1) The study assessed whether epidural chloroprocaine affects the pain relief provided by epidural morphine after cesarean delivery. 2) Forty women were randomly assigned to receive either epidural chloroprocaine or a placebo, followed by epidural morphine. 3) The study found no difference between the groups in the duration of pain relief from the morphine, pain levels, or need for additional pain medication, suggesting that chloroprocaine does not reduce the effectiveness of epidural morphine for post-cesarean analgesia.

1. Original contribution
Chloroprocaine may not affect epidural morphine for
postcesarean delivery analgesia
Philip E. Hess MD*, Caroline E. Snowman RN, Caroline J. Hahn MD, Lisa J. Kunze MD,
Venesa J. Ingold MD, Stephen D. Pratt MD
Department of Anesthesia, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
Received 9 August 2004; accepted 16 May 2005
Abstract
Study Objective: The purpose of this study is to assess the independent effect of epidural
chloroprocaine on morphine used for pain relief after cesarean delivery.
Design: We used a randomized, double blind, placebo-controlled trial.
Setting: The study took place at the labor and delivery ward of an academic medical center.
Patients: Forty pregnant women undergoing elective cesarean delivery under spinal-epidural
anesthesia.
Interventions: Patients were randomized to receive either 150 mg of 3% chloroprocaine or placebo,
followed by 3 mg of epidural morphine.
Measurements: The primary outcome for this investigation was the duration of pain relief after
morphine administration, defined as the time at first use of supplemental opioids for analgesia.
Secondary outcomes included pain scores, blood pressure, heart rate, respiratory rate, anesthetic sensory
level, nausea and vomiting, pruritus, supplemental use of nonsteroidal anti-inflammatory medications,
and satisfaction.
Main Results: The groups were similar in demographics and duration of spinal anesthesia. Using
Kaplan-Meier survival analysis of the duration of morphine analgesia, we found no difference between
the groups (chloroprocaine, 1191 minutes, vs placebo, 1267 minutes, P = 0.52). There was no difference
in pain scores or the need for supplemental analgesics. Side effects of epidural morphine were similar
between the groups.
Conclusions: We found that epidural chloroprocaine did not reduce the duration or effectiveness of
postoperative analgesia from epidural morphine.
D 2006 Elsevier Inc. All rights reserved.
1. Introduction
Administration of epidural morphine is a popular method
of providing postcesarean pain relief because of its
prolonged duration of action. Several authors have reported
0952-8180/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.jclinane.2005.05.003
* Corresponding author. Tel.: +1 617 667 3112; fax: +1 617 667 7849.
E-mail address: phess@bidmc.harvard.edu (P.E. Hess).
Keywords:
Chloroprocaine;
Morphine;
Cesarean delivery;
Epidural anesthesia;
Epidural analgesia;
Spinal anesthesia
Journal of Clinical Anesthesia (2006) 18, 29–33

2. that after receiving even a small dose of chloroprocaine,
epidural morphine provides analgesia of significantly
shorter duration or lesser effectiveness [1,2]. The loss of
analgesia from morphine is of significant clinical concern
because the administration of supplemental opioids to a
patient who has received epidural morphine increases the
risk of respiratory depression. This has led some clinicians
to avoid giving epidural morphine after a cesarean delivery
once chloroprocaine has been administered.
Although the mechanism by which chloroprocaine
affects opioid analgesia is not known, most authors have
suggested an antagonism in the spinal cord, either of the
opioid receptors or of the intracellular second messenger
[3-7]. However, one confounder in these studies is the
differences in the quality and duration of intraoperative
anesthesia between the groups. Most investigations have
compared chloroprocaine to local anesthetics of longer
duration. Because of its short duration, the local anesthetic
blockade remaining at the end of surgery will regress more
rapidly when chloroprocaine is used. This rapid rate of
regression of anesthesia may lead to breakthrough pain
before the peak of analgesia by epidural morphine. Thus,
differences in postcesarean analgesia with epidural mor-
phine could be due to variations in the duration of surgical
anesthesia. A study design that minimizes differences
in the resolution of surgical anesthesia may isolate the
effect that epidural chloroprocaine has on the postcesarean
analgesia provided by epidural morphine. The purpose
of this investigation was to evaluate the independent effect
of preservative-free epidural chloroprocaine on the long-
term analgesia provided by epidural morphine.
2. Materials and methods
This prospective, randomized, double-blinded, placebo-
controlled investigation was approved by the hospital
institutional review board. After obtaining informed con-
sent, 40 healthy parturients with term singleton gestations
who were scheduled for elective cesarean delivery were
randomized to either the chloroprocaine (CPC) group or the
placebo (PLCB) group. Randomization was accomplished
using a computer-generated list, and assignments were made
using sequentially numbered opaque envelopes. After
application of routine monitors and administration of
10 mL/kg of lactated ringers, all patients underwent
a combined spinal-epidural procedure using a needle-
through-needle technique. Spinal medications were
11.25 mg of hyperbaric bupivacaine and 25 lg of fentanyl.
After spinal injection, a 20-gauge 3-holed epidural catheter
was inserted 5 cm into the epidural space. An adequate
spinal anesthesia, defined as at least a T4 sensory block by
15 minutes after spinal injection, was ensured before the
surgical incision. Thirty minutes after spinal injection, the
study solution was injected into the epidural catheter:
the CPC group received 5 mL (150 mg) of preservative-
free 3% chloroprocaine, and the PLCB group received 5 mL
of preservative-free normal saline. Fifteen minutes after the
study drug and 45 minutes after the spinal injection, both
groups received 3 mg of preservative-free morphine through
the epidural catheter.
After completion of surgery, the time to regression of
the anesthetic block was measured at 15-minute intervals
until the patient had acquired a modified Bromage score of
4 (able to flex hips with some weakness). This was defined
as the end of spinal anesthesia. During this time, blood
pressure, heart rate, and respiratory rate were monitored
every 15 minutes. We also evaluated sedation, pruritus,
nausea and vomiting, satisfaction, and pain using an 11-point
verbal pain score at each of these time points. After
regression of the spinal anesthetic blockade, pain, satisfac-
tion, and side effects were evaluated at 1, 2, and 6 hours, and
again 24 hours after morphine administration. Breakthrough
pain experienced any time during the first 24 hours was
treated with 30 mg of ketorolac intravenously (every 6 hours
when necessary). In cases where ketorolac failed to control
pain, subjects would receive one 5-mg oxycodone/325-mg
acetaminophen tablet per os every 4 hours if within 12 hours
of administration of epidural morphine and two 5-mg
oxycodone/325-mg acetaminophen tablets per os every
4 hours if after 12 hours. If this treatment failed to control
pain, the patient would receive intravenous opioids.
The primary outcome for this investigation was the
duration of pain relief after morphine administration, de-
fined as the time at first use of supplemental opioids for
analgesia. The primary outcome was compared using
Kaplan-Meier survival analysis, with log-rank analysis for
comparisons of the medians. Secondary outcomes included
the total amounts of ketorolac and opioids used in the
24-hour postoperative period, the pain scores, the incidence
of side effects, and the requirements for intravenous opioids.
Normally distributed continuous variables were compared
using the t test; Mann-Whitney test was used for non–normal
distributions; and v2
with Yates correction was used for
frequencies. Based on previous studies and the clinical
experience at our center, we estimated we would require
18 subjects per group to identify a 25% difference in duration
of analgesia with a power of 0.8. Data were analyzed using
SPSS for Windows, version 11.0 (SPSS, Chicago, Ill).
3. Results
Forty parturients were enrolled and successfully com-
pleted the study. We found no difference in baseline
demographics and obstetric characteristics between the
groups, with the exception of a 6-day difference in
gestational age at the time of cesarean delivery (Table 1).
All subjects had successful spinal anesthesia for cesarean
delivery, and the duration of spinal anesthesia was similar
between the groups. Maternal vital signs after surgery were
similar between the groups. Eleven-point verbal pain scores
P.E. Hess et al.30

3. were measured from the end of surgery until the end of
spinal anesthesia to identify an early appearance of pain. We
found no difference in the pain scores during this period
between the groups (Table 2). After the regression of spinal
anesthesia, verbal pain scores were similar between the
groups, except at the 2-hour mark where the pain scores of
the CPC group were slightly better.
The cumulative percentage of successful analgesia
during the first 24 hours was examined using Kaplan-Meier
survival analysis (Fig. 1). There was no significant
difference between the groups in the average duration of
analgesia before the first request for oral opioid supplemen-
tation, with the CPC group mean being 973 F 117 minutes
and the PLCB group being 977 F 110 minutes. Because of
the limited size of the study and the lack of normal
distribution of the data, log-rank analysis was used to
compare the median duration of morphine analgesia.
We found no difference in the median duration of anal-
gesia between the groups (CPC, 1191 minutes, vs PLCB,
1267 minutes; P = 0.52). A similar number of subjects in
each group completed the 24-hour study period without
requesting additional opioid analgesic medication (CPC,
7 [35%], vs PLCB, 4 [20%]; P = 0.48). There was no
difference in the use of ketorolac for breakthrough pain
(CPC, 2.4 F 1.3 injections every 24 hours, vs PLCB, 2.6 F
1.1 injections every 24 hours; P = 0.7), in the time to first
request for ketorolac ( P = 0.52), in the need for oral opioid
analgesics ( P = 0.48), or in the number of oral opioid
analgesics used over the first 24 hours (CPC, 1.8 F 2.0, vs
PLCB, 2.5 F 2.2; P = 0.41). The incidence of side effects
(nausea and/or vomiting and pruritus) was similar between
the groups at every evaluation point in the 24-hour study
period. Furthermore, the use of medications to control these
side effects was similar between the groups. There was no
sedation score above 1 in either group. Subjects’ satisfaction
with pain control was similar between the groups at all
evaluation points. Finally, there were no subjects who
needed intravenous opioids for pain control.
4. Discussion
We found that epidural chloroprocaine had no effect on
the analgesia provided by epidural morphine after elective
cesarean delivery. This was true whether we evaluated
the pain scores reported by subjects, the need for
supplemental medications, or the amount of supplemental
medications used. In contrast, several previous studies
have documented that epidural morphine does not consis-
tently produce effective and prolonged pain relief after
chloroprocaine has been given [1,2]. The mechanism of this
apparent antagonism remains unclear. Theories include
Table 2 Quality of anesthesia and analgesia between the
groups
Chloroprocaine Placebo P
Duration of spinal
anesthesia (min)
159 F 25 147 F 23 0.12
Pain scores
After surgery
Time 0 0 (0-4) 0 (0-5) 0.11
Time 15 0 (0-3) 0 (0-6) 0.49
Time 30 0 (0-4) 0 (0-6) 0.85
Time 45 0 (0-6) 0 (0-5) 0.85
Time 60 2 (0-7) 2 (0-5) 0.55
After spinal
analgesia
1 h 3 (1-6) 3 (1-8) 1.0
2 h 2 (1-4) 3 (1-6) 0.05
6 h 2 (0-5) 2 (0-5) 0.42
24 h 2 (0-6) 3 (1-5) 0.91
Nausea and/or
vomiting
10 (50%) 10 (50%) 1.0
Pruritus 3 (15%) 6 (30%) 0.45
The duration of analgesia is reported as mean F SD. All pain scores are
reported as median (range). Side effects are reported as percentage of
groups who complained of this side effect during the first 24 hours.
Fig. 1 Kaplan-Meier survival analysis of the cumulative
percentage of subjects with continued analgesia during the first
24 hours after administration of epidural morphine. Both the CPC
and the PLCB groups have a similar degradation of analgesia over
the time course, with median analgesic survival times of 19 hours
51 minutes (CPC) and 21 hours 7 minutes (PLCB), P = 0.52, using
log-rank analysis.
Table 1 Demographic and obstetric variables
Chloroprocaine Placebo P
Age (y) 32 F 5 35 F 4 0.08
Height (cm) 164 F 6 165 F 8 0.93
Weight (kg) 81 F 10 80 F 12 0.78
Gestational age (wk) 38.3 F 1.8 39.2 F 1.0 0.01
Nulliparity (%) 30 15 0.23
Neonatal weight (g) 3475 F 415 3500 F 430 0.85
Values are reported as mean F SD, except nulliparity, which is reported
as percentage of group.
Epidural chloroprocaine and morphine 31

4. direct receptor antagonism by chloroprocaine or its metab-
olite, or antagonism of the intracellular second messenger.
One possible confounder is the rate of regression of local
anesthetic blockade. Chloroprocaine anesthesia regresses
rapidly, resulting in a shorter period of postoperative
analgesia, even if a dense local anesthetic blockade is
maintained until the end of surgery. In contrast, bupivacaine
and lidocaine both have a long duration of action and a slow
regression, providing prolonged postoperative analgesia. If
the resolution of local anesthetic blockade occurs before the
onset of maximum analgesia provided by epidural mor-
phine, then the patient may experience breakthrough pain
[8]. Karambelkar and Ramanathan [2] found that women
who received chloroprocaine for epidural anesthesia re-
quired dramatically more supplemental intravenous opioids
in the first 24 hours than those who received lidocaine.
The author noted that this difference occurred mostly
in the first 4 hours after delivery, which is consistent with
early breakthrough pain due to early anesthetic regression.
Eisenach et al [1] found a shortened duration of analgesia
after cesarean delivery in women who had received 140 mg
of chloroprocaine as an epidural test dose compared
with those who received lidocaine. Both groups received
epidural bupivacaine as the primary local anesthetic for
cesarean delivery. However, the effectiveness of bupiva-
caine is known to be diminished when used with chlor-
oprocaine [9-12]. Thus, although both groups received the
same drug for cesarean anesthesia, the quality of the
anesthetic was not equal between the groups: significantly,
more subjects in the CPC group required intraoperative
redosing of their bupivacaine and also had shorter 2-
segment regression of anesthesia. This may have also
resulted in the reduced duration of labor analgesia found
by Grice et al [3].
We believe that our findings contradict those of previous
authors because of the use of spinal anesthesia for cesarean
delivery. This method was chosen to ensure similar
anesthetic duration in both groups, reducing the possibility
that the decreased efficacy of morphine would be due to an
early regression of cesarean anesthesia in one group [8]. Our
spinal anesthetic was a combination of bupivacaine and
fentanyl. This combination of medications provides a more
reliable onset, an anesthetic depth, and a consistent duration
of anesthesia than does bupivacaine alone, and these
characteristics were essential in ensuring identical surgical
anesthesia between the groups. Not all studies support the
presence of antagonism. Polley et al [5] found that the
median local anesthetic concentration of chloroprocaine was
reduced with the addition of fentanyl, suggesting a synergy
rather than antagonism. Furthermore, the authors noted
that the ratio of this reduction was similar to that found
with lidocaine; lidocaine is not believe to antagonize
opioids. Coda et al [4] demonstrated that chloroprocaine
does have l-receptor antagonism in vitro, but that this effect
was relatively weak and insufficient to explain the
clinical antagonism.
It must be considered that the addition of spinal fentanyl
may have provided prolonged analgesia, obscuring the
antagonism of morphine. Unfortunately, we do not have a
control group to directly address this point, but we do not
believe it to be likely. Although studies have demonstrated
improved intraoperative anesthesia, women who receive
spinal fentanyl and bupivacaine require similar amounts of
postoperative analgesics as those who receive plain bupi-
vacaine [13-15]. Likewise, the overwhelming weight of
clinical experience suggests that patients who receive
bupivacaine and fentanyl spinal anesthesia require opioid
pain medication during the first 24 hours. The initial
treatment of breakthrough pain was with ketorolac. We
did this because it is our clinical experience that most
women who receive 3 mg of epidural morphine require
some additional analgesic during the first 24 hours, but that
those with overt failure of epidural morphine do not have
significant relief. It is possible that the use of ketorolac
obscured any analgesic antagonism in the CPC group. We
do not believe this to be the case because we could find no
difference in the need for ketorolac, the timing of its use, or
the number of doses received. Furthermore, if supplemen-
tation with ketorolac were an effective method of ensuring
the effectiveness of epidural morphine, then any antagonism
would be of less clinical importance. Finally, based on the
results of previous studies and our clinical experience, the
power analysis was performed with the expectation of
finding a 25% difference in duration of analgesia. We only
found a 6% difference in median duration (0% in mean
duration) between the groups, which would require more
than 750 patients per group to confirm with a power of
0.8. We believe that even if this difference were true, it is
clinically irrelevant.
In conclusion, we found that epidural chloroprocaine had
no effect on the quality or duration of epidural morphine
after cesarean delivery. We believe that this finding was
due to the use of spinal anesthesia in our study, which
resulted in equal and long-lasting anesthesia between the
groups. This supports the theory that the decreased
effectiveness of analgesia with morphine may be due to
the early regression of analgesia and appearance of pain.
When chloroprocaine is used for cesarean anesthesia, we
would recommend ensuring adequate pain relief in the early
postoperative period to allow epidural morphine to achieve
peak effectiveness.
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Epidural chloroprocaine and morphine 33