitations

There are several limitations to our analysis. Article assessors were not blinded, and we did not include non-English
language studies. Only one study published in Italian53
that compared morphine to sufentanil was excluded
for this reason. Unfortunately, only the abstract for this
trial is accessible.53 Although analgesia was found to be
equivalent, the incidence of pruritus and PONV was an
unspecified amount higher with morphine (P < 0.0001).53
Without a proper full-text appraisal of this study, it is
difficult to ascertain how our results would be affected.
We also specified a priori that we would exclude crossover trials due to the potential for inadequate washout
of longer-acting opioids, but no trials had to be excluded
for this reason.
We considered epidural anesthesia-specific quality factors such as surgery-appropriate level of epidural catheter
insertion and confirmation of epidural placement. With
regard to the former, catheter-congruent epidural anesthesia (relative to the surgical incision level) results in
decreased side effects and patient morbidity.54 Although

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Meta-Analysis: Best Epidural Opioid with Least Side Effects

Figure 6. Odds ratios of postoperative pruritus. CI = confidence interval.

only two-thirds of studies described catheter-congruence,

the one-third that did not were mainly concentrated in single studies and had minimal impact on our pooled analyses.
With respect to the latter, the majority of studies did confirm
placement, and it is hoped that the standard of care was followed in cases where it was left undescribed.
There was a paucity of trials comparing certain opioids and much variability in the surgical populations
and outcome reporting among trials. Therefore, some
of our analyses (particularly those related to analgesia)
were relatively underpowered because data could not
be pooled in full. In addition, our subgroup analyses
relied on reported equianalgesic ratios for epidural opioids,14 which some authors argue are widely variable.55
Thus, the results of any dependent analyses may differ if
repeated using a different set. Furthermore, in contrast to
the 10 trials comparing morphine to fentanyl, there was a
relative dearth of data comparing other opioids and thus
less power to detect any differences. Last, due to differences in the timing of pain assessment across studies, we
grouped pain scores by time. These bands of time created

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difficulty with detecting differences in analgesia at finer

time points. The comparison of the same subjects across
many time points also may have introduced an inherent
autocorrelation in the results, obscuring any differences
in analgesia.

CONCLUSIONS

In summary, this meta-analysis did not demonstrate any

convincing or clinically meaningful differences in analgesia
or total opioid consumption among the opioids studied. It is
reasonable to conclude that fentanyl gives rise to less PONV
and perhaps pruritus compared with morphine. As most
trials focused on morphine versus fentanyl and fentanyl
versus sufentanil, further studies are required to elucidate
any differences in analgesia and side effect profiles between
other opioids. E
DISCLOSURES

All authors are members of the McMaster Epidural Research

Group.

ANESTHESIA & ANALGESIA

Figure 7. Weighted mean difference in epidural opioid consumption per day (expressed in morphine equivalence) for morphine versus fentanyl.
CI = confidence interval.

Name: Nayer Youssef, MD.

Contribution: This author was responsible for identifying the
clinical question and performing the literature search.
Attestation: Nayer Youssef approved the final manuscript and
attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: David Orlov, MD.
Contribution: This author was responsible for identifying the
clinical question and performing the literature search.
Attestation: David Orlov approved the final manuscript. David
Orlov attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Tristan Alie, MSc, MD.
Contribution: This author was responsible for extracting methodological data and identifying the approach for data extraction from graphical sources.
Attestation: Tristan Alie approved the final manuscript and
attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Matthew Chong, MD.
Contribution: This author was responsible for extracting numerical data, performing the data analysis, and interpreting the results.
Attestation: Matthew Chong approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Ji Cheng, PhD.
Contribution: This author analyzed the data and reviewed
drafts of the manuscript.

October 2014 Volume 119 Number 4

Attestation: Ji Cheng approved the final manuscript and attests

to the integrity of the original data and the analysis reported in
this manuscript.
Name: Lehana Thabane, PhD.
Contribution: This author supervised the analysis and reviewed
drafts of the manuscript.
Attestation: Lehana Thabane approved the final manuscript.
Name: James Paul, MD, MSc, FRCPC.
Contribution: This author is the principal investigator and
supervised the completion of the project. James Paul will act as
the archival author.
Attestation: James Paul approved the final manuscript.
This manuscript was handled by: Spencer S. Liu, MD.
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