The Effect of Intraperitoneal Local Anesthesia in

Laparoscopic Cholecystectomy: A Systematic Review

and Meta-Analysis
Alexander P. Boddy, BM, BCh
Samir Mehta, BM, BCh
Michael Rhodes, MD
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Intraperitoneal administration of local anesthesia is often used to improve pain
relief after laparoscopic cholecystectomy. We have conducted a meta-analysis to
establish the efficacy of this technique in reducing early postoperative abdominal
pain. A systematic literature search revealed 24 randomized, controlled trials
assessing intraperitoneal local anesthetic use in laparoscopic cholecystectomy that

met inclusion criteria. Of these, 16 studies reported sufficient data to allow pooled
quantitative analysis. The weighted mean differences (WMD) in visual analog pain
score at 4 h after surgery were pooled using a random effects model. Overall, the
use of intraperitoneal local anesthesia resulted in a significantly reduced pain score
at 4 h (WMD, ⫺9 mm; 95% confidence interval [CI], ⫺13 to ⫺5). Subgroup analysis
suggested that the effect was greater when the local anesthetic was given at the
start of the operation (WMD, ⫺13 mm; 95% CI, ⫺19 to ⫺7) compared with
instillation at the end (WMD, ⫺6 mm; 95% CI, ⫺10 to ⫺2). No adverse events
related to local anesthetic toxicity were reported. We conclude that the use of
intraperitoneal local anesthesia is safe, and it results in a statistically significant
reduction in early postoperative abdominal pain.
(Anesth Analg 2006;103:682–8)

L aparoscopic cholecystectomy is the treatment of

choice for symptomatic cholelithiasis. Although there
are clear benefits compared with open surgery, post-
operative pain after laparoscopic cholecystectomy re-
mains an issue. Pain can prolong hospital stay and
lead to increased morbidity, which is particularly
important now that many centers are performing this
operation as a day-case procedure.
Administration of intraperitoneal local anesthetic
(LA), either during or after surgery, is used by many
surgeons as a method of reducing postoperative pain.
This technique was first evaluated in patients under-
going gynecological laparoscopic surgery (1). Its ap-
plication in laparoscopic cholecystectomy was initially
examined in a randomized trial in 1993 (2). Since then,
many trials evaluating the efficacy of intraperitoneal
LA in laparoscopic cholecystectomy have been pub-
lished worldwide. Although a number of these studies
have reported a significant reduction in postoperative
pain after the use of intraperitoneal analgesia, others
From the Department of General Surgery, Norfolk and Norwich
University Hospital, United Kingdom.
Accepted for publication April 25, 2006.
Address correspondence and reprint requests to M. Rhodes,
MD, Consultant Surgeon, Norfolk and Norwich University Hospi-
tal, Colney Lane, Norwich, Norfolk, NR4 7UY, United Kingdom.
Address e-mail to mr@lapsurgeon.co.uk.
Copyright © 2006 International Anesthesia Research Society
DOI: 10.1213/01.ane.0000226268.06279.5a
have reported no benefit. We have performed a sys-
tematic review of the literature to evaluate the effects
of intraperitoneal local analgesia on early postopera-
tive abdominal pain after laparoscopic cholecystec-
tomy.
METHODS
We systematically identified reports of random-
ized, controlled trials assessing the use of intraperito-
neal LA in the setting of laparoscopic cholecystec-
tomy. MEDLINE, EMBASE, and the Cochrane Library
databases were searched in June 2005 using the term:
laparoscopic cholecystectomy AND intraperitoneal
AND [local an(a)esthetic OR local an(a)esthesia OR
lidocaine OR lignocaine OR bupivacaine OR levobupi-
vacaine OR ropivacaine]. No language restrictions
were imposed. Additional reports were identified
from reference lists of retrieved papers.
Studies included were all double-blind, random-
ized comparisons of intraperitoneal LA versus placebo
or no treatment, evaluating abdominal pain in the
setting of laparoscopic cholecystectomy. Trials com-
bining intraperitoneal LA with other interventions
(e.g., port site infiltration or intraperitoneal nonsteroi-
dal antiinflammatory drugs) were included as long as
there were comparable treatment and control groups
in which the only difference was instillation of intra-
peritoneal LA. Trials in which infusions of LA were
administered after the patient had recovered from
anesthesia were excluded. Papers that could not be
supplied by the British Library were not included. The

682 Vol. 103, No. 3, September 2006

literature search, determination of studies meeting the
inclusion criteria, and data extraction were performed
independently by two authors. Consensus was
reached by discussion.
The methodological quality of each eligible study
was assessed using a 3-item, 5-point scale, which has
previously been validated (3). Studies described as
randomized were given either 1 or 2 points if the
method of randomization was described and was
appropriate. One point was deducted if randomiza-
tion was inappropriate. Studies described as double-
blind were either given 1 or 2 points if the method of
blinding was described and was appropriate. One
point was deducted if blinding was inappropriate. If
the numbers were described and reasons for with-
drawals offered, a further point was given. As only
randomized, double-blind trials were included, the
minimum possible score for each study was 2 and the
maximum 5.
The principal outcome measure for quantitative
analysis was abdominal pain score at 4 h after surgery.
Only studies reporting pain scores on a visual analog
scale (VAS) (0 –100 mm or 0 –10 cm) or an equivalent
verbal pain score (0 –10) were included. If both were
given, the VAS was used in preference. Whereas many
studies provided just one overall pain score, several
studies reported pain scores at rest, with movement or
coughing, and for visceral abdominal pain, superficial
pain, and shoulder pain. In these cases, the pain score
that best represented abdominal pain at rest was used.
Most studies reported pain scores at various times
during the postoperative period. If the score at 4 h was
not reported, the nearest time point to 4 h was used
(between 1 and 6 h). Mean pain scores and standard
deviations for the control and intervention groups
were extracted, either from the text or from tables or
graphs included within the report. If the mean score
was not given, the median score was taken as an
approximation to the mean. In some cases, an estima-
tion of standard deviation was made using Cochrane
review methodology (4). Studies offering no measure
of dispersion were not included in the pooled quanti-
tative analysis. The weighted mean difference (WMD)
between the treatment and control groups was calcu-
lated using Review Manager 4.2.8 software (The Co-
chrane Collaboration, Oxford, United Kingdom). The
WMD is reported in millimeters (the units of the VAS
for pain), and a negative value represents lower pain
scores in patients in the treatment groups compared to
the control groups.
Quantitative analysis was also performed on data
given for additional analgesia requirements. The mean
and standard deviation of the additional analgesia
requirements (in milligrams) for the control and inter-
vention groups were extracted from each report. Be-
cause different analgesic drugs with various potencies
were used, comparison among studies required stan-
dardized mean differences to be calculated.
Vol. 103, No. 3, September 2006
Because there was considerable clinical heterogene-
ity among trials (different quantities and concentra-
tions of different LAs were used and different postop-
erative analgesia regimens were used), pooled
analysis was performed using a random effects model.
Studies that involved routine patient-controlled anal-
gesia (PCA) regimens were assessed in a separate
subgroup because it was expected that these patients
would have less postoperative pain than patients who
needed to ask the nursing staff for each dose of
analgesia.
RESULTS
The initial electronic literature searches revealed 59
studies, and after review of the abstracts, 31 random-
ized trials were identified as potentially meeting the
inclusion criteria. Of these, we were unable to retrieve
the full papers of two trials (5,6). Four studies were
excluded because there were differences between
treatment and control arms aside from the instillation
of intraperitoneal local analgesia (7–10), and one study
was excluded because it examined the use of a post-
operative infusion of intraperitoneal local analgesia
(11).
Twenty-four studies were incorporated in this sys-
tematic review (2,12–34) (Table 1). Anesthetic drugs
that were evaluated included bupivacaine, levobupi-
vacaine, lidocaine, and ropivacaine. In some studies,
bupivacaine or levobupivacaine was used in conjunc-
tion with adrenaline (epinephrine). Most studies used
a set dose and concentration of LA. However, some
studies based the quantity of LA used on the patient’s
weight. In these cases, the figures given in Table 1 are
based on the average weight of patients in the treat-
ment arm. In one study, the total quantity of LA used
was stated, but no mention was made of the strength
or volume of the solution (23). The timing and location
of instillation of local analgesia are also shown in
Table 1.
Pain Scores
Twelve of the 24 studies reported a significant
improvement in pain during the early postoperative
period. In one study, this occurred for pain during
inspiration but not for pain at rest (34). In another
study, no significant improvement in pain was noticed
in the treatment arms that received a single bolus
injection of LA, but a 4-h postoperative infusion did
result in significantly lower VAS pain scores (30).
Four studies (18,26,30,32) had treatment arms in
which the LA was instilled at different times in
relation to surgery. However, only one of these studies
reported a significant difference in pain scores be-
tween groups at different times (18). In this study,
pain scores were lower in the group receiving LA
before surgery than the group receiving LA after
surgery. A third group receiving LA both before and
after surgery had even lower scores.
© 2006 International Anesthesia Research Society 683
Table 1. Included Studies
Included in
LA used quantitative analysis?

Timing of Location
Patients Total LA in of LA
Quality (control/ Volume Strength quantity Relation to instil- PCA VAS at Postop Significant
Study and year score treatment) Type (mL) (%) (mg) dissection lation used? 1– 6 h analgesia difference

Chundrigar, 1993 (2) 3 30/28 B 20 0.25 50 after GBB No No No Yes

Rademaker, 1994 (12) 2 15/15 B 20 0.25 50 after SD No Yes Yes No
Joris, 1995 (13) 2 20/20 BA 80 0.125 100 after SD No Yes No No
Raetzell, 1995 (14) 2 12/12 B 50 0.25 125 after SD, GBB Yes Yes Yes No
Scheinin, 1995 (15) 2 20/20 B 100 0.15 150 after SD No No Yes No
Fornari, 1996 (16) 2 50/50 BA 60 0.16 96 after SD, GIP No No No No
Fuhrer, 1996 (17) 3 12/12 B 48 0.375 180 after SD, GBB Yes Yes Yes No
Pasqualucci, 1996 (18) 3 27/28 BA 40 0.5 200 before, after, SD, GBB No Yes Yes Yes
before and aftera
Szem, 1996 (19) 3 29/26 B 100 0.1 100 before SD, GBB No Yes Yes Yes
Mraovic, 1997 (20) 4 40/40 B 30 0.5 150 before and after SD, GBB No Yes Yes Yes
Weber, 1997 (21) 2 50/50 B 10 0.5 120 after SD No No No Yes
Tsimoyiannis, 1998 (22) 3 50/50 B 48 0.25 120 after SD No Yes Yes Yes
Elfberg, 2000 (23) 3 32/33 B ns ns 154 after GBB No Yes No No
Kolsi, 2000 (24) 4 20/20 L 40 1 400 before SD, GBB No Yes No Yes
Zmora, 2000 (25) 4 25/26 B 50 0.2 100 after SD, GBB No No No No
Lee, 2001 (26) 3 25/20 B 40 0.25 100 beforea, after SD, GBB No No No No
Jiranantarat, 2002 (27) 2 41/39 B 20 0.5 100 after SD, GBB No Yes Yes No
Labaille, 2002 (28) 3 12/11 R 40 0.75 300 before and after SD, GBB Yes Yes Yes Yes
Maestroni, 2002 (29) 3 30/30 R 200 0.175 350 before (pneu- GIP No Yes No Yes
moperitoneum)
Karadeniz, 2003 (30) 3 15/15 B 20 0.5 100 before, aftera SD, GBB No No No No (only for
infusion)
Lepner, 2003 (31) 5 20/20 L 200 0.15 300 after SD No Yes No No
Paulson, 2003 (32) 3 14/19 B 30 0.5 150 before, after, SD, GBB No No No Yes
before and aftera
Razek, 2003 (33) 4 20/20 LB 60 0.25 150 after SD, GBB No Yes No Yes
Ng, 2004 (34) 5 22/21 LBA 30 0.25 75 after SD, GBB No Yes No Yes (during
inspiration only)
LA ⫽ local anesthetic; PCA ⫽ patient-controlled analgesia; ns ⫽ not stated; L ⫽ lignocaine (lidocaine); B ⫽ bupivacaine; LB ⫽ levobupivacaine; R ⫽ ropivacaine; A ⫽ adrenaline (epinephrine);
SD ⫽ sub-diaphragmatic; GBB ⫽ gallbladder bed (or over gallbladder if before dissection); GIP ⫽ generalized intraperitoneal.
a
Time had most significant effect.

Many of the studies reported additional analgesic
use by patients, either as the number of patients
requiring additional analgesia (15,16,20,22,29,31,34),
the time to first analgesia request (27), the number of
requests for analgesia (13), the number of doses of
analgesic (25), or the mean and total dose of a single or
combination of analgesic drugs (2,12,14,15,17–22,27,28,
34). In the postoperative period, three studies used
PCA IV regimens (14,17,28), whereas in the other
studies, patients were provided with analgesia by the
nursing staff.
Eight studies measured plasma levels after intra-
peritoneal administration of LA in 161 patients. Three
of these trials studied bupivacaine (14,15,17), one

Figure 1. Effect of intraperitoneal instillation of local anesthetics (LAs) on early postoperative pain.
684 Intraperitoneal Local Anesthesia in Lap Chole ANESTHESIA & ANALGESIA
Figure 2. Effect of timing of intraperitoneal instillation of local anesthetics (LA) on early postoperative pain.
levobupivacaine (33), one lidocaine (24), two ropiva-
caine (28,29), and one both lidocaine and bupivacaine
(12). Potentially toxic plasma levels were reported in 4
patients overall: 1 patient after 50 mL of 0.25% bupiv-
acaine (125 mg) (14), 1 patient after 0.6 mL/kg of
0.375% bupivacaine (17), and 2 patients after 40 mL of
0.75% ropivacaine (300 mg) (28). However, no patient
in any of the trials included in this review suffered any
adverse event attributable to the use of LA.
Two studies examined the effect of intraperitoneal
LA on length of hospital stay. One reported that the
use of intraperitoneal bupivacaine did not affect the
length of hospitalization (15), but another, by combin-
ing treatment arms, reported a significant increase in
the proportion of patients able to be discharged on the
same day as surgery (32).
Two studies assessed respiratory function as an
outcome measure. One found no difference in peak
expiratory flow rates between patients receiving intra-
peritoneal bupivacaine and controls (23). However,
the second study found that intraperitoneal lidocaine
significantly reduced forced vital capacity at 4 h after
surgery and increased hypoxemic periods in the 6 h
after surgery when compared with controls (14).
All of the included studies used postoperative pain
as an outcome measure. However, one study used a
Vol. 103, No. 3, September 2006
4-point scale for recording pain and was therefore not
included in any quantitative analysis (15).
Sixteen of the included studies reported results
such that sufficient data could be extracted for quan-
titative analysis (12–14,17–20,22–24,27–29,31,33,34).
Only one treatment arm per trial was included in the
initial meta-analysis: if the trial compared different
Las, different doses of the same LA, or different times
at which the LA was instilled, the arm in which the
effect was greatest was used for the pooled analysis. In
total, there were 397 patients in the treatment arms
and 400 patients in the control arms. There was a
statistically significant overall WMD in VAS scores of
–9 mm (95% confidence intervals [CI], ⫺13 to ⫺5) in
favor of treatment (Fig. 1). As expected, there was a
significant degree of heterogeneity among the studies,
as demonstrated by an I2 value of 74.8% (I2 is a
measure used to quantify heterogeneity and repre-
sents the percentage of the variability that is caused by
heterogeneity rather than sampling error: a value
more than 50% may be considered to represent sub-
stantial heterogeneity).
To further examine the effects of timing of instilla-
tion, the pooled quantitative analysis was repeated,
grouping the studies according to when LA was used.
Studies in which LA was instilled at the end of surgery
© 2006 International Anesthesia Research Society 685
Figure 3. Effect of intraperitoneal instillation of local anesthetics (LA) on postoperative analgesia requirements.
were placed into Subcategory 1. Studies in which LA
was instilled before any dissection (19,29), or in which
there were two instillations of local analgesia— one at
the beginning and one at the end of surgery
(20,28)—were placed into Subcategory 2. In one study,
data were available that were applicable to both
subcategories (18). The WMD in VAS scores for Sub-
category 1 (LA after surgery) was ⫺6 mm (95% CI,
⫺10 to ⫺2), whereas the WMD for Subcategory 2 (LA
before surgery) was ⫺13 mm (95% CI, ⫺19 to ⫺8) (Fig.
2). This gives a significant difference in WMD between
these subcategories of 7.0 mm in favor of LA before
surgery (approximate 95% CI, 0.1–14.0).
The 10 studies that reported doses of additional
postoperative analgesia to enable quantitative analysis
are identified in Table 1. Pooled analysis of these
studies was performed as shown in Figure 3. Overall,
the standardized mean differences in analgesia use
between treatment and control arms was not signifi-
cant at ⫺0.77 (95% CI, ⫺1.65– 0.12).
DISCUSSION
Laparoscopic cholecystectomy is one of the most
frequently performed elective general surgical opera-
tions. It is an ideal candidate to be performed as a
day-case or short-stay procedure, and therefore, the
provision of adequate postoperative pain relief is of
considerable importance. Instillation of intraperito-
neal LA to reduce postoperative pain has been studied
through randomized trials for more than 10 years, and
this review has collated the available data both quali-
tatively and quantitatively.
We identified 24 studies that were suitable for
qualitative analysis. In half of these, there was a
significant improvement in postoperative pain relief
after instillation of intraperitoneal LA. Meta-analysis
revealed an overall WMD in VAS of ⫺9 mm in favor
of the treatment groups. Although statistically signifi-
cant, this is slightly lower than the difference found in
686 Intraperitoneal Local Anesthesia in Lap Chole
a meta-analysis (35) published in 2000. This previous
review reported improved pain relief in 7 of 13 trials
and a meta-analysis of 10 trials found an overall WMD
in VAS of ⫺13 mm in favor of the treatment groups.
However, we did not find a significant effect of
intraperitoneal LA on the total amount of analgesia
delivered in the postoperative period. This might be
explained by the fact that LA has its effects only over
the initial few hours. In many of the studies, delivery
of analgesia was measured over periods far in excess
of this timescale.
The results of this meta-analysis highlight the con-
siderable heterogeneity of results from available trials.
Some of the factors that may be responsible for the
clinical heterogeneity among trials are summarized in
Table 2. These factors may either directly influence the
efficacy of the LA or may affect postoperative pain
independently (36), thus reducing the potential benefit
from the administration of intraperitoneal LA. For
example, patients in trials where PCA was used
generally had lower pain scores than patients who had
to request each dose of analgesia from medical or
nursing staff. This may explain why, in trials where
PCA was used, intraperitoneal LA resulted in a
smaller reduction in early postoperative pain than in
Table 2. Factors That May Influence the Benefits of
Intraperitoneal Anesthesia
Factor
Dose and concentration of local anesthetic used
Site of instillation (sub-diaphragmatic versus sub-hepatic)
Timing of instillation (before versus after surgery)
Pneumoperitoneum (volume, pressure, and temperature
of)
Volume of residual CO2 (causing diaphragmatic irritation)
Spillage of bile and blood (may interfere with absorption)
Degree of nonvisceral pain (e.g., from incision sites)
Instillation in head-down position versus supine
Postoperative analgesia regimen
ANESTHESIA & ANALGESIA
trials not using PCA (WMD, ⫺6 versus ⫺10 mm).
However, we did not find that patients who received
intraperitoneal LA used a significantly smaller total
dose of PCA than control patients.
As well as differences in surgical and anesthetic
technique, there were also differences in pain out-
comes that different studies tried to measure. Al-
though many studies reported only an overall ab-
dominal pain score, several asked patients to
distinguish visceral pain from superficial abdominal
pain (2,13,26,28) or shoulder-tip pain (13,16,21,22,
26,28,31,34) and also measured pain on movement
(8,13,15,28), coughing (8,13,14,28), deep inspiration
(14,34), and at rest. Although we tried to extract
comparable data for the pooled quantitative analysis,
these differences may have had an influence on the
heterogeneity of the meta-analysis. Figure 4. Relationship between strength (concentration) of
Some authors have suggested that the timing of LA local anesthetic (LA) and early postoperative mean differ-
administration has an important role in the success of ence in Visual Analog Scale (VAS) pain score. Unweighted,
the technique (18,29,37). It has been argued that post- linear regression of all trials evaluating bupivacaine or
operative pain is reduced if suppression of central levobupivacaine (identified by reference number) was per-
formed using SPSS 13.0 for Windows (SPSS Inc, Chicago,
neural sensitization by intraperitoneal LA occurs be- IL).
fore nociceptive stimuli have triggered the activation
of pain pathways, compared with afterwards. Pooled
analyses seemed to support this view: the WMD in
in this study, significantly more patients who received
VAS scores for studies in which LA was only admin-
intraperitoneal LA were discharged on the day of the
istered at the end of surgery was smaller than for
procedure (79% versus 43%; P ⬍ 0.02) (32).
studies in which at least some LA was administered
Overall, this review does lend limited support to
before any dissection took place.
the use of intraperitoneal LA in laparoscopic cholecys-
There is little evidence with regard to which type of
tectomy as part of a multimodal approach to pain
LA is most effective because limited data are available
management. The technique seems to be safe and
for drugs other than bupivacaine. Bupivacaine itself
results in a statistically significant reduction in early
(or levobupivacaine) is an excellent choice for intra-
postoperative abdominal pain. It may be of particular
peritoneal LA because of its long duration of action.
benefit when the operation is planned as an ambula-
Linear regression analysis of the VAS pain scores from
tory procedure to improve same-day discharge rates.
all trials using bupivacaine or levobupivacaine sug-
Finally, there is some evidence to suggest that LA may
gested that there was a significant correlation (P ⫽
be more effective if used at a larger strength and if at
0.02; R2 ⫽ 0.32) between the strength of bupivacaine
least some is instilled before any dissection.
used and difference in pain score between treatment
and control groups, i.e., larger concentrations of bu-
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ANESTHESIA & ANALGESIA