gaba colecistectomia cochrane 2014
TRANSCRIPT
Cochrane Database of Systematic Reviews
Pharmacological interventions for prevention or treatment of
postoperative pain in people undergoing laparoscopic
cholecystectomy (Review)
Gurusamy KS, Vaughan J, Toon CD, Davidson BR
Gurusamy KS, Vaughan J, Toon CD, Davidson BR.
Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy.
Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD008261.
DOI: 10.1002/14651858.CD008261.pub2.
www.cochranelibrary.com
Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
8BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
33DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 NSAID versus control, Outcome 1 Morbidity. . . . . . . . . . . . . . . . 90
Analysis 1.2. Comparison 1 NSAID versus control, Outcome 2 Proportion discharged as day-surgery. . . . . . 90
Analysis 1.3. Comparison 1 NSAID versus control, Outcome 3 Length of hospital stay. . . . . . . . . . . 91
Analysis 1.4. Comparison 1 NSAID versus control, Outcome 4 Pain (4 to 8 hours). . . . . . . . . . . . . 91
Analysis 1.5. Comparison 1 NSAID versus control, Outcome 5 Pain (9 to 24 hours). . . . . . . . . . . . 93
Analysis 1.6. Comparison 1 NSAID versus control, Outcome 6 Morbidity (sensitivity analysis). . . . . . . . . 94
Analysis 1.7. Comparison 1 NSAID versus control, Outcome 7 Proportion discharged as day-surgery (sensitivity
analysis). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Analysis 1.8. Comparison 1 NSAID versus control, Outcome 8 Pain (4 to 8 hours) sensitivity analysis. . . . . . 97
Analysis 1.9. Comparison 1 NSAID versus control, Outcome 9 Pain (9 to 24 hours) sensitivity analysis. . . . . . 98
Analysis 1.10. Comparison 1 NSAID versus control, Outcome 10 Pain (4 to 8 hours) stratified by drug. . . . . . 99
Analysis 1.11. Comparison 1 NSAID versus control, Outcome 11 Pain (4 to 8 hours) stratified by time. . . . . . 101
Analysis 1.12. Comparison 1 NSAID versus control, Outcome 12 Pain (9 to 24 hours) stratified by drug. . . . . 102
Analysis 1.13. Comparison 1 NSAID versus control, Outcome 13 Pain (9 to 24 hours) stratified by time. . . . . 104
Analysis 2.1. Comparison 2 Opioid versus control, Outcome 1 Pain (4 to 8 hours). . . . . . . . . . . . . 106
Analysis 2.2. Comparison 2 Opioid versus control, Outcome 2 Pain (9 to 24 hours). . . . . . . . . . . . 107
Analysis 2.3. Comparison 2 Opioid versus control, Outcome 3 Pain (4 to 8 hours) (sensitivity analysis). . . . . . 107
Analysis 2.4. Comparison 2 Opioid versus control, Outcome 4 Pain (9 to 24 hours) (sensitivity analysis). . . . . 108
Analysis 3.1. Comparison 3 Anticonvulsant analgesic versus control, Outcome 1 Morbidity. . . . . . . . . . 108
Analysis 3.2. Comparison 3 Anticonvulsant analgesic versus control, Outcome 2 Pain (4 to 8 hours). . . . . . . 109
Analysis 3.3. Comparison 3 Anticonvulsant analgesic versus control, Outcome 3 Pain (9 to 24 hours). . . . . . 110
Analysis 3.4. Comparison 3 Anticonvulsant analgesic versus control, Outcome 4 Morbidity (sensitivity analysis). . . 111
Analysis 3.5. Comparison 3 Anticonvulsant analgesic versus control, Outcome 5 Pain (4 to 8 hours) sensitivity analysis. 111
Analysis 3.6. Comparison 3 Anticonvulsant analgesic versus control, Outcome 6 Pain (9 to 24 hours) sensitivity analysis. 112
Analysis 4.1. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 1 Morbidity. . . . . . . . . . 112
Analysis 4.2. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 2 Pain (4 to 8 hours). . . . . . . 113
Analysis 4.3. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 3 Pain (9 to 24 hours). . . . . . 113
iPharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.4. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 4 Morbidity (sensitivity analysis). . 114
Analysis 5.1. Comparison 5 Anticonvulsant analgesic versus opioid, Outcome 1 Pain (4 to 8 hours). . . . . . . 115
Analysis 5.2. Comparison 5 Anticonvulsant analgesic versus opioid, Outcome 2 Pain (9 to 24 hours). . . . . . . 115
115APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
117CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
117DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
118NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iiPharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Pharmacological interventions for prevention or treatment ofpostoperative pain in people undergoing laparoscopiccholecystectomy
Kurinchi Selvan Gurusamy1, Jessica Vaughan1 , Clare D Toon2 , Brian R Davidson1
1Department of Surgery, Royal Free Campus, UCL Medical School, London, UK. 2Public Health, West Sussex County Council,
Chichester, UK
Contact address: Kurinchi Selvan Gurusamy, Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital,
Rowland Hill Street, London, NW3 2PF, UK. [email protected].
Editorial group: Cochrane Hepato-Biliary Group.
Publication status and date: New, published in Issue 3, 2014.
Review content assessed as up-to-date: 3 March 2013.
Citation: Gurusamy KS, Vaughan J, Toon CD, Davidson BR. Pharmacological interventions for prevention or treatment of post-
operative pain in people undergoing laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.:
CD008261. DOI: 10.1002/14651858.CD008261.pub2.
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
While laparoscopic cholecystectomy is generally considered less painful than open surgery, pain is one of the important reasons
for delayed discharge after day-surgery and overnight stay following laparoscopic cholecystectomy. The safety and effectiveness of
different pharmacological interventions such as non-steroidal anti-inflammatory drugs, opioids, and anticonvulsant analgesics in people
undergoing laparoscopic cholecystectomy is unknown.
Objectives
To assess the benefits and harms of different analgesics in people undergoing laparoscopic cholecystectomy.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Ex-
panded, and the World Health Organization International Clinical Trials Registry Platform portal (WHO ICTRP) to March 2013 to
identify randomised clinical trials of relevance to this review.
Selection criteria
We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing different pharmaco-
logical interventions with no intervention or inactive controls for outcomes related to benefit in this review. We considered comparative
non-randomised studies with regards to treatment-related harms. We also considered trials that compared one class of drug with another
class of drug for this review.
Data collection and analysis
Two review authors collected the data independently. We analysed the data with both fixed-effect and random-effects models using
Review Manager 5 analysis. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals
(CI).
1Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
We included 25 trials with 2505 participants randomised to the different pharmacological agents and inactive controls. All the trials
were at unclear risk of bias. Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy.
Participants were allowed to take additional analgesics as required in 24 of the trials. The pharmacological interventions in all the included
trials were aimed at preventing pain after laparoscopic cholecystectomy. There were considerable differences in the pharmacological
agents used and the methods of administration. The estimated effects of the intervention on the proportion of participants who were
discharged as day-surgery, the length of hospital stay, or the time taken to return to work were imprecise in all the comparisons in which
these outcomes were reported (very low quality evidence). There was no mortality in any of the groups in the two trials that reported
mortality (183 participants, very low quality evidence). Differences in serious morbidity outcomes between the groups were imprecise
across all the comparisons (very low quality evidence). None of the trials reported patient quality of life or time taken to return to
normal activity. The pain at 4 to 8 hours was generally reduced by about 1 to 2 cm on the visual analogue scale of 1 to 10 cm in the
comparisons involving the different pharmacological agents and inactive controls (low or very low quality evidence). The pain at 9 to
24 hours was generally reduced by about 0.5 cm (a modest reduction) on the visual analogue scale of 1 to 10 cm in the comparisons
involving the different pharmacological agents and inactive controls (low or very low quality evidence).
Authors’ conclusions
There is evidence of very low quality that different pharmacological agents including non-steroidal anti-inflammatory drugs, opioid
analgesics, and anticonvulsant analgesics reduce pain scores in people at low anaesthetic risk undergoing elective laparoscopic chole-
cystectomy. However, the decision to use these drugs has to weigh the clinically small reduction in pain against uncertain evidence of
serious adverse events associated with many of these agents. Further randomised clinical trials of low risk of systematic and random
errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their
assessment.
P L A I N L A N G U A G E S U M M A R Y
Regular painkillers in people undergoing laparoscopic cholecystectomy
Background
About 10% to 15% of the adult western population have gallstones. Between 1% and 4% become symptomatic each year. Removal
of the gallbladder (cholecystectomy) is the mainstay treatment for symptomatic gallstones. More than half a million cholecystectomies
are performed per year in the US alone. Laparoscopic cholecystectomy (removal of gallbladder through a keyhole, also known as port)
is now the preferred method of cholecystectomy.
Laparoscopic surgery is associated with less pain than open surgery for removal of the gallbladder but postoperative pain is one the
major reasons for delayed hospital discharge after laparoscopic cholecystectomy. Administration of painkillers may be an effective way of
decreasing the pain after laparoscopic cholecystectomy. The different types of painkillers include those that decrease the inflammation
(non-steroidal anti-inflammatory drugs or NSAIDS), which include drugs that are available over-the-counter such as paracetamol
and ibuprofen and other drugs that are not available over-the-counter such as diclofenac; opium-like painkillers such as codeine and
morphine, and some painkillers that are used to treat fits but also possess the ability to decrease the pain such as gabapentin and
pregabalin. The last two classes of drugs are available only as prescription drugs except for low dose codeine in some countries. The
benefits and harms of giving painkillers on a regular basis in people undergoing laparoscopic cholecystectomy is unknown. We sought
to answer these questions by reviewing the medical literature and obtaining information from randomised clinical trials for benefits
(where people are randomly allocated to one of two or more treatment groups) and comparative non-randomised studies for treatment-
related harms. We compared the regular use of painkillers with no regular use of painkillers (ie, painkillers were administered as and
when required) and the different type of painkillers.
Study characteristics
We identified 25 randomised clinical trials involving 2505 people undergoing laparoscopic cholecystectomy. Most participants in
the trials were low anaesthetic risk people undergoing planned laparoscopic cholecystectomy. The choice of whether the participants
received the different painkillers (or not) was determined by a method similar to the toss of coin so that the treatments compared were
conducted in people who were as similar as possible. The treatments in all the included trials were aimed at decreasing the pain after
2Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
laparoscopic cholecystectomy before the participants reported pain. Participants were allowed to take additional painkillers as required
in most of the trials.
Key results
There were no deaths in either group in three trials (183 participants) that reported deaths. The differences in the serious complications
between the groups was imprecise in all the comparisons. None of the trials reported quality of life or the time taken to return to
normal activity. The differences in length of hospital stay and the time taken to return to work was imprecise in all the comparisons
that reported these. Pain was lower in the participants who received painkillers compared with those who received controls at 4 to 8
hours and at 9 to 24 hours as measured by the visual analogue scale (a chart that rates the amount of pain on a scale of 1 to 10). This is a
modest reduction and is comparable to other methods of pain reduction such as administering local anaesthetics (drugs that numb part
of the body, similar to the ones used by the dentist to prevent the people from feeling pain) during the operation. In summary, different
painkillers reduce pain scores in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the decision
to use these drugs has to weigh the clinically small reduction in pain against uncertain evidence of serious adverse events associated
with many of these agents.
Quality of evidence
The overall quality of evidence was very low.
Future research
Further trials are necessary. Such trials should include outcomes such as quality of life, the time taken to return to normal activity, and
the time taken to return to work, which are important for the person undergoing laparoscopic cholecystectomy and the people who
provide funds for the treatment.
3Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Various interventions compared with control for people undergoing laparoscopic cholecystectomy
Patient or population: people undergoing laparoscopic cholecystectomy
Settings: secondary or tertiary
Intervention: various interventions versus control
Outcomes Illustrative comparative risks* (95% CI) Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Assumed risk Corresponding risk
Control Various interventions
Non-steroidal anti-inflammatory drugs (NSAIDs) versus no active intervention
Morbidity 59 per 1000 44 per 1000
(22 to 90)
RR 0.75
(0.37 to 1.53)
543
(5 studies)
⊕©©©
very low1,2
Proportion discharged as
day-surgery
603 per 1000 603 per 1000
(447 to 809)
RR 1
(0.74 to 1.34)
116
(1 study)
⊕©©©
very low1,2
Length of hospital stay The mean length of hospital
stay in the control groups was
1.1 days
The mean length of hospital
stay in the intervention group
was
0.1 lower
(0.72 lower to 0.52 higher)
- 119
(1 study)
⊕©©©
very low1,3
Pain (4 to 8 hours) The mean pain (4 to 8 hours)
in the control groups was
3.49 cm VAS
The mean pain (4 to 8 hours)
in the intervention groups was
0.88 lower
(1.07 to 0.7 lower)
- 999
(11 studies)
⊕©©©
very low1,4
Pain (9 to 24 hours) The mean pain (9 to 24 hours)
in the control groups was
2.2 cm VAS
The mean pain (9 to 24 hours)
in the intervention groups was
0.5 lower
(0.67 to 0.33 lower)
- 707
(9 studies)
⊕©©©
very low1,4
4P
harm
aco
logic
alin
terven
tion
sfo
rp
reven
tion
or
treatm
en
to
fp
osto
pera
tive
pain
inp
eo
ple
un
derg
oin
gla
paro
sco
pic
ch
ole
cyste
cto
my
(Revie
w)
Co
pyrig
ht
©2014
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td.
Mortality, patient quality of life, and return to normal activity were not reported in any trials. Return to work was not reported adequately in any of the trials
Opioids versus no active intervention
Pain (4 to 8 hours) The mean pain (4 to 8 hours)
in the control groups was
4.00 cm VAS
The mean pain (4 to 8 hours)
in the intervention groups was
2.51 lower
(3.02 to 2.01 lower)
- 425
(3 studies)
⊕⊕©©
low1
Pain (9 to 24 hours) The mean pain (9 to 24 hours)
in the control groups was
2.76 cm VAS
The mean pain (9 to 24 hours)
in the intervention groups was
0.32 lower
(0.44 to 0.2 lower)
- 425
(3 studies)
⊕⊕©©
low1
Mortality, patient quality of life, hospital stay, and return to normal activity or work were not reported in any trials. Morbidity was reported adequately in any of the trials
Anticonvulsant analgesics versus no active intervention
Mortality There was no mortality in either group Not estimable 123
(1 study)
⊕©©©
very low1,2
Morbidity 40 per 1000 120 per 1000
(13 to 1000)
RR 3
(0.33 to 26.92)
50
(1 study)
⊕©©©
very low1,2
Pain (4 to 8 hours) The mean pain (4 to 8 hours)
in the control groups was
4 cm VAS
The mean pain (4 to 8 hours)
in the intervention groups was
2.52 lower
(2.95 to 2.09 lower)
- 402
(3 studies)
⊕©©©
very low1,4
Pain (9 to 24 hours) The mean pain (9 to 24 hours)
in the control groups was
3 cm VAS
The mean pain (9 to 24 hours)
in the intervention groups was
0.55 lower
(0.68 to 0.42 lower)
- 402
(3 studies)
⊕⊕©©
low1
Patient quality of life, hospital stay, and return to normal activity were not reported in any trials. Return to work was not reported adequately in any of the trials
5P
harm
aco
logic
alin
terven
tion
sfo
rp
reven
tion
or
treatm
en
to
fp
osto
pera
tive
pain
inp
eo
ple
un
derg
oin
gla
paro
sco
pic
ch
ole
cyste
cto
my
(Revie
w)
Co
pyrig
ht
©2014
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td.
Opioids versus NSAIDs
Only one trial was included in this comparison. None of the outcomes was reported adequately in this trial
Anticonvulsant analgesics versus NSAIDs
Mortality There was no mortality in either group Not estimable 60
(1 study)
⊕©©©
very low1,2
Morbidity 37 per 1000 80 per 1000
(8 to 829)
RR 2.16
(0.21 to 22.38)
52
(1 study)
⊕©©©
very low1,2
Pain (4 to 8 hours) The mean pain (4 to 8 hours)
in the control groups was
4.3 cm VAS
The mean pain (4 to 8 hours)
in the intervention groups was
2.5 lower
(2.84 to 2.16 lower)
- 60
(1 study)
⊕©©©
very low1,3
Pain (9 to 24 hours) The mean pain (9 to 24 hours)
in the control groups was
2.1 cm VAS
The mean pain (9 to 24 hours)
in the intervention groups was
0.5 lower
(0.84 to 0.16 lower)
- 60
(1 study)
⊕©©©
very low1,3
Patient quality of life, hospital stay, and return to normal activity were not reported in any trials. Return to work was not reported adequately in any of the trials
Anticonvulsant analgesics versus opioids
Pain (4 to 8 hours) The mean pain (4 to 8 hours)
in the control groups was
2.97 VAS
The mean pain (4 to 8 hours)
in the intervention groups was
0.32 lower
(0.92 lower to 0.28 higher)
- 306
(1 study)
⊕©©©
very low1,3
Pain (9 to 24 hours) The mean pain (9 to 24 hours)
in the control groups was
0.87 VAS
The mean pain (9 to 24 hours)
in the intervention groups was
0.22 lower
(0.34 to 0.1 lower)
- 306
(1 study)
⊕©©©
very low1,3
6P
harm
aco
logic
alin
terven
tion
sfo
rp
reven
tion
or
treatm
en
to
fp
osto
pera
tive
pain
inp
eo
ple
un
derg
oin
gla
paro
sco
pic
ch
ole
cyste
cto
my
(Revie
w)
Co
pyrig
ht
©2014
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td.
Mortality, patient quality of life, hospital stay, and return to normal activity or work were not reported in the only trial that was included in the comparison. Morbidity was not reported
adequately in any of the trials
*The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison
group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; NSAID: non-steroidal anti-inflammatory drug; VAS: visual analogue scale.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 The trial(s) was (were) of high risk of bias (2 points).2 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both. The number of events in the intervention and control group was
fewer than 300 (2 points).3 There were fewer than 400 participants in total (1 point).4 There was severe heterogeneity as noted by the I2statistic and the lack of overlap of confidence intervals (2 points).
7P
harm
aco
logic
alin
terven
tion
sfo
rp
reven
tion
or
treatm
en
to
fp
osto
pera
tive
pain
inp
eo
ple
un
derg
oin
gla
paro
sco
pic
ch
ole
cyste
cto
my
(Revie
w)
Co
pyrig
ht
©2014
Th
eC
och
ran
eC
olla
bo
ratio
n.P
ub
lished
by
Joh
nW
iley
&S
on
s,L
td.
B A C K G R O U N D
Description of the condition
About 5% to 25% of the adult western population have gall-
stones (GREPCO 1984; GREPCO 1988; Bates 1992; Halldestam
2004). The annual incidence of gallstones is about 1 in 200 peo-
ple (NIH 1992). Only 2% to 4% of people with gallstones be-
come symptomatic with biliary colic (pain), acute cholecystitis
(inflammation), obstructive jaundice, or gallstone pancreatitis in
a year (Attili 1995; Halldestam 2004). Cholecystectomy (removal
of gallstones) is the preferred option in the treatment of symp-
tomatic gallstones (Strasberg 1993) and every year, 1.5 million
cholecystectomies are performed in the US and 60,000 in the UK
(Dolan 2009; HES 2011). Approximately 80% of the cholecys-
tectomies are performed laparoscopically (keyhole) (Ballal 2009).
While laparoscopic cholecystectomy is generally considered less
painful than open surgery, pain is one of the important reasons for
delayed discharge after laparoscopic cholecystectomy (Gurusamy
2008a; Gurusamy 2008b). The pain after laparoscopic cholecys-
tectomy could be incisional pain, shoulder pain, or abdominal
pain (Ng 2004). While the incisional pain is because of damage to
the nerve endings because of the incision along with the associated
inflammation, the aetiology of abdominal pain and shoulder pain
after laparoscopic cholecystectomy is unclear. Peritoneal irritation,
caused by carbonic acid and creation of space between diaphragm
and liver, leading to loss of suction support of the heavy liver have
been suggested as possible mechanisms of pain (Alexander 1987).
However, use of an overnight drain to let out the gas has not been
effective in the reduction of pain (Gurusamy 2013).
Description of the intervention
Analgesics provide pain relief (analgesia). There are different types
of analgesics. The common analgesics used peri-operatively can
be broadly classified into non-steroidal anti-inflammatory drugs
(NSAIDs), such as paracetamol, diclofenac, or ibuprofen; opioid
analgesics (opium derivatives and synthetic substances that have
similar action), such as tramadol or codeine; and anticonvulsant
analgesics, such as gabapentin or pregabalin used to treat neuro-
pathic pain (Argoff 2013). The analgesics can be administered by
different routes including orally, sublingually, intravenously, sub-
cutaneously, by transdermal patches, or rectally (Martindale 2011;
Argoff 2013). The most common adverse events associated with
short-term use of NSAIDs include gastrointestinal disturbances,
such as gastrointestinal discomfort, nausea, and diarrhoea; these
are usually mild and reversible but in some people peptic ulcer-
ation and severe gastrointestinal bleeding may occur (Martindale
2011). The most common adverse events related to opioids used
in usual doses include nausea, vomiting, constipation, drowsi-
ness, confusion, difficulty in micturition, dry mouth, dizziness,
sweating, facial flushing, headache, vertigo, bradycardia, tachycar-
dia, palpitations, orthostatic hypotension, hypothermia, restless-
ness, changes of mood, decreased libido or potency, hallucinations,
and raised intracranial pressure. Larger doses of opioids produce
muscle rigidity, respiratory depression, hypotension with circula-
tory failure, and deepening coma (Martindale 2011). The most
commonly reported adverse events associated with gabapentin are
somnolence, dizziness, ataxia, and fatigue although psychiatric ef-
fects including confusion, depression, and nervousness can occur
in some people (Martindale 2011). Common adverse events re-
lated to pregabalin include dizziness, somnolence, blurred vision,
diplopia (double vision), dry mouth, constipation, vomiting, flat-
ulence, euphoria, confusion, reduced libido, erectile dysfunction,
irritability, vertigo, ataxia, tremor, dysarthria, paraesthesia, fatigue,
oedema, and disturbances of attention, memory, co-ordination,
and gait (Martindale 2011).
How the intervention might work
NSAIDs inhibit cyclo-oxygenase, an enzyme in the pathway of
synthesis of prostaglandins, which play an important role in
inflammation (Martindale 2011; Argoff 2013). NSAIDs may
also have a central action in addition to their peripheral action
(Martindale 2011). Opioid analgesics act on opioid receptors in
the peripheral and central nervous system and inhibit the neuronal
transmission (transmission by nerve) of pain sensation (Inturrisi
2002). Gabapentin and pregabalin are anticonvulsant drugs that
inhibit the α2δ subunit of presynaptic, voltage-gated calcium
channels (Argoff 2013). This results in decreased excitability of
nerves.
Why it is important to do this review
One systematic review by the Procedure Specic Postoperative Pain
Management (PROSPECT) group recommended routine use of
NSAIDs and recommended against routine use of opioid anal-
gesics during or after laparoscopic cholecystectomy (Kehlet 2005).
Another systematic review by Bisgaard et al. made similar recom-
mendations as the PROSPECT group and, in addition, recom-
mended against routine use of gabapentin during or after laparo-
scopic cholecystectomy (Bisgaard 2006). Reduction in pain may
improve quality of life and allow earlier return to normal activ-
ity and work, which may have financial implications to the peo-
ple undergoing the operations, their carers, and their employers.
Reduction in pain may also improve the proportion of laparo-
scopic cholecystectomies performed as day-surgery and decrease
the length of hospital stay, which may be important for the peo-
ple undergoing the procedure in a private-funded healthcare sys-
tem and may be important for state-funded or insurance-funded
healthcare systems. We have been unable to identify any recent
8Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
systematic reviews or Cochrane reviews assessing the role of differ-
ent analgesics in people undergoing laparoscopic cholecystectomy.
O B J E C T I V E S
To assess the benefits and harms of different analgesics in people
undergoing laparoscopic cholecystectomy.
M E T H O D S
Criteria for considering studies for this review
Types of studies
We considered all randomised clinical trials (irrespective of lan-
guage, blinding, publication status, or sample size) for inclusion.
We excluded quasi-randomised trials (where the method of allocat-
ing participants to a treatment are not strictly random, for exam-
ple, date of birth, hospital record number, alternation) and non-
randomised studies regarding assessment of benefit, but planned
to include these studies regarding assessment of treatment-related
harms.
Types of participants
People undergoing laparoscopic cholecystectomy irrespective of
age, elective or emergency surgery, and the reason why the laparo-
scopic cholecystectomy was performed.
Types of interventions
We included the following comparisons.
• NSAIDs versus inactive controls (no intervention or
placebo).
• Opioid analgesics versus inactive controls (no intervention
or placebo).
• Anticonvulsant analgesics versus inactive controls (no
intervention or placebo).
• Comparison of one of the above three classes of drugs with
another class.
We included only trials that compared the above analgesics ad-
ministered orally, sublingually, intravenously, and rectally, which
are the routes that are commonly used to administer the above
agents. We excluded trials that compared administration of anal-
gesics by intraperitoneal, intrathecal, or intrapleural routes; wound
infiltration; or nerve blocks as we considered these as extensions
of anaesthetic regimens. We excluded comparison of drugs within
the same class of drugs, as inclusion of such trials would make
the review very difficult to read. We planned to perform separate
reviews for comparison of drugs within the same class if we found
that one or more classes were safe and effective in people under-
going laparoscopic cholecystectomy. We excluded trials that in-
volved a combination of two or more classes of drugs against inac-
tive interventions. We excluded trials considering pharmacological
agents not primarily meant for analgesia such as intravenous ke-
tamine (used for its sedative property to perform short procedures)
(Gottschling 2005), α2-adrenoceptor antagonist, such as cloni-
dine (aimed at improving the circulatory stability) (Yu 2003), and
beta-blockers such as esmolol (aimed at decreasing stress response)
(Collard 2007). We excluded wound infiltration or intraperitoneal
instillation of local anaesthetics because they have been considered
in other reviews (Gurusamy 2014; Loizides 2014). We excluded
epidural or intrathecal interventions because we consider these to
be extensions of the anaesthetic regimen used.
We allowed co-interventions if carried out equally in the trial
groups.
Types of outcome measures
Primary outcomes
1. Mortality.
2. Serious adverse events defined as any event that would
increase mortality, was life-threatening, required hospitalisation,
resulted in a persistent or significant disability, or any important
medical event that might have jeopardised the person or required
intervention to prevent it (ICH-GCP 1997). We classified
complications such as bile duct injury; re-operations; intra-
abdominal collections requiring drainage (radiological or
surgical); infected intra-abdominal collections; bile leaks
requiring drainage, stent, or surgery; gastrointestinal
disturbances that required endoscopic investigations or
treatment; respiratory depression that required monitoring and
hence prolonged hospital stay as serious adverse events. We
considered complications such as wound infections, bile leaks,
abdominal collections, or minor gastrointestinal disturbances
that did not require treatment and settled spontaneously to be
non-serious adverse events.
3. Patient quality of life (however defined by authors using a
validated scale such as Euro-QoL or 36-item Short Form (SF-
36)).
Secondary outcomes
1. Hospital stay (length of hospital stay, proportion discharged
as day-surgery laparoscopic cholecystectomy).
2. Pain (overall pain) at different time points (4 to 8 hours and
9 to 24 hours) using visual analogue scale (VAS).
3. Return to activity.
4. Return to work.
9Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We have reported all the outcomes with at least one trial in the
Summary of findings for the main comparison.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials
(CENTRAL), MEDLINE, EMBASE, Science Citation Index Ex-
panded (Royle 2003), and the World Health Organization Inter-
national Clinical Trials Registry Platform portal (WHO ICTRP)
(apps.who.int/trialsearch/) to March 2013. The WHO ICTRP
portal allows search of various trial registers including clinicaltri-
als.gov and ISRCTN among other registers. We have given the
search strategies in Appendix 1 with the time span for the searches.
Searching other resources
We also searched the references of the identified trials to identify
further relevant trials.
Data collection and analysis
We performed the systematic review according to the recommen-
dations of The Cochrane Collaboration (Higgins 2011) and the
Cochrane Hepato-Biliary Group Module (Gluud 2014).
Selection of studies
Two review authors (KSG and CT) identified the trials for in-
clusion independently of each other. We have also listed the ex-
cluded studies with the reasons for the exclusion (Characteristics
of excluded studies).
Data extraction and management
Two review authors (JV and CT) extracted the following data
independently of each other.
1. Year and language of publication.
2. Country in which the trial was conducted.
3. Year of trial.
4. Inclusion and exclusion criteria.
5. Sample size.
6. Elective surgery or acute cholecystitis.
7. Pharmacological agent used.
8. Dose of pharmacological agent.
9. Route of pharmacological agent.
10. Timing of administration.
11. Other co-interventions.
12. Outcomes (Primary outcomes; Secondary outcomes).
13. Risk of bias (Risk of bias in included studies).
We sought any unclear or missing information by contacting the
authors of the individual trials. If there was any doubt whether
the trials shared the same participants - completely or partially (by
identifying common authors and centres) - we planned to contact
the authors of the trials to clarify whether the trial report had been
duplicated.
We resolved any differences in opinion through discussion or ar-
bitration of the third review author (BRD).
Assessment of risk of bias in included studies
We followed the instructions given in the Cochrane Handbookfor Systematic Reviews of Intervention (Higgins 2011) and the
Cochrane Hepato-Biliary Group Module (Gluud 2014). Accord-
ing to empirical evidence (Schulz 1995; Moher 1998; Kjaergard
2001; Wood 2008; Lundh 2012; Savovic 2012a; Savovic 2012b),
the risk of bias of the trials was assessed based on the following
bias risk domains.
Allocation sequence generation
• Low risk of bias: sequence generation was achieved using
computer random number generation or a random number
table. Drawing lots, tossing a coin, shuffling cards, and throwing
dice are adequate if performed by an independent person not
otherwise involved in the trial.
• Uncertain risk of bias: the method of sequence generation
was not specified.
• High risk of bias: the sequence generation method was not
random.
Allocation concealment
• Low risk of bias: the participant allocations could not have
been foreseen in advance of, or during, enrolment. Allocation
was controlled by a central and independent randomisation unit.
The allocation sequence was unknown to the investigators (eg, if
the allocation sequence was hidden in sequentially numbered,
opaque, and sealed envelopes).
• Uncertain risk of bias: the method used to conceal the
allocation was not described so that intervention allocations may
have been foreseen in advance of, or during, enrolment.
• High risk of bias: the allocation sequence was likely to be
known to the investigators who assigned the participants.
Blinding of participants and personnel
• Low risk of bias: blinding was performed adequately, or the
assessment of outcomes was not likely to be influenced by lack of
blinding.
• Uncertain risk of bias: there was insufficient information to
assess whether blinding was likely to introduce bias on the results.
10Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• High risk of bias: no blinding or incomplete blinding, and
the assessment of outcomes were likely to be influenced by lack
of blinding.
Blinding of outcome assessors
• Low risk of bias: blinding was performed adequately, or the
assessment of outcomes was not likely to be influenced by lack of
blinding.
• Uncertain risk of bias: there was insufficient information to
assess whether blinding was likely to induce bias on the results.
• High risk of bias: no blinding or incomplete blinding, and
the assessment of outcomes were likely to be influenced by lack
of blinding.
Incomplete outcome data
• Low risk of bias: missing data were unlikely to make
treatment effects depart from plausible values. Sufficient
methods, such as multiple imputation, have been employed to
handle missing data.
• Uncertain risk of bias: there was insufficient information to
assess whether missing data in combination with the method
used to handle missing data were likely to induce bias on the
results.
• High risk of bias: the results were likely to be biased due to
missing data.
Selective outcome reporting
• Low risk of bias: all outcomes were pre-defined and
reported, or all clinically relevant and reasonably expected
outcomes were reported. For this purpose, the trial should have
been registered either on the www.clinicaltrials.gov website or a
similar register with sufficient evidence that the protocol had not
been revised during the update, or there should be a protocol, for
example, published in a paper journal. In the case when the trial
was run and published in the years when trial registration was
not required, we carefully scrutinized all publications reporting
on the trial to identify the trial objectives and outcomes and
determine whether usable data were provided in the publication
results section on all outcomes specified in the trial objectives.
• Uncertain risk of bias: it is unclear whether all pre-defined
and clinically relevant (mortality and morbidity) and reasonably
expected outcomes were reported.
• High risk of bias: one or more clinically relevant and
reasonably expected outcomes were not reported, and data on
these outcomes were likely to have been recorded.
For-profit bias
• Low risk of bias: the trial appeared to be free of industry
sponsorship or other type of for-profit support that may
manipulate the trial design, conductance, or results of the trial.
• Uncertain risk of bias: the trial may or may not be free of
for-profit bias as no information on clinical trial support or
sponsorship was provided.
• High risk of bias: the trial was sponsored by the industry or
had received other type of for-profit support.
We considered trials that were classified as low risk of bias in all
the above domains as trials with low risk of bias and the remaining
as trials with high risk of bias.
Measures of treatment effect
For dichotomous variables, we calculated the risk ratio (RR) with
95% confidence interval (CI). We also calculated the risk differ-
ence with 95% CI. We planned to report the risk difference only
if the conclusions were different from those of RR. Risk difference
includes ’zero event trials’ (trials in which both groups had no
events) for calculating the summary treatment effect, while such
trials will not be taken into account while calculating the summary
treatment effect in the case of RR. For continuous variables, we
calculated the mean difference (MD) with 95% CI for outcomes
such as total hospital stay or standardised mean difference (SMD)
with 95% CI for outcomes such as quality of life, where different
authors used different scales of quality of life.
Unit of analysis issues
The units of analysis was the participant about to undergo laparo-
scopic cholecystectomy and randomised to the intraperitoneal lo-
cal anaesthetic instillation or control.
Dealing with missing data
We performed an intention-to-treat analysis whenever possible (
Newell 1992). We imputed data for binary outcomes using various
scenarios such as best-best, best-worst, worst-best, and worst-worst
scenario (Gurusamy 2009; Gluud 2014).
For continuous outcomes, we used available-case analysis. We im-
puted the standard deviation from P values according to the in-
structions given in the Cochrane Handbook for Systematic Reviewsof Intervention (Higgins 2011), and we used the median for the
meta-analysis when the mean was not available. If it was not possi-
ble to calculate the standard deviation from the P value or the CI,
we planned to impute the standard deviation as the highest stan-
dard deviation in the other trials included under that outcome,
fully recognising that this form of imputation would decrease the
weight of the study for calculation of MDs and bias the effect
estimate to no effect in the case of SMD (Higgins 2011).
Assessment of heterogeneity
We explored heterogeneity using the Chi2 test with significance
set at a P value less than 0.10, and measured the quantity of het-
erogeneity using the I2 statistic (Higgins 2002). We also used over-
lapping of CIs on the forest plot to determine heterogeneity.
11Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Assessment of reporting biases
We used visual asymmetry on a funnel plot to explore reporting
bias since the search identified more than 10 trials (Egger 1997;
Macaskill 2001). We used the linear regression approach described
by Egger 1997 to determine the funnel plot asymmetry. Selective
reporting was also considered as evidence for reporting bias.
Data synthesis
We performed the meta-analyses using the software package Re-
view Manager 5 (RevMan 2012), and following the recommen-
dations of The Cochrane Collaboration (Higgins 2011), and the
Cochrane Hepato-Biliary Group Module (Gluud 2014). We used
both a random-effects model (DerSimonian 1986) and a fixed-
effect model (DeMets 1987) meta-analysis. In the case of discrep-
ancy between the two models, we have reported both results; oth-
erwise, we have reported the results of the fixed-effect model. We
planned to use the generic inverse method to combine the hazard
ratios for time-to-event outcomes.
Trial sequential analysis
Cumulative meta-analyses run the risk of producing random er-
rors of both type I and type II due to sparse data and repetitive
analysis of accumulating data. The underlying assumption of trial
sequential analysis is that testing for significance may be performed
each time a new trial is added to the meta-analysis. We added the
trials according to the year of publication, and if more than one
trial was published in a year the trials were added alphabetically
according to the last name of the first author. On the basis of the
required information size, trial sequential monitoring boundaries
were constructed. These boundaries determine the statistical in-
ference one may draw regarding the cumulative meta-analysis that
has not reached the required information size; if the trial sequen-
tial monitoring boundary is crossed before the required informa-
tion size is reached, firm evidence may perhaps be established and
further trials may turn out to be superfluous. In contrast, if the
boundaries are not surpassed, it is most probably necessary to con-
tinue doing trials in order to detect or reject a certain intervention
effect (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009;
Wetterslev 2009; Thorlund 2010).
We applied trial sequential analysis (CTU 2011; Thorlund 2011)
using a diversity-adjusted required information size calculated
from an alpha error of 0.05, a beta error of 0.20, a control event
proportion obtained from the results, and a relative risk reduction
of 20% for binary outcomes if there were two or more trials report-
ing the outcome to determine whether more trials are necessary
on this topic (if the trial sequential alpha-spending monitoring
boundary or the futility zone is crossed, then more trials may be
unnecessary) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund
2009; Wetterslev 2009; Thorlund 2010). Since trial sequential
analysis cannot be performed for SMD, we did not plan to per-
form the trial sequential analysis for quality of life. For pain, we
calculated the diversity-adjusted required information size from
an alpha error of 0.05, a beta error of 0.20, the variance estimated
from the meta-analysis results of low risk of bias trials, and an
MD of 1 cm on the VAS (Todd 1996). For length of hospital stay,
return to work, and return to activity, we planned to calculate the
required sample size using an MD of one day with the remaining
parameters kept the same as that for pain.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses.
• Trials with low bias risk compared to trials with high bias
risk.
• Elective compared to emergency laparoscopic
cholecystectomy.
• Different times of administration (one to two hours before
surgery, on induction, or at the end of surgery).
• Different pharmacological agents.
• With and without intraperitoneal local anaesthetic
instillation.
• With and without peri-laparoscopic-portal infiltration with
local anaesthetic.
We used the ’test for subgroup differences’ available through Re-
view Manager 5 (RevMan 2012) to identify the differences be-
tween subgroups. We used the random-effects model for this pur-
pose.
Sensitivity analysis
We performed a sensitivity analysis by imputing data for binary
outcomes using various scenarios such as best-best, best-worst,
worst-best, and worst-worst scenario (Gurusamy 2009; Gluud
2014). We performed a sensitivity analysis by excluding the trials
in which the mean and the standard deviation were imputed.
’Summary of findings’ table
We have summarised the results of all the reported outcomes in
the Summary of findings for the main comparison prepared using
GRADEPro 3.6 (ims.cochrane.org/revman/gradepro).
R E S U L T S
Description of studies
Results of the search
We identified 1238 references through electronic searches of CEN-
TRAL (n = 274), MEDLINE (n = 269), EMBASE (n = 302), and
12Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Science Citation Index Expanded (n = 393). We did not identify
any new trials from the trial registers. We excluded 604 duplicates
and 572 clearly irrelevant references through screening titles and
reading abstracts. We retrieved 62 references for further assess-
ment. We identified no references through scanning reference lists
of the identified randomised trials. We excluded 25 references for
the reasons listed in the Characteristics of included studies table.
In total, 37 references of 36 completed randomised clinical trials
met the inclusion criteria. This is summarised in the study flow
diagram Figure 1. We did not identify any comparative non-ran-
domised studies that reported treatment-related harms.
13Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 1. Study flow diagram.
14Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Included studies
Of the 36 randomised clinical trials that reported the inclusion
criteria, 10 trials did not provide any information for this system-
atic review (Liu 1993; Belzarena 1998; Muñoz 2002; Cheng 2004;
Puura 2006; Akinci 2008; Fanelli 2008; Karakoc 2011; Balaban
2012; Gomez-Vazquez 2012). These trials reported some specific
aspects of pain, for example, shoulder pain or abdominal pain,
used other scales of pain, or reported other outcomes such as stress
response. One other trial did not report the number of partici-
pants randomised to the intervention and control groups (Schuster
2005). Thus, we included 25 randomised clinical trials including
2505 participants randomised to different interventions and con-
trols in this review. In 15 trials, we included two arms in this review
(Wilson 1994; Munro 1998; Chung 2004; Horattas 2004; Joshi
2004; Yeh 2004; Zajaczkowska 2004; Agarwal 2008; Akaraviputh
2009; Salihoglu 2009; Sen 2010; Sandhu 2011; Zhu 2011; Akarsu
2012; Sarakatsianou 2013), that is, although some of these trials
randomised participants to more than two arms, only two arms
were eligible for inclusion in this review. In the remaining 10 trials,
we included more than two arms in this review (Forse 1996; Lane
1996; Dong 2003; Pandey 2004; Mebazaa 2008; Gilron 2009; Ji
2010; Peng 2010; Abdulla 2012; Nesek-Adam 2012).
Participant characteristics
The pharmacological interventions in all the included trials were
aimed at decreasing pain after laparoscopic cholecystectomy be-
fore the participants reported pain. Nineteen trials reported that
they included only people undergoing elective laparoscopic chole-
cystectomy (Wilson 1994; Forse 1996; Chung 2004; Horattas
2004; Joshi 2004; Pandey 2004; Yeh 2004; Zajaczkowska 2004;
Akaraviputh 2009; Gilron 2009; Salihoglu 2009; Peng 2010; Sen
2010; Sandhu 2011; Zhu 2011; Abdulla 2012; Akarsu 2012;
Nesek-Adam 2012; Sarakatsianou 2013). None of the remain-
ing six trials stated whether people undergoing emergency la-
paroscopic cholecystectomy were included (Lane 1996; Munro
1998; Dong 2003; Agarwal 2008; Mebazaa 2008; Ji 2010). Fif-
teen trials stated that they included only people with American
Society of Anesthesiologists (ASA) I or II status (Forse 1996;
Lane 1996; Pandey 2004; Yeh 2004; Zajaczkowska 2004; Agarwal
2008; Mebazaa 2008; Gilron 2009; Salihoglu 2009; Ji 2010; Sen
2010; Sandhu 2011; Zhu 2011; Nesek-Adam 2012; Sarakatsianou
2013). Three trials stated that they included only people with
ASA I to III status (Peng 2010; Abdulla 2012; Akarsu 2012).
The remaining seven trials did not state the ASA status of the
people undergoing laparoscopic cholecystectomy (Wilson 1994;
Munro 1998; Dong 2003; Chung 2004; Horattas 2004; Joshi
2004; Akaraviputh 2009).
Intervention and control
Eighteen trials compared NSAIDs with inactive control (Wilson
1994; Forse 1996; Lane 1996; Munro 1998; Dong 2003; Chung
2004; Horattas 2004; Joshi 2004; Yeh 2004; Mebazaa 2008;
Akaraviputh 2009; Gilron 2009; Salihoglu 2009; Ji 2010; Sen
2010; Sandhu 2011; Abdulla 2012; Nesek-Adam 2012). Four tri-
als compared opioids versus inactive controls (Lane 1996; Pandey
2004; Zajaczkowska 2004; Zhu 2011). Five trials compared an-
ticonvulsant analgesics versus inactive controls (Pandey 2004;
Agarwal 2008; Gilron 2009; Peng 2010; Sarakatsianou 2013).
Twenty-one trials used placebo as control (Wilson 1994; Forse
1996; Lane 1996; Munro 1998; Chung 2004; Horattas 2004;
Joshi 2004; Pandey 2004; Yeh 2004; Agarwal 2008; Akaraviputh
2009; Gilron 2009; Salihoglu 2009; Ji 2010; Peng 2010; Sen
2010; Sandhu 2011; Zhu 2011; Abdulla 2012; Nesek-Adam 2012;
Sarakatsianou 2013). Three trials used no intervention as control
(Dong 2003; Zajaczkowska 2004; Mebazaa 2008). One trial com-
pared opioid versus NSAID (Lane 1996). Two trials compared
anticonvulsant analgesics versus NSAID (Gilron 2009; Akarsu
2012). One trial compared anticonvulsant analgesics versus opi-
oid (Pandey 2004).
Co-interventions
Intraperitoneal local anaesthetic instillation was used as a co-inter-
vention in one trial (Peng 2010). Intraperitoneal local anaesthetic
instillation was not used as a co-intervention in five trials (Lane
1996; Munro 1998; Joshi 2004; Mebazaa 2008; Sandhu 2011).
The remaining trials did not provide this information.
Peri-laparoscopic portal local anaesthetic infiltration was used as
co-intervention in three trials (Forse 1996; Gilron 2009; Peng
2010). Peri-laparoscopic portal local anaesthetic infiltration was
not used as co-intervention in five trials (Lane 1996; Munro 1998;
Joshi 2004; Zajaczkowska 2004; Sandhu 2011). The remaining
trials did not provide this information.
Participants were allowed to take additional analgesics as required
in 24 trials (Wilson 1994; Forse 1996; Lane 1996; Munro 1998;
Chung 2004; Horattas 2004; Joshi 2004; Pandey 2004; Yeh 2004;
Zajaczkowska 2004; Agarwal 2008; Mebazaa 2008; Akaraviputh
2009; Gilron 2009; Salihoglu 2009; Ji 2010; Peng 2010; Sen
2010; Sandhu 2011; Zhu 2011; Abdulla 2012; Akarsu 2012;
Nesek-Adam 2012; Sarakatsianou 2013). This information was
not available from one trial (Dong 2003).
The other co-interventions used in the trials is are shown in the
Characteristics of included studies table.
Further details about sample size, participant characteristics, the
inclusion and exclusion criteria used in the trials, post-randomisa-
tion drop-outs, intervention and control, comparisons, outcomes,
15Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
and the risk of bias in the trials are shown in the Characteristics
of included studies table.
Risk of bias in included studies
All the remaining trials were at high risk of bias. The risk of bias in
the included trials is summarised in the ’Risk of bias’ graph (Figure
2) and ’Risk of bias’ summary (Figure 3).
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
16Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
17Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Allocation
Only three trials (3/36 (8.3%)) described random sequence gener-
ation and allocation concealment adequately (Joshi 2004; Gilron
2009; Abdulla 2012). These three trials were considered to be at
low risk of selection bias.
Blinding
Five trials (5/36 (13.9%)) reported that the participants, healthcare
personnel involved in patient care, and outcome assessors were
blinded and were considered to be at low risk of performance and
detection bias (Chung 2004; Joshi 2004; Agarwal 2008; Fanelli
2008; Abdulla 2012).
Incomplete outcome data
Nine trials (9/36 (25.0%)) had no post-randomisation drop-outs
and were considered to be at low risk of attrition bias (Lane 1996;
Cheng 2004; Fanelli 2008; Salihoglu 2009; Ji 2010; Abdulla 2012;
Akarsu 2012; Balaban 2012; Gomez-Vazquez 2012).
Selective reporting
None of the trials reported mortality and morbidity in the par-
ticipants and so all the trials were considered to be at high risk of
selective reporting bias.
Other potential sources of bias
Six trials (6/36 (16.7%)) were considered to be at low risk of ’for-
profit’ bias (Puura 2006; Fanelli 2008; Akaraviputh 2009; Gilron
2009; Sandhu 2011; Akarsu 2012).
Effects of interventions
See: Summary of findings for the main comparison Various
interventions compared with control for people undergoing
laparoscopic cholecystectomy
The results are summarised in Summary of findings for the main
comparison.
Non-steroidal anti-inflammatory drugs versus control
Mortality
None of the trials reported mortality.
Morbidity
Five trials reported serious adverse events (Chung 2004; Joshi
2004; Gilron 2009; Salihoglu 2009; Sandhu 2011). It is not clear
whether any of the serious adverse events could be drug-related.
There was no significant difference in the proportion of people
with serious adverse events between NSAID and control (RR 0.75;
95% CI 0.37 to 1.53; 543 participants; very low quality evidence)
(Analysis 1.1). The results did not change by using the random-
effects model. Although the remaining trials did not report the
overall morbidity, one other trial (52 participants) stated that there
were no intraoperative complications (Forse 1996). Five other tri-
als stated there were no drug-related serious adverse events in any
of the 226 participants who received NSAID (Wilson 1994; Lane
1996; Munro 1998; Abdulla 2012; Nesek-Adam 2012). The trial
sequential analysis revealed that the proportion of information ac-
crued was only 4.5% of the diversity-adjusted required informa-
tion size and so the trial sequential monitoring boundaries were
not drawn (Figure 4). The cumulative Z curve did not cross the
conventional statistical boundaries. Sensitivity analysis by imput-
ing missing outcomes according to different scenarios resulted in
different results (Analysis 1.6).
18Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 4. Trial sequential analysis of morbidity (non-steroidal anti-inflammatory drug (NSAID) versus
control)The diversity-adjusted required information size (DARIS) was calculated to 11,338 participants, based
on the proportion of participants in the control group with the outcome of 5.90%, a relative risk reduction of
20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero-event groups, a continuity
correction of 0.01 was used in the calculation of the cumulative Z curve (blue line). After accruing 543
participants in five trials, only 4.79% of the DARIS has been reached. Accordingly, the trial sequential analysis
does not show the required information size and the trial sequential monitoring boundaries. As shown, the
conventional boundaries have also not been crossed by the cumulative Z curve.
19Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
Proportion discharged as day-surgery
One trial reported the proportion of participants discharged as
day-surgery (Horattas 2004). There were no significant differences
in the proportion of participants discharged as day-surgery be-
tween NSAID and control (RR 1.00; 95% CI 0.74 to 1.34; 116
participants; very low quality evidence) (Analysis 1.2). Trial se-
quential analysis was not performed because of the presence of only
one trial. The results were robust to sensitivity analysis by imput-
ing missing outcomes according to different scenarios (Analysis
1.7).
Length of hospital stay
One trial reported length of hospital stay (Sandhu 2011). There
were no significant differences in the length of hospital stay be-
tween the two groups (MD -0.10 days; 95% CI -0.72 to 0.52;
119 participants; very low quality evidence) (Analysis 1.3). Trial
sequential analysis was not performed because of the presence of
only one trial. The standard deviation was imputed from standard
error. We did not perform the sensitivity analysis as this was the
only trial included in this outcome.
Pain
Pain at 4 to 8 hours
Eleven trials reported pain at 4 to 8 hours (Wilson 1994; Munro
1998; Dong 2003; Chung 2004; Joshi 2004; Yeh 2004; Mebazaa
2008; Akaraviputh 2009; Ji 2010; Sen 2010; Abdulla 2012). The
pain scores as measured using the VAS were significantly lower in
the NSAID group than the control group (MD -0.88 cm VAS;
95% CI -1.07 to -0.70; 999 participants; very low quality ev-
idence) (Analysis 1.4). There were no changes in the interpre-
tation of results by using a random-effects meta-analysis. Either
the mean or the standard deviation was imputed in seven trials
(Wilson 1994; Munro 1998; Chung 2004; Joshi 2004; Yeh 2004;
Mebazaa 2008; Akaraviputh 2009). Exclusion of these trials did
not alter the results (MD -0.91 cm VAS; 95% CI -1.10 to -0.71)
(Analysis 1.8). One trial contributed to more than 50% of the
weight of the analysis (Sen 2010). It was not clear whether the
values were standard deviation or standard error. Therefore, we
performed another sensitivity analysis excluding this trial along
with the other trials where mean or standard deviation was im-
puted. There was no change in the results by excluding this trial
(MD -1.73 cm VAS; 95% CI -2.04 to -1.42). The trial sequential
analysis revealed that the trial sequential monitoring boundaries
were crossed by cumulative Z curve favouring NSAID. The find-
ings were consistent with NSAID decreasing pain between 4 and
8 hours compared with inactive control with a low risk of random
errors (Figure 5).
20Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 5. Trial sequential analysis of pain (4 to 8 hours) (non-steroidal anti-inflammatory drug (NSAID)
versus control)The diversity-adjusted required information size (DARIS) was 2050 participants based on a
minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 4.51, an alpha (a)
of 5%, a beta (b) of 20%, and a diversity (D2) of 93.07%. The conventional statistical boundaries (dotted red
line) are crossed by the cumulative Z curve (blue line) after the third trial. The trial sequential monitoring
boundaries (red line) are crossed by cumulative Z curve after the fifth trial. Although the DARIS has not been
reached, the findings are consistent with NSAID decreasing pain between 4 and 8 hours compared with
inactive control with low risk of random errors.
21Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pain at 9 to 24 hours
Nine trials reported pain at 9 to 24 hours (Wilson 1994; Munro
1998; Dong 2003; Yeh 2004; Mebazaa 2008; Akaraviputh 2009;
Ji 2010; Sen 2010; Abdulla 2012). The pain scores as measured
by VAS were significantly lower in the NSAID group than the
control group (MD -0.50 cm VAS; 95% CI -0.67 to -0.33; 707
participants; very low quality evidence) (Analysis 1.5). On using
the random-effects model, there was no significant difference be-
tween the two groups (MD -0.65 cm VAS; 95% CI -1.37 to 0.08).
There were no changes in the interpretation of results by using
a random-effects meta-analysis. Either the mean or the standard
deviation was imputed in five trials (Wilson 1994; Munro 1998;
Yeh 2004; Mebazaa 2008; Akaraviputh 2009). Exclusion of these
trials did not alter the results (MD -0.50 cm VAS; 95% CI -0.67
to -0.33) (Analysis 1.9). One trial contributed to more than 50%
of the weight of the analysis (Sen 2010). It was not clear whether
the values were standard deviation or standard error. Therefore,
we performed another sensitivity analysis excluding this trial along
with the other trials where mean or standard deviation was im-
puted. There was no change in the results by excluding this trial
(MD -1.14 cm VAS; 95% CI -1.39 to -0.89). The trial sequential
analysis revealed that the trial sequential monitoring boundaries
were crossed by cumulative Z curve favouring NSAID. The find-
ings were consistent with NSAID decreasing pain between 9 and
24 hours compared with inactive control with a low risk of ran-
dom errors (Figure 6).
22Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 6. Trial sequential analysis of pain (9 to 24 hours) (non-steroidal anti-inflammatory drug (NSAID)
versus control)The diversity-adjusted required information size (DARIS) was 1525 participants based on a
minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 2.62, an alpha (a)
of 5%, a beta (b) of 20%, and a diversity (D2) of 94.56%. The conventional statistical boundaries (dotted red
line) are crossed by the cumulative Z curve (blue line) after the third trial. The trial sequential monitoring
boundaries (red line) are crossed by cumulative Z curve after the fifth trial. Although the DARIS has not been
reached, the findings are consistent with NSAID decreasing pain between 9 and 24 hours compared with
inactive control with low risk of random errors.
23Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Return to normal activity
None of the trials reported return to normal activity.
Return to work
One trial (54 participants) reported return to work (Gilron 2009).
The trial did not report the standard deviation. The trial reported
that there were no significant differences in the time taken to return
to work. Trial sequential analysis was not performed because of
the presence of only one trial and because of the lack of standard
deviation in the trial that reported this outcome (Gilron 2009).
Subgroup analysis
Only pain at 4 to 8 hours and pain at 9 to 24 hours were suitable
for various subgroup analyses because of the paucity of data in
the other outcomes. We did not perform the following subgroup
analyses.
• Trials with low bias risk compared to trials with high bias
risk. None of the trials were at low risk of bias.
• Elective compared with emergency laparoscopic
cholecystectomy. None of the trials reported data for emergency
laparoscopic cholecystectomy separately.
• With and without intraperitoneal local anaesthetic
instillation. None of the trials that provided information about
intraperitoneal local anaesthetic instillation used local anaesthetic
instillation.
• With and without peri-laparoscopic-portal infiltration with
local anaesthetic. None of the trials that provided information
about local anaesthetic wound infiltration used local anaesthetic
wound infiltration.
The results of the other two subgroup analyses are as follows.
• Different times of administration (one to two hours before
surgery, on induction, or at the end of surgery). The tests for
subgroup differences were significant for both pain at 4 to 8
hours and for pain at 9 to 24 hours (P value < 0.00001). At both
4 to 8 hours and 9 to 24 hours, NSAID administration during
the surgery appeared to be more effective than administration at
other times.
• Different pharmacological agents. The test for subgroup
differences were significant for both pain at 4 to 8 hours and for
pain at 9 to 24 hours (P value < 0.00001). At 4 to 8 hours,
diclofenac, flurbiprofen, and lornoxicam appeared to be more
effective than other agents (celecoxib, etofenomate, metamizol,
paracetamol, parecoxib, and tenoxicam). At 9 to 24 hours,
lornoxicam appeared to be more effective than other agents
(celecoxib, diclofenac, etofenomate, fluribiprofen, metamizol,
paracetamol, parecoxib, and tenoxicam).
Reporting bias
We explored reporting bias only for pain at 4 to 8 hours and for
pain at 9 to 24 hours by funnel plots because of the presence of
an adequate number of trials for these two outcomes only. The
funnel plots did not reveal any evidence of reporting bias. The
Egger’s test did not reveal any evidence of reporting bias (pain at
4 to 8 hours: P value = 0.716; pain at 9 to 24 hours: P value =
0.871).
Opioids versus control
Mortality
None of the trials reported mortality.
Morbidity
None of the trials reported overall serious adverse events. Two
trials reported drug-related serious adverse event (Lane 1996;
Pandey 2004). There were six serious adverse events (respiratory
depression) in the opioid group compared with one serious adverse
event (respiratory depression) in the control group in one trial
(Pandey 2004). There were no drug-related serious adverse events
in the other trial (Lane 1996).
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
None of the trials reported the proportion of people discharged as
day-surgery or the length of hospital stay.
Pain
Pain at 4 to 8 hours
Three trials reported pain at 4 to 8 hours (Pandey 2004;
Zajaczkowska 2004; Zhu 2011). The pain scores as measured by
VAS were significantly lower in the opioid group than the control
group (MD -2.51 cm VAS; 95% CI -3.02 to -2.01; 425 partici-
pants; low quality evidence) (Analysis 2.1). There were no changes
in the interpretation of results by using a random-effects meta-
analysis. Either the mean or the standard deviation was imputed
in two trials (Zajaczkowska 2004; Zhu 2011). Exclusion of these
trials did not alter the results (MD -2.56 cm VAS; 95% CI -3.07
24Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
to -2.05) (Analysis 2.3). Trial sequential analysis revealed that the
trial sequential monitoring boundaries were crossed by cumula-
tive Z curve favouring opioid. The findings were consistent with
opioid decreasing pain between 4 and 8 hours compared with in-
active control with a low risk of random errors (Figure 7).
Figure 7. Trial sequential analysis of pain (4 to 8 hours) (opioid versus control)The diversity-adjusted
required information size (DARIS) was 445 participants based on a minimal relevant difference (MIRD) of 1 cm
on the visual analogue scale, a variance (VAR) of 14.16, an alpha (a) of 5%, a beta (b) of 20%, and a diversity
(D2) of 0%. The conventional statistical boundaries (dotted red line) and the trial sequential monitoring
boundaries (red line) are crossed by the cumulative Z curve (blue line) after the first trial. Although the DARIS
is not reached, the findings are consistent with opioid decreasing pain between 4 and 8 hours compared with
inactive control with low risk of random errors.
25Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pain at 9 to 24 hours
Three trials reported pain at 9 to 24 hours (Pandey 2004;
Zajaczkowska 2004; Zhu 2011). The pain scores as measured by
VAS were significantly lower in the opioid group than the control
group (MD -0.32 cm VAS; 95% CI -0.44 to -0.20; 425 partici-
pants; low quality evidence) (Analysis 2.2). There were no changes
in the interpretation of results by using a random-effects meta-
analysis. Either the mean or the standard deviation was imputed
in two trials (Zajaczkowska 2004; Zhu 2011). Exclusion of these
trials did not alter the results (MD -0.32 cm VAS; 95% CI -0.44
to -0.20) (Analysis 2.4). Trial sequential analysis revealed that the
diversity-adjusted required information size was 25 participants
based on a minimal relevant difference (MIRD) of 1 cm on the
VAS, a variance (VAR) of 0.78, an alpha (a) of 5%, a beta (b) of
20%, and a diversity (D2) of 0%. As this was crossed by the first
trial, the trial sequential boundaries were not drawn. A post hoc
analysis with the MIRD revised to 0.25 cm was performed. The
conventional statistical boundaries and the trial sequential moni-
toring boundaries were crossed by the cumulative Z curve after the
second trial. The findings were consistent with opioid decreasing
pain between 9 and 24 hours compared with inactive control with
low risk of random errors (Figure 8).
26Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 8. Trial sequential analysis of pain (9 to 24 hours) (opioid versus control)The diversity-adjusted
required information size (DARIS) was 25 participants based on a minimal relevant difference (MIRD) of 1 cm
on the visual analogue scale, a variance (VAR) of 0.78, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2)
of 0%. As this was crossed by the first trial, the trial sequential boundaries were not drawn. A post-hoc analysis
with the MIRD revised to 0.25 cm was performed. The conventional statistical boundaries (dotted red line)
and trial sequential monitoring boundaries (red line) are crossed by cumulative Z curve (blue line) after the
first trial. Although the DARIS has not been reached, the findings are consistent with opioid decreasing pain
between 9 and 24 hours compared with inactive control with low risk of random errors.
27Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Return to normal activity
None of the trials reported return to normal activity.
Return to work
None of the trials reported return to work.
Subgroup analysis
We did not perform subgroup analysis because of the few trials
included in this comparison.
Reporting bias
We did not assess the reporting bias by using funnel plots because
of the few trials included in this comparison.
Anticonvulsant analgesics versus control
Mortality
One trial (123 participants) reported mortality (Peng 2010). There
was no mortality in either group (0/82 (0%) in anticonvulsant
analgesic group versus 0/41 (0%) in control group). Trial sequen-
tial analysis was not performed because of the presence of only one
trial for this comparison.
Morbidity
One trial reported morbidity (Gilron 2009). There was no sig-
nificant difference in the morbidity between the two groups (RR
3.00; 95% CI 0.33 to 26.92; 50 participants; very low quality
evidence) (Analysis 3.1). Two other trials reported drug-related
serious adverse events (Pandey 2004; Agarwal 2008).There was
one respiratory depression in the anticonvulsant analgesic group
(1/27 (3.7%)) compared with none in the control group (0/29
(0%)) in one trial (Agarwal 2008). There were no drug-related se-
rious adverse events (0/153 (0%)) compared with one respiratory
depression in the control group (1/153 (0.7%)) in another trial
(Pandey 2004). The severity of the respiratory depression was not
reported. Trial sequential analysis was not performed because of
the presence of only one trial that reported morbidity for this com-
parison. The results were robust to sensitivity analysis by imputing
missing outcomes according to different scenarios (Analysis 3.4).
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
Proportion discharged as day-surgery
None of the trials reported the proportion of people discharged as
day surgery or the length of hospital stay.
Pain
Pain at 4 to 8 hours
Three trials reported pain at 4 to 8 hours (Pandey 2004; Agarwal
2008; Sarakatsianou 2013). The pain scores as measured by VAS
were significantly lower in the anticonvulsant analgesic group than
the control group (MD -2.52 cm VAS; 95% CI -2.95 to -2.09;
402 participants; very low quality evidence) (Analysis 3.2). There
were no changes in the interpretation of results by using a ran-
dom-effects meta-analysis. Either the mean or the standard de-
viation was imputed in two trials (Agarwal 2008; Sarakatsianou
2013). Exclusion of these trials did not alter the results (MD -2.88
cm VAS; 95% CI -3.36 to -2.40) (Analysis 3.5). Trial sequential
analysis revealed that there was a high risk of random errors even
though there was a statistically significant reduction in pain in the
anticonvulsant analgesic group compared with the control group
(Figure 9), that is, more trials are needed before a firm conclusion
about reduction in pain scores by anticonvulsants can be reached.
28Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 9. Trial sequential analysis of pain (4 to 8 hours) (anticonvulsant analgesics versus control)The
diversity-adjusted required information size (DARIS) was 4571 participants based on a minimal relevant
difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 9.56, an alpha (a) of 5%, a beta (b)
of 20%, and a diversity (D2) of 93.42%. The conventional statistical boundaries (dotted red line) are crossed by
the cumulative Z curve (blue line) after the third trial. After accruing 402 participants in three trials, only
8.79% of DARIS has been reached. Accordingly, the futility area is not shown. The conventional monitoring
boundaries (dotted red line) are crossed by the cumulative Z curve (blue line) after the first trial. The trial
sequential monitoring boundaries (red line) are not crossed by cumulative Z curve. The findings are consistent
with high risk of random errors even though there is a statistically significant reduction in pain in the
anticonvulsant analgesic group compared with the control group.
29Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pain at 9 to 24 hours
Three trials reported pain at 9 to 24 hours (Pandey 2004; Agarwal
2008; Sarakatsianou 2013). The pain scores as measured by VAS
were significantly lower in the anticonvulsant analgesic group than
the control group (MD -0.55 cm VAS; 95% CI -0.68 to -0.42;
402 participants; very low quality evidence) (Analysis 3.3). There
were no changes in the interpretation of results by using a random-
effects meta-analysis. Either the mean or the standard deviation
was imputed in two trials (Agarwal 2008; Sarakatsianou 2013).
Exclusion of these trials did not alter the results (MD -0.54 cm
VAS; 95% CI -0.67 to -0.41) (Analysis 3.6). Trial sequential anal-
ysis revealed that the diversity-adjusted required information size
(DARIS) was 25 participants based on a minimal relevant differ-
ence (MIRD) of 1 cm on the VAS, a variance (VAR) of 0.78, an
alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. As
this was crossed by the first trial, the trial sequential boundaries
were not drawn. A post hoc analysis with the MIRD revised to
0.25 cm was performed. The conventional statistical boundaries
and the trial sequential monitoring boundaries were crossed by
the cumulative Z curve after the second trial. The findings were
consistent with anticonvulsant analgesics decreasing pain between
9 and 24 hours compared with inactive control with low risk of
random errors (Figure 10).
30Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 10. Trial sequential analysis of pain (9 to 24 hours) (anticonvulsant analgesics versus control)The
diversity-adjusted required information size (DARIS) was 28 participants based on a minimal relevant
difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 0.88, an alpha (a) of 5%, a beta (b)
of 20%, and a diversity (D2) of 0%. As this was crossed by the first trial, the trial sequential boundaries were not
drawn. A post-hoc analysis with the MIRD revised to 0.25 cm was performed. The conventional statistical
boundaries (dotted red line) and the trial sequential monitoring boundaries (red line) are crossed by the
cumulative Z curve (blue line) after the first trial. Although the DARIS has not been reached, the findings are
consistent with anticonvulsant analgesics decreasing pain between 9 and 24 hours compared with inactive
control with low risk of random errors.
31Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Return to normal activity
None of the trials reported return to normal activity.
Return to work
One trial (50 participants) reported return to work (Gilron 2009).
The trial did not report the standard deviation. The trial reported
that there were no significant differences in the time taken to return
to work. Trial sequential analysis was not performed because of
the presence of only one trial and because of the lack of standard
deviation in the trial that reported this outcome (Gilron 2009).
Subgroup analysis
We did not perform subgroup analysis because of the few trials
included in this comparison.
Reporting bias
We did not assess the reporting bias by using funnel plots because
of the few trials included in this comparison.
Opioids versus non-steroidal anti-inflammatory drugs
Only one trial compared opioids versus NSAIDs. The only out-
come reported in this trial was drug-related serious adverse events.
There were no drug-related serious adverse events related to either
group (0/51 (0%) in opioid group versus 0/51 (0%) in NSAID
group). Trial sequential analysis, sensitivity analysis, subgroup
analysis, and assessment of reporting bias by funnel plot were not
performed because of the paucity of data.
Anticonvulsant analgesics versus non-steroidal anti-
inflammatory drugs
Mortality
One trial reported mortality (Akarsu 2012). There was no mortal-
ity in either group in this trial (0/30 (0%) in anticonvulsant anal-
gesic group versus 0/30 (0%) in NSAID group). Trial sequential
analysis was not performed because of the presence of only one
trial.
Morbidity
One trial reported morbidity (Gilron 2009). There was no signifi-
cant difference in the morbidity between the two groups (RR 2.16;
95% CI 0.21 to 22.38; 52 participants; very low quality evidence)
(Analysis 4.1). Another trial reported drug-related serious adverse
events (Akarsu 2012). There were no serious adverse events in the
anticonvulsant analgesic group (0/30 (0%)) and one serious ad-
verse event (respiratory depression) (1/30 (3.3%)) in the NSAID
group. The severity of the respiratory depression was not reported
(Akarsu 2012). Trial sequential analysis was not performed be-
cause of the presence of only one trial.
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
None of the trials reported the proportion of people discharged as
day-surgery or the length of hospital stay.
Pain
Pain at 4 to 8 hours
One trial reported pain at 4 to 8 hours (Akarsu 2012). The pain
scores as measured by VAS were significantly lower in the anti-
convulsant analgesic group than the NSAID group (MD -2.50
cm VAS; 95% CI -2.84 to -2.16; 60 participants; very low quality
evidence) (Analysis 4.2). Neither the mean nor the standard de-
viation was imputed in this trial. Trial sequential analysis was not
performed because of the presence of only one trial.
Pain at 9 to 24 hours
One trial reported pain at 9 to 24 hours (Akarsu 2012). The
pain scores as measured by VAS were significantly lower in the
anticonvulsant analgesic group than the NSAID group (MD -
0.50 cm VAS; 95% CI -0.84 to -0.16; 60 participants; very low
quality evidence) (Analysis 4.3). Neither the mean nor the standard
deviation was imputed in this trial. Trial sequential analysis was
not performed because of the presence of only one trial.
Return to normal activity
None of the trials reported return to normal activity.
32Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Return to work
One trial (52 participants) reported return to work (Gilron 2009).
The trial did not report the standard deviation. The trial reported
that there were no significant differences in the time taken to return
to work. Trial sequential analysis was not performed because of
the presence of only one trial and because of the lack of standard
deviation in the trial that reported this outcome (Gilron 2009).
Subgroup analysis
We did not perform subgroup analysis because of the few trials
included in this comparison.
Reporting bias
We did not assess reporting bias by using funnel plots because of
the few trials included in this comparison.
Anticonvulsant analgesics versus opioids
Only one trial could be included under this comparison (Pandey
2004). The outcomes reported by this trial were drug-related se-
rious adverse events (respiratory depression) (0/153 (0%) in anti-
convulsant analgesic group versus 6/153 (3.9%) in opioid group;
severity of respiratory depression not known), pain at 4 to 8 hours,
and pain at 9 to 24 hours. There were no significant differences
in pain at 4 to 8 hours between the groups (MD -0.32 cm VAS;
95% CI -0.92 to 0.28; 306 participants; very low quality evidence)
(Analysis 5.1). Pain at 9 to 24 hours was significantly lower in the
anticonvulsant analgesic group versus opioid group (MD -0.22
cm VAS; 95% CI -0.34 to -0.10; 306 participants; very low qual-
ity evidence) (Analysis 5.2). Trial sequential analysis, sensitivity
analysis, subgroup analysis, and assessment of reporting bias by
funnel plot were not performed because of the paucity of data.
D I S C U S S I O N
Summary of main results
In this review, we have compared different pharmacological agents
aimed at reducing pain during laparoscopic cholecystectomy. We
included 25 randomised clinical trials including 2505 participants
randomised to different groups and contributing to one or more
of the outcomes. There were no significant differences in mor-
tality or morbidity between the groups in different comparisons.
The overall mortality after laparoscopic cholecystectomy is low
(0.2%) (Giger 2011). In this review, the trials excluded high-risk
participants and we would anticipate that mortality would be even
lower in these studies. To detect a 20% relative risk difference
in mortality, more than 350,000 people are necessary. It is un-
likely that trials will be powered to measure differences in mor-
tality during laparoscopic cholecystectomy. Major complications
during laparoscopic cholecystectomy are also rare. Although res-
piratory depression was reported as complications in some of the
comparisons, the severity of the respiratory depression were not
reported and whether these respiratory depressions were related to
the drug per se or whether they were related to the anaesthetics that
the participants received was not clear. Respiratory depression is
one of the complications of opioids and anticonvulsant analgesics
(Martindale 2011). Common adverse effects of opioids include
nausea, vomiting, constipation, drowsiness, confusion, and uri-
nary retention (Martindale 2011). Common adverse effects of an-
ticonvulsant analgesics include drowsiness and sedation, although
very serious adverse effects such as coma can occur rarely following
overdose (Martindale 2011). Common adverse events related to
NSAIDs include mild and reversible gastrointestinal discomfort,
nausea, and diarrhoea, although in some people, peptic ulceration
and severe gastrointestinal bleeding may occur (Martindale 2011).
Various other rare adverse events include blood disorders such as
anaemia; thrombocytopenia; neutropenia; eosinophilia; agranulo-
cytosis; renal toxicity; central nervous system-related adverse ef-
fects including depression, drowsiness, and insomnia; fluid reten-
tion; congestive heart failure; photosensitivity; and hypersensitiv-
ity reactions (Martindale 2011). The serious adverse events profile
differs from one NSAID to another (Martindale 2011). Thus, all
the drugs compared in this review have one of more potentially
serious adverse events. To warrant routine use of these agents, the
adverse events have to be balanced against the benefits that these
agents may provide. Future trials should include drug-related se-
rious adverse events as an important outcome.
None of the trials reported quality of life or return to normal ac-
tivity. There were no significant differences in the proportion of
people discharged as day-surgery, length of hospital stay, or the
time taken to return to work in any of the comparisons that re-
ported return to work. The main purpose of the pharmacolog-
ical agents is to decrease pain enabling people to be discharged
from hospital and to return to normal activity and work as early
as possible. These outcomes are not only important for the person
but are also important for the state-funded health system. While
quality of life is the outcome that is used for assessing the cost-
effectiveness of an intervention, return to normal activity and re-
turn to work may also have relevance to the state in terms of lack
of productivity of the individual. Proportion of people discharged
as day-surgery and the length of the hospital stay are important for
people in a private health setting and for the state in a state-funded
health system because of the costs associated with hospital stay.
However, only a few trials reported one of more of these outcomes
(Horattas 2004; Gilron 2009; Sandhu 2011). Future trials on this
topic should include these outcomes.
Pain at 4 to 8 hours and at 9 to 24 hours were significantly reduced
in the various comparisons. The findings were robust to differ-
33Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ent sensitivity analyses in most of the comparisons. Trial sequen-
tial analysis also confirmed the risk of random errors in conclud-
ing that the pharmacological intervention decreased pain was low
in many of the comparisons. Although some subgroup analyses
showed significant influence of some factors over the effect esti-
mates, much importance should be not given to these subgroup
analyses because of the presence of only one or two trials in the
various subgroups. The mean reduction in pain was about 1 cm on
the 0 to 10 cm VAS for 4 to 8 hours and about 0.5 cm on the 0 to
10 cm for 9 to 24 hours in most comparisons. Differences in pain
scores of between 0.9 and 1.8 cm are generally considered clin-
ically significant (Todd 1996). Thus, it appears that some phar-
macological agents may have a role in increasing the proportion
of laparoscopic cholecystectomies performed as day-surgery since
people undergoing day-surgery laparoscopic cholecystectomy are
discharged between 4 and 8 hours. There was no significant differ-
ence in the proportion of participants who were discharged as day-
surgery in this review. It does not appear from the description in
the trials that day-surgery was attempted in most trials. Future tri-
als should investigate the role of different pharmacological agents
in the day-surgery laparoscopic cholecystectomy setting.
Surgical complications such as bile duct injury may increase the
pain after laparoscopic cholecystectomy. However, the proportion
of participants who develop serious complications after laparo-
scopic cholecystectomy is less than 0.5% (Giger 2011). It should
be noted that the pharmacological interventions do not reduce the
surgical complications and hence pharmacological interventions
cannot be advocated routinely in all people undergoing laparo-
scopic cholecystectomy in order to decrease pain due to surgical
complications.
Given that there are other alternatives that are safe and effective
in reducing pain after laparoscopic cholecystectomy to a similar
degree, for example, intraperitoneal local anaesthetic instillation
(Gurusamy 2014) or local anaesthetic wound infiltration (Loizides
2014), the use of NSAIDs, opioids, and anticonvulsant analgesics
can be questioned. Of course, local anaesthetic agents work only
for a short time while NSAIDs, opioids, and anticonvulsant anal-
gesics can be administered orally on a regular basis for a few days
postoperatively. The question is whether such routine administra-
tion is more beneficial than administration as required or whether
there is any benefit in administering prescription-only agents com-
pared with analgesics available over-the-counter (eg, NSAIDs such
as paracetamol or ibuprofen), which are generally considered safe
for short-term use in most people. There is currently no evidence
to suggest any clinical benefit in administering these agents rou-
tinely.
Overall completeness and applicability ofevidence
Most of the trials included in this review included people un-
dergoing elective laparoscopic cholecystectomy (Included studies;
Characteristics of included studies). Most trials included only low
anaesthetic risk participants (Included studies; Characteristics of
included studies). The findings of this review are applicable only
to such people.
Quality of the evidence
The overall quality of evidence was low to very low (Summary of
findings for the main comparison). Although it is difficult to blind
many interventions in surgery, this is one of the few interventions
in which adequate blinding can be achieved and high-quality ev-
idence is possible. Nevertheless, this is the best evidence that is
currently available.
Potential biases in the review process
We performed a thorough search of literature. However, we in-
cluded ’pain’ as one of the domains in this search strategy. Con-
sidering that reduction in pain is the main reason for the use of
these treatments, we expected that all the trials related to the topic
would be identified, and given the number of trials included in
this review, it is likely that most of the trials on this topic have
been identified, However, it is possible that trials did not mention
pain or words related to pain, and such trials might have been
missed by this search strategy. The impact of this is likely to be
small since it is likely that most trials would have mentioned the
purpose of the use of the intervention. At least two review au-
thors independently identified trials for inclusion and extracted
data, thus minimising errors. However, we imputed the mean and
standard deviation when these were not available. We performed
a sensitivity analysis excluding such trials but this did not change
the results significantly thus demonstrating the minimal impact
of missing mean or standard deviation.
Agreements and disagreements with otherstudies or reviews
A systematic review by Procedure Specic Postoperative Pain
Management (PROSPECT) group recommended routine use of
NSAIDs and recommended against routine use of opioid anal-
gesics during laparoscopic cholecystectomy (Kehlet 2005). An-
other systematic review by Bisgaard et al. made similar recommen-
dations as the PROSPECT group and in addition recommended
against routine use of gabapentin during laparoscopic cholecys-
tectomy (Bisgaard 2006). We do not recommend routine use of
any of these pharmacological agents.
A U T H O R S ’ C O N C L U S I O N S
34Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Implications for practice
There is evidence of very low quality that different pharmaco-
logical agents including non-steroidal anti-inflammatory drugs
(NSAIDs), opioid analgesics, and anticonvulsant analgesics reduce
pain scores in people at low anaesthetic risk undergoing elective
laparoscopic cholecystectomy. However, the decision to use these
drugs has to weigh the clinically small reduction in pain against
uncertain evidence of serious adverse events associated with many
of these agents.
Implications for research1. Further randomised clinical trials are necessary to evaluate
the role of pharmacological agents in the emergency and in the
elective set-up particularly in the day-surgery elective
laparoscopic cholecystectomy.
2. Future trials should include drug-related serious adverse
events, quality of life, hospital stay, return to normal activity, and
return to work as outcomes.
3. Future trials need to be designed according to the SPIRIT
(Standard Protocol Items: Recommendations for Interventional
Trials) guidelines (www.spirit-statement.org/) and conducted and
reported according to the CONSORT (Consolidated Standards
for Reporting of Trials) Statement (www.consort-statement.org).
A C K N O W L E D G E M E N T S
To The Cochrane Hepato-Biliary Group for the support that they
have provided.
Peer reviewers: Anders Mark Christensen, Denmark; Achmet Ali,
Turkey.
Contact editor: Christian Gluud, Denmark.
This project was funded by the National Institute for Health Re-
search.
Disclaimer of the Department of Health: “The views and opinions
expressed in the review are those of the authors and do not nec-
essarily reflect those of the National Institute for Health Research
(NIHR), National Health Services (NHS), or the Department of
Health”.
R E F E R E N C E S
References to studies included in this review
Abdulla 2012 {published data only}
Abdulla S, Eckhardt R, Netter U, Abdulla W. A randomized,
double-blind, controlled trial on non-opioid analgesics
and opioid consumption for postoperative pain relief after
laparoscopic cholecystectomy. Acta Anaesthesiologica Belgica2012;63(1):43–50.
Agarwal 2008 {published data only}
Agarwal A, Gautam S, Gupta D, Agarwal S, Singh PK,
Singh U. Evaluation of a single preoperative dose of
pregabalin for attenuation of postoperative pain after
laparoscopic cholecystectomy. British Journal of Anaesthesia2008;101(5):700–4.
Akaraviputh 2009 {published data only}
Akaraviputh T, Leelouhapong C, Lohsiriwat V,
Aroonpruksakul S. Efficacy of perioperative parecoxib
injection on postoperative pain relief after laparoscopic
cholecystectomy: a prospective, randomized study. WorldJournal of Gastroenterology 2009;15(16):2005–8.
Akarsu 2012 {published data only}
Akarsu T, Tur H, Bolat C, Ozkaynak I. Comparison
of pre-emptive pregabalin with placebo and diclofenac
combination for postoperative analgesia and cognitive
functions after laparoscopic cholecystectomy. Turkiye
Klinikleri Journal of Medical Sciences 2012;32(4):963–70.
Akinci 2008 {published data only}
Akinci SB, Ayhan B, Aycan IO, Tirnaksiz B, Basgul E,
Abbasoglu O, et al. The postoperative analgesic efficacy
of intraperitoneal tramadol compared to normal saline or
intravenous tramadol in laparoscopic cholecystectomy.
European Journal of Anaesthesiology 2008;25(5):375–81.
Balaban 2012 {published data only}
Balaban F, Yagar S, Ozgok A, Koc M, Gullapoglu H.
A randomized, placebo-controlled study of pregabalin
for postoperative pain intensity after laparoscopic
cholecystectomy. Journal of Clinical Anesthesia 2012;24(3):
175–8.
Belzarena 1998 {published data only}
Belzarena SD. Intravenous tenoxicam for postoperative pain
relief after laparoscopic cholecystectomy. A comparison
among placebo, 20 and 40 mg of tenoxicam [Tenoxicam
venoso para analgesia pos operatoria em colecistectomia
videolaparascopica. Comparacao entre placebo, 20 e 40 mg
de tenoxicam]. Revista Brasileira De Anestesiologia 1998;48
(1):7–13.
Cheng 2004 {published data only}
Cheng PGB, Lim MJ, Onsiong MK, Chiu KYW, Chan
MK, Li KWM, et al. Celecoxib premedication in post-
operative analgesia for laparoscopic cholecystectomy. AcutePain 2004;6(1):23–8.
Chung 2004 {published data only}
Chung F, Tong D, Miceli PC, Reiz J, Harsanyi Z, Darke
AC, et al. Controlled-release codeine is equivalent to
35Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
acetaminophen plus codeine for post-cholecystectomy
analgesia. Canadian Journal of Anaesthesia 2004;51(3):
216–21.
Dong 2003 {published data only}
Dong FT, Yang YL, Guo J. Postoperative analgesia
with lornoxicam in patients undergoing laparoscopic
cholecystectomy. Academic Journal of Kunming MedicalCollege 2003;24(2):71–3.
Fanelli 2008 {published data only}
Fanelli G, Ghisi D, Berti M, Troglio R, Ortu A, Consigli
C, et al. Preoperative administration of controlled-
release oxycodone as a transition opioid for total
intravenous anaesthesia in pain control after laparoscopic
cholecystectomy. Surgical Endoscopy 2008;22(10):2220–8.
Forse 1996 {published data only}
Forse A, El Beheiry H, Butler PO, Pace RF. Indomethacin
and ketorolac given preoperatively are equally effective
in reducing early postoperative pain after laparoscopic
cholecystectomy. Canadian Journal of Surgery 1996;39(1):
26–30.
Gilron 2009 {published data only}
Gilron I, Orr E, Tu D, Mercer CD, Bond D. A
randomized, double-blind, controlled trial of perioperative
administration of gabapentin, meloxicam and their
combination for spontaneous and movement-evoked pain
after ambulatory laparoscopic cholecystectomy. Anesthesiaand Analgesia 2009;108(2):623–30.
Gomez-Vazquez 2012 {published data only}
Gomez-Vazquez ME, Hernandez-Salazar E, Novelo-Otanez
JD, Cabrera-Pivaral CE, Davalos-Rodriguez IP, Salazar-
Paramo M. Effect of endovenous morphine vs. ketorolac on
proinflammatory cytokines during postoperative analgesia
in laparoscopic cholecystectomy. Cirugia y Cirujanos 2012;
80(1):56–62.
Horattas 2004 {published data only}
Horattas MC, Evans S, Sloan-Stakleff KD, Lee C, Snoke JW.
Does preoperative rofecoxib (Vioxx) decrease postoperative
pain with laparoscopic cholecystectomy?. American Journalof Surgery 2004;188(3):271–6.
Ji 2010 {published data only}
Ji FH, Jin X, Yang JP, Zan LL. Analgesic effect of parecoxib
and flurbiprofen axetil for patients undergoing laparoscopic
cholecystectomy and their influences on platelet aggregation.
Chinese Medical Journal 2010;123(12):1607–9.
Joshi 2004 {published data only}
Gan TJ, Joshi GP, Viscusi E, Cheung RY, Dodge W, Fort
JG, et al. Preoperative parenteral parecoxib and follow-up
oral valdecoxib reduce length of stay and improve quality of
patient recovery after laparoscopic cholecystectomy surgery.
Anesthesia and Analgesia 2004;98(6):1665–73.∗ Joshi GP, Viscusi ER, Gan TJ, Minkowitz H, Cippolle
M, Schuller R, et al. Effective treatment of laparoscopic
cholecystectomy pain with intravenous followed by oral
COX-2 specific inhibitor. Anesthesia and Analgesia 2004;98
(2):336–42.
Karakoc 2011 {published data only}
Karakoc F, Akcaboy EY, Akcaboy ZN, Gogus N. The effects
of intravenous dexketoprofen trometamol on postoperative
analgesia and morphine consumption undergoing
laparoscopic cholecystectomy. Regional Anesthesia and Pain
Medicine 2011;2:E165–E166.
Lane 1996 {published data only}
Lane GE, Lathrop JC, Boysen DA, Lane RC. Effect of
intramuscular intraoperative pain medication on narcotic
usage after laparoscopic cholecystectomy. American Surgeon
1996;62(11):907–10.
Liu 1993 {published data only}
Liu J, Ding Y, White PF, Feinstein R, Shear JM. Effects
of ketorolac on postoperative analgesia and ventilatory
function after laparoscopic cholecystectomy. Anesthesia andAnalgesia 1993;76(5):1061–6.
Mebazaa 2008 {published data only}
Mebazaa MS, Frikha N, Hammouda NB, Mestiri T,
Mestiri H, Khalfallah T, et al. Postoperative analgesia
after laparoscopic cholecystectomy: comparison of the
preoperative administration of celecoxib with paracetamol?.
Tunisie Medicale 2008;86(10):869–73.
Muñoz 2002 {published data only}
Muñoz HR, Guerrero ME, Brandes V, Cortínez LI. Effect
of timing of morphine administration during remifentanil-
based anaesthesia on early recovery from anaesthesia and
postoperative pain. British Journal of Anaesthesia 2002;88
(6):814–8.
Munro 1998 {published data only}
Munro FJ, Young SJ, Broome IJ, Robb HM, Wardall GJ.
Intravenous tenoxicam for analgesia following laparoscopic
cholecystectomy. Anaesthesia and Intensive Care 1998;26(1):
56–60.
Nesek-Adam 2012 {published data only}
Nesek-Adam V, Grizelj-Stojcic E, Mrsic V, Rasic Z,
Schwarz D. Preemptive use of diclofenac in combination
with ketamine in patients undergoing laparoscopic
cholecystectomy: a randomized, double-blind, placebo-
controlled study. Surgical Laparoscopy, Endoscopy &Percutaneous Techniques 2012;22(3):232–8.
Pandey 2004 {published data only}
Pandey CK, Priye S, Singh S, Singh U, Singh RB, Singh
PK. Preemptive use of gabapentin significantly decreases
postoperative pain and rescue analgesic requirements
in laparoscopic cholecystectomy. Canadian Journal ofAnaesthesia 2004;51(4):358–63.
Peng 2010 {published data only}
Peng PW, Li C, Farcas E, Haley A, Wong W, Bender J,
et al. Use of low-dose pregabalin in patients undergoing
laparoscopic cholecystectomy. British Journal of Anaesthesia2010;105(2):155–61.
Puura 2006 {published data only}
Puura A, Puolakka P, Rorarius M, Salmelin R, Lindgren
L. Etoricoxib pre-medication for post-operative pain
after laparoscopic cholecystectomy. Acta Anaesthesiologica
Scandinavica 2006;50(6):688–93.
36Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Salihoglu 2009 {published data only}
Salihoglu Z, Yildirim M, Demiroluk S, Kaya G, Karatas
A, Ertem M, et al. Evaluation of intravenous paracetamol
administration on postoperative pain and recovery
characteristics in patients undergoing laparoscopic
cholecystectomy. Surgical Laparoscopy, Endoscopy &Percutaneous Techniques 2009;19(4):321–3.
Sandhu 2011 {published data only}
Sandhu T, Paiboonworachat S, Ko-iam W. Effects of
preemptive analgesia in laparoscopic cholecystectomy:
a double-blind randomized controlled trial. SurgicalEndoscopy 2011;25(1):23–7.
Sarakatsianou 2013 {published data only}
Sarakatsianou C, Theodorou E, Georgopoulou S, Stamatiou
G, Tzovaras G. Effect of pre-emptive pregabalin on pain
intensity and postoperative morphine consumption after
laparoscopic cholecystectomy. Surgical Endoscopy 2013;27
(7):2504–11.
Schuster 2005 {published data only}
Schuster R, Stewart D, Schuster L, Greaney G, Waxman
K. Preoperative oral rofecoxib and postoperative pain in
patients after laparoscopic cholecystectomy: a prospective,
randomized, double-blinded, placebo-controlled trial.
American Surgeon 2005;71(10):827–9.
Sen 2010 {published data only}
Sen M, Inan A, Sert H, Akpinar A, Dener C. Preemptive
use of etofenamate in laparoscopic cholecystectomy: a
randomized, placebo-controlled, double-blind study.
European Journal of General Medicine 2010;7(1):50–5.
Wilson 1994 {published data only}
Wilson YG, Rhodes M, Ahmed R, Daugherty M, Cawthorn
SJ, Armstrong CP. Intramuscular diclofenac sodium for
postoperative analgesia after laparoscopic cholecystectomy:
a randomised, controlled trial. Surgical Laparoscopy &Endoscopy 1994;4(5):340–4.
Yeh 2004 {published data only}
Yeh CC, Wu CT, Lee MS, Yu JC, Yang CP, Lu CH, et
al. Analgesic effects of preincisional administration of
dextromethorphan and tenoxicam following laparoscopic
cholecystectomy. Acta Anaesthesiologica Scandinavica 2004;
48(8):1049–53.
Zajaczkowska 2004 {published data only}
Zajaczkowska R, Wnek W, Wordliczek J, Dobrogowski J.
Peripheral opioid analgesia in laparoscopic cholecystectomy.
Regional Anesthesia and Pain Medicine 2004;29(5):424–9.
Zhu 2011 {published data only}
Zhu Y, Jing G, Yuan W. Preoperative administration of
intramuscular dezocine reduces postoperative pain for
laparoscopic cholecystectomy. Journal of Biomedical Research2011;25(5):356–61.
References to studies excluded from this review
Aftab 2008 {published data only}
Aftab S, Rashdi S. Comparison of intravenous ketorolac
with diclofenac for postoperative analgesia. Journal of
Surgery Pakistan 2008;13(2):62–6.
Akca 2004 {published data only}
Akca T, Colak T, Kanik A, Yaylak F, Caglikulekci M, Aydin
S. The effect of preoperative intravenous use of tenoxicam:
a prospective, double-blind, placebo-controlled study.
Journal of Investigative Surgery 2004;17(6):333–8.
Bajaj 2004 {published data only}
Bajaj P, Ballary CC, Dongre NA, Baliga VP, Desai AA. Role
of parecoxib in pre-emptive analgesia: comparison of the
efficacy and safety of pre- and postoperative parecoxib in
patients undergoing general surgery. Journal of the IndianMedical Association 2004;102(5):272–8.
Boccara 2005 {published data only}
Boccara G, Chaumeron A, Pouzeratte Y, Mann C. The
preoperative administration of ketoprofen improves
analgesia after laparoscopic cholecystectomy in comparison
with propacetamol or postoperative ketoprofen. BritishJournal of Anaesthesia 2005;94(3):347–51.
Collard 2007 {published data only}
Collard V, Mistraletti G, Taqi A, Asenjo JF, Feldman LS,
Fried GM, et al. Intraoperative esmolol infusion in the
absence of opioids spares postoperative fentanyl in patients
undergoing ambulatory laparoscopic cholecystectomy.
Anesthesia and Analgesia 2007;105(5):1255–62.
Elhakim 2000 {published data only}
Elhakim M, Amine H, Kamel S, Saad F. Effects of
intraperitoneal lidocaine combined with intravenous or
intraperitoneal tenoxicam on pain relief and bowel recovery
after laparoscopic cholecystectomy. Acta Anaesthesiologica
Scandinavica 2000;44(8):929–33.
Gan 2004 {published data only}
Gan TJ, Joshi GP, Zhao SZ, Hanna DB, Cheung RY, Chen
C. Presurgical intravenous parecoxib sodium and follow-
up oral valdecoxib for pain management after laparoscopic
cholecystectomy surgery reduces opioid requirements
and opioid-related adverse effects. Acta AnaesthesiologicaScandinavica 2004;48(9):1194–207.
Hernandez-Palazon 2003 {published data only}
Hernandez-Palazon J, Tortosa JA, de la Rosa VN,
Gimenez-Viudes J, Ramirez G, Robles R. Intraperitoneal
application of bupivacaine plus morphine for pain relief
after laparoscopic cholecystectomy. European Journal ofAnaesthesiology 2003;20(11):891–6.
Kocaayan 2007 {published data only}
Kocaayan E, Ozkardeler S, Ozzeybek D, Bayindir S, Akan
M. Comparison of effects of preoperatively administered
lornoxicam and tenoxicam on morphine consumption
after laparoscopic cholecystectomy. European Journal ofAnaesthesiology 2007;24(8):714–9.
Koch 2008 {published data only}
Koch S, Ahlburg P, Spangsberg N, Brock B, Tonnesen E,
Nikolajsen L. Oxycodone vs. fentanyl in the treatment of
early post-operative pain after laparoscopic cholecystectomy:
a randomised double-blind study. Acta Anaesthesiologica
Scandinavica 2008;52(6):845–50.
37Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kokki 2012 {published data only}
Kokki M, Broms S, Eskelinen M, Neuvonen PJ, Halonen
T, Kokki H. The analgesic concentration of oxycodone with
co-administration of paracetamol - a dose-finding study in
adult patients undergoing laparoscopic cholecystectomy.
Basic & Clinical Pharmacology & Toxicology 2012;111(6):
391–5.
Matkap 2011 {published data only}
Matkap E, Bedirli N, Akkaya T, Gümü H. Preincisional
local infiltration of tramadol at the trocar site versus
intravenous tramadol for pain control after laparoscopic
cholecystectomy. Journal of Clinical Anesthesia 2011;23(3):
197–201.
Naguib 1998 {published data only}
Naguib M, Seraj M, Attia M, Samarkandi AH, Seet M,
Jaroudi R. Perioperative antinociceptive effects of tramadol.
A prospective, randomized, double-blind comparison with
morphine. Canadian Journal of Anaesthesia 1998;45(12):
1168–75.
O’Hanlon 2002 {published data only}
O’Hanlon DM, Colbert S, Ragheb J, McEntee GP,
Chambers F, Moriarty DC. Intraperitoneal pethidine
versus intramuscular pethidine for the relief of pain after
laparoscopic cholecystectomy: randomized trial. World
Journal of Surgery 2002;26(12):1432–6.
Ozkocak 2002 {published data only}
Ozkocak I, Kirdemir P, Rasa K, Aksu C, Gogus N. The
comparison of preemptive intraperitoneal analgesic effects
of tramadol, pethidine and bupivacaine. Anestezi Dergisi2002;10(1):49–52.
Sanchez-Rodriguez 2010 {published data only}
Sanchez-Rodriguez PE, Fuentes-Orozco C, Gonzalez-Ojeda
A. Effect of dexamethasone on postoperative symptoms in
patients undergoing elective laparoscopic cholecystectomy:
randomized clinical trial. World Journal of Surgery 2010;34
(5):895–900.
Sozbilen 2007 {published data only}
Sozbilen M, Yeniay L, Unalp O, Makay O, Pirim A,
Ulukaya S, et al. Effects of ropivacaine on pain after
laparoscopic cholecystectomy: a prospective, randomized
study. Advances in Therapy 2007;24(2):247–57.
Stempin 2007 {published data only}
Stempin S, Gajdosz R. Intraperitoneal morphine for
prevention of postoperative shoulder pain after laparoscopic
cholecystectomy. Anestezjologia Intensywna Terapia 2007;39
(1):18–20.
Tiippana 2008 {published data only}
Tiippana E, Bachmann M, Kalso E, Pere P. Effect of
paracetamol and coxib with or without dexamethasone
after laparoscopic cholecystectomy. Acta Anaesthesiologica
Scandinavica 2008;52(5):673–80.
Wininger 2010 {published data only}
Wininger SJ, Miller H, Minkowitz HS, Royal MA, Ang
RY, Breitmeyer JB, et al. A randomized, double-blind,
placebo-controlled, multicenter, repeat-dose study of
two intravenous acetaminophen dosing regimens for the
treatment of pain after abdominal laparoscopic surgery.
Clinical Therapeutics 2010;32(14):2348–69.
Wu 1999 {published data only}
Wu CT, Yu JC, Yeh CC, Liu ST, Li CY, Ho ST, et
al. Preincisional dextromethorphan treatment decreases
postoperative pain and opioid requirement after laparoscopic
cholecystectomy. Anesthesia and Analgesia 1999;88(6):
1331–4.
Wu 2005 {published data only}
Wu CT, Borel CO, Lee MS, Yu JC, Liou HS, Yi HD, et
al. The interaction effect of perioperative cotreatment
with dextromethorphan and intravenous lidocaine on pain
relief and recovery of bowel function after laparoscopic
cholecystectomy. Anesthesia and Analgesia 2005;100(2):
448–53.
Yamazaki 2003 {published data only}
Yamazaki E, Murao K, Asai T, Matsumoto S, Shingu K.
Comparison of analgesic effects of intravenous flurbprofen
and suppository indomethacin after laparoscopic
cholecystectomy. Masui. The Japanese Journal of
Anesthesiology 2003;52(11):1186–90.
Zambouri 2002 {published data only}
Zambouri A, Petropoulou P, Petra K, Ralli M, Douvantzi A,
Papachristou D. Do early postoperative pain, nausea and
vomiting really differ when remifentanil or fentanyl are used
in laparoscopic cholecystectomy?. 10th World Society of
Pain Clinicians of the International Pain Clinic; 2002 May
04-08, Sardinia, Italy. World Society of Pain Clinicians,
2002:257–63.
Zghidi 2011 {published data only}
Zghidi SM, Jaoua H, Ghariani S, Saada S, Laabidi S,
Khemiri K, et al. Effectiveness of dexamethasone in
postoperative analgesia after laparoscopic cholecystectomy.
Regional Anesthesia and Pain Medicine 2011;2:E278–9.
References to studies awaiting assessment
Gan 2003 {published data only}
Gan TJ, Joshi G, Viscusi E, Chen C, Cheung R.
Postdischarge recovery experience after single presurgery
does of IV parecoxib sodium, a novel COX-2 inhibitor,
followed by oral valdecoxib for pain after laparoscopic
cholecystectomy. International Journal of Obstetrics &Gynecology 2003;83(3):23.
Additional references
Alexander 1987
Alexander JI, Hull MG. Abdominal pain after laparoscopy:
the value of a gas drain. British Journal of Obstetrics andGynaecology 1987;94(3):267–9.
Argoff 2013
Argoff CE. Recent management advances in acute
postoperative pain. Pain Practice 2013 Aug 15 [Epub ahead
of print].
38Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Attili 1995
Attili AF, De Santis A, Capri R, Repice AM, Maselli S. The
natural history of gallstones: the GREPCO experience. The
GREPCO group. Hepatology 1995;21(3):655–60.
Ballal 2009
Ballal M, David G, Willmott S, Corless DJ, Deakin M,
Slavin JP. Conversion after laparoscopic cholecystectomy in
England. Surgical Endoscopy 2009;23(10):2338–44.
Bates 1992
Bates T, Harrison M, Lowe D, Lawson C, Padley N.
Longitudinal study of gall stone prevalence at necropsy. Gut
1992;33(1):103–7.
Bisgaard 2006
Bisgaard T. Analgesic treatment after laparoscopic
cholecystectomy: a critical assessment of the evidence.
Anesthesiology 2006;104(4):835–46.
Brok 2008
Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential
analysis reveals insufficient information size and potentially
false positive results in many meta-analyses. Journal ofClinical Epidemiology 2008;61(8):763–9.
Brok 2009
Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently
conclusive meta-analyses may be inconclusive - trial
sequential analysis adjustment of random error risk due
to repetitive testing of accumulating data in apparently
conclusive neonatal meta-analyses. International Journal ofEpidemiology 2009;38(1):287–98.
CTU 2011
Copenhagen Trial Unit. TSA - trial sequential analysis,
2011. ctu.dk/tsa/ (accessed 25 March 2014).
DeMets 1987
DeMets DL. Methods for combining randomized clinical
trials: strengths and limitations. Statistics in Medicine 1987;
6(3):341–50.
DerSimonian 1986
DerSimonian R, Laird N. Meta-analysis in clinical trials.
Controlled Clinical Trials 1986;7(3):177–88.
Dolan 2009
Dolan JP, Diggs BS, Sheppard BC, Hunter JG. The
national mortality burden and significant factors associated
with open and laparoscopic cholecystectomy: 1997-2006.
Journal of Gastrointestinal Surgery 2009;13(12):2292–301.
Egger 1997
Egger M, Davey SG, Schneider M, Minder C. Bias in meta-
analysis detected by a simple, graphical test. BMJ (Clinical
Research Ed.) 1997;315(7109):629–34.
Giger 2011
Giger U, Ouaissi M, Schmitz SF, Krahenbuhl S, Krahenbuhl
L. Bile duct injury and use of cholangiography during
laparoscopic cholecystectomy. British Journal of Surgery2011;98(3):391–6.
Gluud 2014
Nikolova D, Klingenberg SL, Gluud C, Als-Nielsen B,
Bjelakovic G, Casazza G, et al. Cochrane Hepato-Biliary
Group. About The Cochrane Collaboration (Cochrane
Review Groups (CRGs)). 2014, Issue 2. Art. No.: LIVER.
Gottschling 2005
Gottschling S, Meyer S, Krenn T, Reinhard H, Lothschuetz
D, Nunold H, et al. Propofol versus midazolam/ketamine
for procedural sedation in pediatric oncology. Journal of
Pediatric Hematology/Oncology 2005;27(9):471–6.
GREPCO 1984
GREPCO. Prevalence of gallstone disease in an Italian adult
female population. Rome group for the epidemiology and
prevention of cholelithiasis (GREPCO). American Journalof Epidemiology 1984;119(5):796–805.
GREPCO 1988
GREPCO. The epidemiology of gallstone disease in Rome,
Italy. Part i. Prevalence data in men. The Rome group for
epidemiology and prevention of cholelithiasis (GREPCO).
Hepatology 1988;8(4):904–6.
Gurusamy 2008a
Gurusamy K, Junnarkar S, Farouk M, Davidson B. Day-
case versus overnight stay for laparoscopic cholecystectomy.
Cochrane Database of Systematic Reviews 2008, Issue 3.
[DOI: 10.1002/14651858.CD006798.pub3]
Gurusamy 2008b
Gurusamy K, Junnarkar S, Farouk M, Davidson BR. Meta-
analysis of randomized controlled trials on the safety and
effectiveness of day-case laparoscopic cholecystectomy.
British Journal of Surgery 2008;95(2):161–8.
Gurusamy 2009
Gurusamy KS, Gluud C, Nikolova D, Davidson BR.
Assessment of risk of bias in randomized clinical trials in
surgery. British Journal of Surgery 2009;96(4):342–9.
Gurusamy 2013
Gurusamy KS, Koti R, Davidson BR. Routine abdominal
drainage versus no abdominal drainage for uncomplicated
laparoscopic cholecystectomy. Cochrane Database ofSystematic Reviews 2013, Issue 9. [DOI: 10.1002/
14651858.CD006004.pub4]
Gurusamy 2014
Gurusamy KS, Nagendran M, Guerrini GP, Toon CD,
Zinnuroglu M, Davidson BR. Intraperitoneal local
anaesthetic instillation versus no intraperitoneal local
anaesthetic instillation for laparoscopic cholecystectomy.
Cochrane Database of Systematic Reviews 2014, Issue 3.
[DOI: 10.1002/14651858.CD007337.pub3]
Halldestam 2004
Halldestam I, Enell EL, Kullman E, Borch K. Development
of symptoms and complications in individuals with
asymptomatic gallstones. British Journal of Surgery 2004;91
(6):734–8.
HES 2011
HESonline. Hospital episode statistics. Main
procedures and interventions: 3 character, 2011.
www.hesonline.nhs.uk/Ease/servlet/ContentServer?siteID=
1937&categoryID=205 (accessed on 25 March 2014).
39Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Higgins 2002
Higgins JPT, Thompson SG. Quantifying heterogeneity in a
meta-analysis. Statistics in Medicine 2002;21(11):1539–58.
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook
for Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration,
2011. Available from www.cochrane-handbook.org.
ICH-GCP 1997
International Conference on Harmonisation Expert
Working Group. International conference on harmonisationof technical requirements for registration of pharmaceuticals for
human use. ICH harmonised tripartite guideline. Guidelinefor good clinical practice CFR & ICH Guidelines. Vol. 1, PA
19063-2043, USA: Barnett International/PAREXEL, 1997.
Inturrisi 2002
Inturrisi CE. Clinical pharmacology of opioids for pain.
Clinical Journal of Pain 2002;18(4 Suppl):S3–13.
Kehlet 2005
Kehlet H, Gray AW, Bonnet F, Camu F, Fischer HB,
McCloy RF, et al. A procedure-specific systematic review
and consensus recommendations for postoperative analgesia
following laparoscopic cholecystectomy. Surgical Endoscopy2005;19(10):1396–415.
Kjaergard 2001
Kjaergard LL, Villumsen J, Gluud C. Reported
methodologic quality and discrepancies between large and
small randomized trials in meta-analyses. Annals of Internal
Medicine 2001;135(11):982–9.
Loizides 2014
Loizides S, Gurusamy KS, Nagendran M, Rossi M, Guerrini
GP, Davidson BR. Wound infiltration with local anaesthetic
agents for laparoscopic cholecystectomy. Cochrane Databaseof Systematic Reviews 2014, Issue 3. [DOI: 10.1002/
14651858.CD007049.pub2]
Lundh 2012
Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L.
Industry sponsorship and research outcome. CochraneDatabase of Systematic Reviews 2012, Issue 12. [DOI:
10.1002/14651858.MR000033.pub2]
Macaskill 2001
Macaskill P, Walter SD, Irwig L. A comparison of methods
to detect publication bias in meta-analysis. Statistics inMedicine 2001;20(4):641–54.
Martindale 2011
Sweetman S (editor). Martindale: the complete
drug reference (online version), 37th edition, 2011.
www.pharmpress.com/product/MC˙MART/martindale-
the-complete-drug-reference (accessed 25 March 2014).
Moher 1998
Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher
M, et al. Does quality of reports of randomised trials affect
estimates of intervention efficacy reported in meta-analyses?
. Lancet 1998;352(9128):609–13.
Newell 1992
Newell DJ. Intention-to-treat analysis: implications for
quantitative and qualitative research. International Journal
of Epidemiology 1992;21(5):837–41.
Ng 2004
Ng A, Swami A, Smith G, Robertson G, Lloyd DM. Is
intraperitoneal levobupivacaine with epinephrine useful
for analgesia following laparoscopic cholecystectomy?
A randomized controlled trial. European Journal of
Anaesthesiology 2004; Vol. 21, issue 8:653–7.
NIH 1992
NIH. NIH consensus statement on gallstones and
laparoscopic cholecystectomy, 1992. consensus.nih.gov/
1992/1992GallstonesLaparoscopy090html.htm (accessed
25 March 2014).
RevMan 2012 [Computer program]
The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan). Version 5.2. Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration,
2012.
Royle 2003
Royle P, Milne R. Literature searching for randomized
controlled trials used in Cochrane reviews: rapid versus
exhaustive searches. International Journal of Technology
Assessment in Health Care 2003;19(4):591–603.
Savovic 2012a
Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal
J, et al. Influence of reported study design characteristics on
intervention effect estimates from randomized, controlled
trials. Health Technology Assessment 2012;16(35):1–82.
Savovic 2012b
Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal
J, et al. Influence of reported study design characteristics on
intervention effect estimates from randomized, controlled
trials. Annals of Internal Medicine 2012;157(6):429–38.
Schulz 1995
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical
evidence of bias. Dimensions of methodological quality
associated with estimates of treatment effects in controlled
trials. JAMA 1995;273(5):408–12.
Strasberg 1993
Strasberg SM, Clavien PA. Overview of therapeutic
modalities for the treatment of gallstone diseases. American
Journal of Surgery 1993;165(4):420–6.
Thorlund 2009
Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G,
Ioannidis JP, Thabane L, et al. Can trial sequential
monitoring boundaries reduce spurious inferences from
meta-analyses. International Journal of Epidemiology 2009;
38(1):276–86.
Thorlund 2010
Thorlund K, Anema A, Mills E. Interpreting meta-analysis
according to the adequacy of sample size. An example using
isoniazid chemoprophylaxis for tuberculosis in purified
40Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
protein derivative negative HIV-infected individuals.
Clinical Epidemiology 2010;2:57–66.
Thorlund 2011
Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G,
Gluud C. User manual for trial sequential analysis (TSA),
2011. ctu.dk/tsa/files/tsa˙manual.pdf (accessed 25 March
2014).
Todd 1996
Todd KH, Funk JP. The minimum clinically important
difference in physician-assigned visual analog pain
scores. Academic Emergency Medicine 1996;3(2):142–6.
[PUBMED: 8808375]
Wetterslev 2008
Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential
analysis may establish when firm evidence is reached in
cumulative meta-analysis. Journal of Clinical Epidemiology
2008;61(1):64–75.
Wetterslev 2009
Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating
required information size by quantifying diversity in
random-effects model meta-analyses. BMC Medical ResearchMethodology 2009;9:86.
Wood 2008
Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman
DG, et al. Empirical evidence of bias in treatment effect
estimates in controlled trials with different interventions
and outcomes: meta-epidemiological study. BMJ (ClinicalResearch Ed.) 2008;336(7644):601–5.
Yu 2003
Yu HP, Hseu SS, Yien HW, Teng YH, Chan KH. Oral
clonidine premedication preserves heart rate variability for
patients undergoing laparoscopic cholecystectomy. ActaAnaesthesiologica Scandinavica 2003;47(2):185–90.
∗ Indicates the major publication for the study
41Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Abdulla 2012
Methods Randomised clinical trial.
Participants Country: Germany.
Number randomised: 120.
Post-randomisation drop-outs: 0 (0%).
Revised sample size: 120.
Mean age: 52 years.
Females: 90 (75%).
Inclusion criteria:
1. ASA I to III.
2. Aged 18 to 75 years.
Exclusion criteria:
1. Cardiac, pulmonary, hepatic, or renal disease.
2. Morbid obesity.
3. Chronic pain.
4. Drug or alcohol abuse.
5. Adverse drug reactions to study drugs.
Interventions Participants were randomly assigned to 1 of 4 groups.
Group 1: postoperative saline IV (n = 30).
Group 2: postoperative parecoxib 40 mg IV twice daily (n = 30).
Group 3: postoperative metamizol 1 mg IV 3 times daily (n = 30).
Group 4: postoperative paracetamol (acetaminophen) 1 mg IV 3 times daily (n = 30)
Outcomes Drug-related serious adverse events and pain.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer generated randomisation table used”.
Allocation concealment (selection bias) Low risk Quote: “Group assignment code retained until the conclu-
sion of the study”
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “Group assignment code retained until the conclu-
sion of the study”
42Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Abdulla 2012 (Continued)
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “Group assignment code retained until the conclu-
sion of the study”
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There were no post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Agarwal 2008
Methods Randomised clinical trial.
Participants Country: India.
Number randomised: 60.
Post-randomisation drop-outs: 4 (6.7%).
Revised sample size: 56.
Mean age: 46 years.
Females: 19 (33.9%).
Inclusion criteria:
1. Aged 16 to 60 years.
2. ASA physical status I or II.
3. Undergoing laparoscopic cholecystectomy under general anaesthesia.
4. Written informed consent given.
Exclusion criteria:
1. Impaired kidney functions.
2. History of drug or alcohol abuse.
3. History of chronic pain or daily intake of analgesics.
4. Uncontrolled medical disease.
5. History of intake of NSAIDs in 24 h before surgery.
6. Inability to operated patient-controlled analgesia.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: pregabalin 150 mg orally 1 h before surgery (n = 27).
Group 2: placebo 1 h before orally surgery (n = 29).
Outcomes Drug-related serious adverse events and pain.
Notes Reasons for post-randomisation drop-outs: conversion to open cholecystectomy (n = 3)
, re-exploration on account of postoperative bleeding (n = 1)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
43Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Agarwal 2008 (Continued)
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated table of random numbers
used”.
Allocation concealment (selection bias) Unclear risk Quote: “Selected using sealed envelopes to be opened by
anesthesia resident”
Comment: Further details not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “All the medications…were identical, and were ad-
ministered…by a staff nurse who was not involved in the
study”
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “Outcomes were assessed by an independent anaes-
thesia registrar blinded to group allocation”
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Akaraviputh 2009
Methods Randomised clinical trial.
Participants Country: Thailand.
Number randomised: 70.
Post-randomisation drop-outs: not stated.
Revised sample size: 70.
Mean age: 57 years.
Females: 41 (58.6%).
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy.
2. Aged > 18 years.
Exclusion criteria:
1. Hypersensitivity to NSAIDs.
2. Conversion to open cholecystectomy.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: parecoxib 20 mg infusion 30 min before induction of anaesthesia and at 12 h
after the first dose (n = 40).
Group 2: saline infusion 30 min before induction of anaesthesia and at 12 h after the
first dose (n = 30)
Outcomes Pain.
Notes Attempts were made to contact authors in August 2013.
44Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Akaraviputh 2009 (Continued)
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Quote: “Sealed envelope technique used”.
Comment: Further details were not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: Further details were not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “The degree of postoperative pain was assessed…by
nursing staff who were unaware of the perioperative inter-
vention”
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Low risk Comment: Supported by Faculty of Medicine Siriraj Hos-
pital Research Project Grant
Akarsu 2012
Methods Randomised clinical trial.
Participants Country: Turkey.
Number randomised: 60.
Post-randomisation drop-outs: 0 (0%).
Revised sample size: 60.
Mean age: 59 years.
Females: 24 (40%).
Inclusion criteria:
1. ASA physical status I to III.
2. Aged ≥ 18 years.
3. Weighed > 40 kg.
Exclusion criteria:
1. Known allergy, sensitivity, or contraindication to pregabalin, diclofenac sodium,
and pethidine, or any NSAID.
2. Renal insufficiency.
3. Severe coronary, pulmonary, hepatic disease.
4. History of previous neurological disease or seizure disorder.
5. A history of peptic ulcer.
6. A history of alcohol or substance abuse.
45Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Akarsu 2012 (Continued)
7. Ongoing therapy with sustained-release opioids.
8. Pregnancy.
9. History of intake of NSAID and antidepressant drugs in 24 h before surgery.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: pregabalin 300 mg orally 1 h before surgery (n = 30).
Group 2: diclofenac 75 mg IM 15 to 20 min before completion of surgery (n = 30)
Outcomes Mortality, drug-related serious adverse events, and pain.
Notes Attempts were made to contact authors in August 2013. Authors provided replies
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
High risk Quote: “Single-blind study, subjects do not know the
methodology applied. The investigator knows” (author
replies)
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “The outcome assessors were blinded” (author
replies)
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There were no post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Overall morbidity was not reported.
For-profit bias Low risk Quote: “The study was funded by us” (author replies).
Akinci 2008
Methods Randomised clinical trial.
Participants Country: Turkey.
Number randomised: 41.
Post-randomisation drop-outs: not stated.
Revised sample size: 41.
Mean age: 45 years.
Females: 27 (65.9%).
Inclusion criteria:
1. ASA status I or II.
46Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Akinci 2008 (Continued)
Exclusion criteria:
1. Acute cholecystitis.
2. History of analgesic or narcotic use.
3. Previous abdominal surgery.
4. Hypersensitivity to study drugs.
5. Needed conversion to open cholecystectomy.
6. Needed postoperative drains.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: tramadol 100 mg IV (n = 21).
Group 2: placebo (n = 20).
Outcomes No outcomes of interest for this review were reported.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computerised allocation schedule used”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Quote: “Coded syringes used”.
Comment: Further details were not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Balaban 2012
Methods Randomised clinical trial.
Participants Country: Turkey.
Number randomised: 90.
Post-randomisation drop-outs: 0 (0%).
Revised sample size: 90.
47Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Balaban 2012 (Continued)
Mean age: 53 years.
Females: 69 (76.7%).
Inclusion criteria:
1. ASA physical status I or II.
2. Aged ≥ 18 years.
3. Scheduled for laparoscopic cholecystectomy.
Exclusion criteria:
1. Inability to co-operate.
2. Pregnancy.
3. Emergency surgical intervention.
4. Severe renal or hepatic dysfunction, or both.
5. History of allergy to pregabalin.
6. Limited or insufficient respiratory reserve.
7. Conversion to open cholecystectomy.
8. Duration of surgery in excess of 60 min.
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: pregabalin 150 mg orally 1 h before surgery (n = 30).
Group 2: pregabalin 300 mg orally 1 h before surgery (n = 30).
Group 3: placebo orally (n = 30).
Outcomes No outcomes of interest for this review were reported.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available
Allocation concealment (selection bias) Unclear risk Quote: “Randomisation achieved sealed envelope assign-
ment”.
Comment: Further details were not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There were no post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
48Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Balaban 2012 (Continued)
For-profit bias Unclear risk Comment: This information was not available.
Belzarena 1998
Methods Randomised clinical trial.
Participants Country: Portugal.
Number randomised: 90.
Post-randomisation drop-outs: not stated.
Revised sample size: 90.
Mean age: 42 years.
Females: 65 (72.2%).
Inclusion criteria:
1. ASA I or II.
Exclusion criteria:
1. History of allergy or intolerance to NSAIDs.
2. Concomitant disease that would allow any patient classification criteria ASA III or
IV.
3. Previous use of NSAIDs for any indication or self medication in the last 4 weeks.
4. Liver or kidney disease.
5. Pre-existing asthma.
6. Coagulation disorders or use of anticoagulants.
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: tenoxicam 20 mg in 4-mL saline IV (n = 30).
Group 2: tenoxicam 40 mg in 4-mL saline IV (n = 30).
Group 3: saline IV (n = 30).
Outcomes No outcomes of interest for this review were reported.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated table”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Quote: “Venipuncture was performed by a nurse who was
unaware of the nature of the study”.
Comment: Further details were not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
49Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Belzarena 1998 (Continued)
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Cheng 2004
Methods Randomised clinical trial.
Participants Country: China.
Number randomised: 60.
Post-randomisation drop-outs: 1 (1.7%).
Revised sample size: 59.
Mean age: 50 years.
Females: 37 (62.7%).
Inclusion criteria:
1. ASA I or II.
2. Aged 18 to 75 years.
3. Elective laparoscopic cholecystectomy.
Exclusion criteria:
1. Chronic pain other than gallstones.
2. Acute cholecystitis.
3. Advanced renal disease.
4. Fluid retention.
5. Heart failure.
6. Pre-operative NSAIDs or opioids within 24 h of the scheduled operation.
7. Prescribed aspirin and sulphonamides.
8. Known hypersensitivity to NSAIDs.
9. Pregnancy.
10. Unable to use patient-controlled analgesia.
11. Procedures converted to laparotomies.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: celecoxib 200 mg orally before surgery (n = 30).
Group 2: placebo orally before surgery (n = 29).
Outcomes Pain.
Notes Reasons for post-randomisation drop-outs: non-standardisation of the anaesthetic drugs
(n = 1)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
50Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cheng 2004 (Continued)
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Quote: “Patients were randomized into two groups by sealed
envelopes”.
Comment: Further details were not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Quote: “A post-anaesthetic care unit nurse, who was un-
aware of the study drug recorded the time of the first dose of
PCA morphine and evaluated the post operative pain and
intensity”.
Comment: Further details were not available.
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There was a post-randomisation drop-out but
this was unlikely to be related to the intervention
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Chung 2004
Methods Randomised clinical trial.
Participants Country: Canada.
Number randomised: 84.
Post-randomisation drop-outs: 15 (17.9%).
Revised sample size: 69.
Mean age: 48 years.
Females: not stated.
Inclusion criteria:
1. Aged ≥ 18 years.
2. Scheduled to undergo laparoscopic cholecystectomy.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: paracetamol (acetaminophen) 300 mg orally every 6 h for 48 h (n = 33).
Group 2: placebo (n = 36).
Co-intervention: codeine 48 h postoperatively
Outcomes Serious adverse events and pain.
Notes Reasons for post-randomisation drop-outs: lack of pain (n = 4), loss to follow-up (n = 3)
, adverse events (n = 3), inadequate pain control (n = 6) (note that there was discrepancy
in the number of post-randomisation drop-outs and the reasons for drop-outs in the
51Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Chung 2004 (Continued)
report)
Attempts were made to contact the authors. Replies were received from authors in August
2013
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer generated sequence (author replies)”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “Double-dummy technique, with matching
placebo used”.
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “Outcome blinded” (author replies).
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality was not reported.
For-profit bias High risk Quote: “This study was partially supported by a grant from
Purdue Pharma (Canada) Inc”
Dong 2003
Methods Randomised clinical trial.
Participants Country: not stated.
Number randomised: 150.
Post-randomisation drop-outs: not stated.
Revised sample size: 150.
Mean age: 48 years.
Females: not stated.
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy.
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: lornoxicam 16 mg (8 mg IM and 8 mg IV) (n = 50).
Group 2: lornoxicam 24 mg (8 mg IM and 16 mg IV) (n = 50).
Group 3: control (n = 50).
Outcomes Pain.
52Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dong 2003 (Continued)
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Fanelli 2008
Methods Randomised clinical trial.
Participants Country: Italy.
Number randomised: 50.
Post-randomisation drop-outs: 0 (0%).
Revised sample size: 50.
Mean age: 57 years.
Females: not stated.
Inclusion criteria:
1. People scheduled for elective laparoscopic cholecystectomy.
2. Aged ≥ 18 years.
3. ASA status I, II, or III.
Exclusion criteria:
1. Allergy or contraindication to protocol drugs.
2. Documented myocardial infarction in the previous 6 months.
3. Impaired renal function.
4. Uncontrolled hypertension.
5. Body mass index > 30.
6. Clinical history of respiratory pathologies with pharmacological therapy.
7. Psychiatric disorders.
53Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Fanelli 2008 (Continued)
8. Actual or suspected pregnancy.
9. Anaemia.
10. Epilepsy.
11. Family history or previous history of malignant hyperthermia.
12. Chronic treatment with pain medications.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: oxycodone, 10 mg for people with age ≥ 60 years and 20 mg for those aged <
60 years, orally 1 h before surgery and 12 h after the first administration (n = 25).
Group 2: placebo 1 h before surgery and 12 h after the first administration (n = 25)
Outcomes No outcomes of interest for this review were reported.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated random number table used”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “Placebo tablets were apparently identical to the
active drug tablets and all treatments were given to patients
double blindly”
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “The patient was first asked by a blind observer to
express his/her pain”
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There were no post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Low risk Quote: “Sources of financial support for the work: Univer-
sity of Parma”
Forse 1996
Methods Randomised clinical trial.
Participants Country: Canada.
Number randomised: 60.
Post-randomisation drop-outs: 8 (13.3%).
Revised sample size: 52.
54Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Forse 1996 (Continued)
Mean age: 47 years.
Females: 32 (61.5%).
Inclusion criteria:
1. ASA I or II.
Exclusion criteria:
1. Allergy to study medications.
2. History of prolonged bleeding.
3. Peptic ulcer disease.
4. Cardiac, lung, renal, or liver disease.
5. Use of opiate or NSAIDs within 2 weeks of surgery.
6. Open cholecystectomy.
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: ketorolac IM before surgery (n = 17).
Group 2: indomethacin rectally before surgery (n= 17).
Group 3: placebo (n = 18).
Outcomes Operative complications.
Notes Reasons for post-randomisation drop-outs: not stated.
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Quote: “Sealed numbered envelopes”.
Comment: Further details were not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
55Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Gilron 2009
Methods Randomised clinical trial.
Participants Country: Canada.
Number randomised: 89.
Post-randomisation drop-outs: 12 (13.5%).
Revised sample size: 77.
Mean age: 46 years.
Females: 64 (83.1%).
Inclusion criteria:
1. Aged > 18 years.
2. Body mass index < 36.
3. ASA I or II.
4. Elective cholecystectomy.
Exclusion criteria:
1. Hypersensitivity to any drugs to be used in the study.
2. Serious organ disease/dysfunction.
3. Persistent postoperative pain.
4. Daily intake, or intake within 48 h before surgery, of any glucocorticoid drugs,
NSAIDs, or other analgesics.
5. Evidence of substance or alcohol abuse.
6. Major psychiatric disorder.
7. Bleeding disorder.
8. Peptic ulcer disease.
9. Moderate-to-severe asthma.
10. Seizure disorder requiring treatment with anticonvulsant.
11. Language barrier to communicating with research staff.
Interventions Participants were randomly assigned to 1 of 3 groups:
Group 1: meloxicam 15 mg daily orally, 1 h before until 2 days after surgery (n = 25).
Group 2: gabapentin 1200 to 1600 mg daily orally 1 h before until 2 days after surgery
(n = 27)
Group 3: meloxicam 15 mg and gabapentin 1200 to 1600 mg daily orally 1 h before
until 2 days after surgery (n = 25)
Outcomes Serious adverse events and return to work.
Notes Reasons for post-randomisation drop-outs: surgery cancellation (n = 2), dizziness (n = 3)
, liver laceration (n = 1), hypoxaemia (n = 1), intra-operative electrocardiogram changes
(n =1), personal reasons (n = 1), protocol withdrawal (n =1), reflux (n = 1), pruritus (n
= 1)
Attempts were made to contact the authors in August 2013. Replies from authors were
received in August 2013
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “A concealed, computer-generated random treat-
ment allocation schedule, which randomized... three treat-
56Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Gilron 2009 (Continued)
ments”
Allocation concealment (selection bias) Low risk Quote: “The investigational pharmacist and the biostatisti-
cian determine the treatment randomization sequence and
block size without sharing this information with trial inves-
tigators and research personnel (author replies)”
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “Study medications were encapsulated in identically
appearing red (rofecoxib or ”rofecoxib“ placebo) and gray
(gabapentin or ”gabapentin“ placebo) gelatin capsules”
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality was not reported.
For-profit bias Low risk Quote: “Supported by Physicians’ Services Incorporated
Foundation Grant no. 03-30 and by Canadian Institutes of
Health Research Grant no. MSH-55041”
Gomez-Vazquez 2012
Methods Randomised clinical trial.
Participants Country: Mexico.
Number randomised: 40.
Post-randomisation drop-outs: 0 (0%).
Revised sample size: 40.
Mean age: 30 years.
Females: not stated
Inclusion criteria:
1. Aged 20 to 60 years.
2. Weight 55 to 100 kg.
3. Diagnosis of cholecystitis to be operated on electively.
4. ASA status I or II.
Exclusion criteria:
1. History of alcohol.
2. Psychotropic substances.
3. Chronic obstructive pulmonary disease, asthma, or bronchospasm.
4. Kidney or liver disease.
5. History of cognitive impairment.
6. Seizures.
7. Peptic ulcer.
57Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Gomez-Vazquez 2012 (Continued)
Interventions Participants were randomly assigned to 1 of 2 groups:
Group 1: morphine 0.15 mg/kg IV postoperatively for 40 min (n = 20).
Group 2: ketorolac 0.7 mg/kg IV postoperatively for 40 min (n = 20)
Outcomes No outcomes of interest for this review were reported.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There were no post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Horattas 2004
Methods Randomised clinical trial.
Participants Country: USA.
Number randomised: 120.
Post-randomisation drop-outs: 4 (3.3%).
Revised sample size: 116.
Mean age: 49 years.
Females: 85 (73.3%).
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy.
Exclusion criteria:
1. Allergy to rofecoxib or any other NSAIDs.
2. Acute cholecystitis or pancreatitis.
3. History of hepatic or renal disease.
58Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Horattas 2004 (Continued)
4. History of pain management problems.
5. Chemical substance abuse.
6. Emergency or non-elective surgery.
7. Conversion to open cholecystectomy.
8. Pregnancy.
9. Analgesic usage 6 h prior to scheduled surgery time.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: rofecoxib 50 mg orally preoperatively (n = 58).
Group 2: placebo (n = 58).
Outcomes Proportion discharged as day-surgery.
Notes Reasons for post-randomisation drop-outs: incomplete data extraction (n = 2), conver-
sion to open cholecystectomy (n = 2)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “The hospital pharmacist prepared individual un-
marked 30 cc bottles of rofecoxib elixir (50 mg), or an
identical amount of indistinguishable strawberry-flavored
placebo elixir. Bottles were randomly identified by num-
ber and then sequentially administered to each participat-
ing patient in the presurgery unit 1 to 2 hours before their
surgery”
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
59Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ji 2010
Methods Randomised clinical trial.
Participants Country: China.
Number randomised: 30.
Post-randomisation drop-outs: 0 (0%).
Revised sample size: 30.
Mean age: not stated.
Females: not stated.
Inclusion criteria:
1. ASA I or II.
2. Laparoscopic cholecystectomy.
Exclusion criteria:
1. History of bleeding liability.
2. Gastrointestinal ulcer.
3. Renal or hepatic dysfunction.
4. Severe cardiovascular disease.
5. Heave hypertension.
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: flurbiprofen axetil 1.0 mg/kg parenteral (IV or IM not stated) postoperative
(n = 15).
Group 2: parecoxib 0.8 mg/kg parenteral (IV or IM not stated) postoperative (n = 15).
Group 3: saline 10 mL postoperative (n = 15).
Outcomes Pain.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There were no post-randomisation drop-outs.
60Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ji 2010 (Continued)
Selective reporting (reporting bias) High risk Comment: Some important outcomes which will generally
be assessed were not reported
For-profit bias Unclear risk Comment: This information was not available.
Joshi 2004
Methods Randomised clinical trial.
Participants Country: USA.
Number randomised: 276.
Post-randomisation drop-outs: 13 (4.7%).
Revised sample size: 263.
Mean age: 44 years.
Females: 215 (81.7%).
Inclusion criteria:
1. People aged 18 to 75 years requiring elective ambulatory laparoscopic
cholecystectomy.
Exclusion criteria:
1. Clinically diagnosed acute pancreatitis.
2. Scheduled to undergo any surgical procedure expected to produce more trauma
than laparoscopic cholecystectomy alone.
3. Had acute preoperative pain other than biliary colic.
4. Required chronic pain treatment.
5. Had current or recent cancer or any condition that would contraindicate
participation in a surgical study of this nature.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: parecoxib 40 mg IV 30 to 45 min before surgery plus oral valdecoxib 40 mg
6 to 12 h after IV parecoxib (n = 134).
Group 2: placebo IV 30 to 45 min before surgery and oral placebo 6 to 12 h after IV
placebo (n = 129)
Outcomes Serious adverse events and pain.
Notes Attempts were made to contact the authors in August 2013.
Reasons for post-randomisation drop-outs: did not receive medication
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Based on the computer generated randomization
scheme”
Allocation concealment (selection bias) Low risk Quote: “The hospital pharmacist who was not involved
with patient care or data
61Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Joshi 2004 (Continued)
collection prepared the IV study drugs (2 mL solution iden-
tical in appearance) and provided them to the investigator”
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “The hospital pharmacist who was not involved
with patient care or data
collection prepared the IV study drugs (2 mL solution iden-
tical in appearance) and provided them to the investigator”
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “The hospital pharmacist who was not involved
with patient care or data
collection prepared the IV study drugs (2 mL solution iden-
tical in appearance) and provided them to the investigator”
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality was not reported.
For-profit bias High risk Quote: “Supported, in part, by Pharmacia Corporation and
Pfizer Inc”
Karakoc 2011
Methods Randomised clinical trial.
Participants Country: Turkey.
Number randomised: 80.
Post-randomisation drop-outs: not stated.
Revised sample size: 80.
Mean age: not stated.
Females: not stated.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: dexketoprofen trometamol 50 mg IV 30 min before the completion of surgery
(n = not stated).
Group 2: 0.9% normal saline IV 30 min before the completion of surgery (n = not
stated).
Co-intervention: morphine at end of surgery in both groups, then delivered by patient-
controlled analgesia
Outcomes No outcomes of interest for this review were reported.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
62Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Karakoc 2011 (Continued)
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Some important outcomes which will generally
be assessed were not reported
For-profit bias Unclear risk Comment: This information was not available.
Lane 1996
Methods Randomised clinical trial.
Participants Country: USA.
Number randomised: 125.
Post-randomisation drop-outs: 0 (0%).
Revised sample size: 125.
Mean age: 44.
Females: 107.
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy.
2. ASA status I or II.
Exclusion criteria:
1. Mentally and physically unable to fill out a simple form.
2. Hypersensitivity to study medication.
3. Receiving monoamine oxidase inhibitors.
Interventions Participants were randomly assigned to 1 of 5 groups:
Group 1: placebo (n = 23)
Group 2: meripedine 100 mg IM intra-operatively, pre-procedure (n = 31)
Group 3: meripedine 100 mg IM intra-operatively, post-procedure (n = 20)
Group 4: ketorolac tromethamine 60 mg IM intra-operatively, pre-procedure (n = 25)
Group 5: ketorolac tromethamine 60 mg IM intra-operatively, post-procedure (n = 26)
Outcomes Drug-related serious adverse events.
63Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lane 1996 (Continued)
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There were no post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Liu 1993
Methods Randomised clinical trial.
Participants Country: USA.
Number randomised: 60.
Post-randomisation drop-outs: not stated.
Revised sample size: 60.
Mean age: 46 years.
Females: 15 (25%).
Inclusion criteria:
1. ASA physical status I or II.
2. Aged 18 to 65 years.
3. Scheduled for elective laparoscopic cholecystectomy.
Exclusion criteria:
1. Pregnancy.
2. Anyone chronically taking analgesics and psychotropic drugs.
3. History of opioid abuse.
4. Allergic reactions to NSAIDs or opioid analgesics.
64Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Liu 1993 (Continued)
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: ketorolac 60 mg in 2 mL IM 20 to 40 min before surgery (n = 31).
Group 2: saline 2 mL IM 20 to 40 min before surgery (n = 29)
Co-intervention: midazolam 2 mg.
Outcomes No outcomes of interest for this review were reported.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Quote: “Medication was prepared in a 2-mL numbered
(unlabeled) syringe by the pharmacy”.
Comment: Further details were not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Quote: “Recorded by a blinded nurse observer”.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Mebazaa 2008
Methods Randomised clinical trial.
Participants Country: Canada.
Number randomised: 75.
Post-randomisation drop-outs: not stated.
Revised sample size: 75.
Mean age: 46 years.
Females: not stated
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy.
2. Aged 18 to 75 years.
3. ASA class I or II.
Exclusion criteria:
65Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mebazaa 2008 (Continued)
1. Surgical complications.
2. Surgery > 180 min.
3. Use of intraperitoneal local anaesthetics.
4. Deviation from the anaesthetic protocol.
5. Surgical conversion.
6. Contraindications to paracetamol (acetaminophen) and celecoxib.
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: paracetamol (acetaminophen) 1000 mg orally 1 h before induction (n = 24).
Group 2: celecoxib 200 mg orally 1 h before induction (n= 25).
Group 3: control (n = 26).
Outcomes Pain.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Munro 1998
Methods Randomised clinical trial.
Participants Country: not stated.
Number randomised: 40.
Post-randomisation drop-outs: 3 (7.5%).
Revised sample size: 37.
Mean age: 51 years.
66Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Munro 1998 (Continued)
Females: 30 (81.1%).
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy.
2. Aged 18 to 70 years.
Exclusion criteria:
1. Hypersensitivity to NSAIDs.
2. Possibility of pregnancy.
3. Administration of opioid or NSAID 24 h before surgery.
4. Use of diuretics or angiotensin-converting enzyme inhibitors.
5. Asthma.
6. Peptic ulcers or peptic bleeding.
7. Bleeding disorders.
8. Renal impairment.
9. Hepatic, cardiac, or haemopoietic disease.
10. Inability to operate a patient-controlled analgesia device.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: tenoxicam 40 mg IV on skin closure (n = 19).
Group 2: placebo on skin closure (n = 18).
Outcomes Drug-related serious adverse events and pain.
Notes Reasons for post-randomisation drop-outs: conversion to open cholecystectomy (n = 3)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
67Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Muñoz 2002
Methods Randomised clinical trial.
Participants Country: Chile.
Number randomised: 120.
Post-randomisation drop-outs: not stated.
Revised sample size: 120.
Mean age: 42 years.
Females: 80 (66.7%).
Inclusion criteria:
1. ASA status I or II.
2. Aged 20 to 60 years.
Exclusion criteria:
1. Chronic or acute (within last 48 h) intake of sedatives or analgesic drugs.
2. Adverse reaction to study drugs.
Interventions Participants were randomly assigned to 1 of 4 groups.
Group 1: morphine 0.15 mg/kg IV < 20 min before surgery (n = 33).
Group 2: morphine 0.15 mg/kg IV 20 to 40 min before surgery (n = 30).
Group 3: morphine 0.15 mg/kg IV > 40 min before surgery (n= 27).
Group 4: placebo (n = 30).
Outcomes No outcomes of interest for this review were reported.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated list”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
68Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nesek-Adam 2012
Methods Randomised clinical trial.
Participants Country: Croatia.
Number randomised: 80.
Post-randomisation drop-outs: not stated.
Revised sample size: 80.
Mean age: 51 years.
Females: 58 (72.5%).
Inclusion criteria:
1. Aged 18 to 70 years.
2. Scheduled for laparoscopic cholecystectomy.
3. ASA physical status I or II.
Exclusion criteria:
1. Pre-existing neurological or psychiatric disease.
2. Chronic pain syndrome.
3. History of peptic ulceration, hepatic, and renal insufficiency.
4. Pregnancy.
5. Receiving regular opioids or drugs with any analgesic properties in 24 h before
surgery.
6. Operation for acute cholecystitis.
7. Operation converted to an open procedure.
Interventions Participants were randomly assigned to 1 of 4 groups.
Group 1: diclofenac 1 mg/kg IV 20 min before induction (n = 20).
Group 2: saline 100 mL IV 20 min before induction (n = 20).
Group 3: same as group 1 with ketamine IV as co-intervention (n = 20).
Group 4: same as group 2 with ketamine IV as co-intervention (n = 20)
Outcomes Drug-related serious adverse events.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated table of random numbers”.
Allocation concealment (selection bias) Unclear risk Quote: “An envelope containing group assignment was pre-
pared, sealed, and numbered for each patient”
Comment: Further details were not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Quote: “On the morning of surgery, anesthesia technician
opened the envelope and prepared completely identical sy-
ringes and infusion that were labeled ”infusion“ and ”skin
bolus“ in equal volume to make the study double blind”
Comment: Further details were not available.
69Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nesek-Adam 2012 (Continued)
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Pandey 2004
Methods Randomised clinical trial.
Participants Country: India.
Number randomised: 459.
Post-randomisation drop-outs: not stated.
Revised sample size: 459.
Mean age: 42 years.
Females: 308 (67.1%).
Inclusion criteria:
1. ASA I or II.
2. Aged 18 to 70 years.
3. Elective laparoscopic cholecystectomy.
Exclusion criteria:
1. Body weight exceeding 20% of the ideal body weight.
2. Known history of hypersensitivity to any drug.
3. History of drug or alcohol abuse.
4. Uncontrolled concomitant medical diseases.
5. People with history of chronic pain conditions.
6. Impaired kidney or liver function.
7. Cholelithiasis with known common bile duct pathology or indications of
cholecystectomy other than cholelithiasis, laparoscopic converted into open
cholecystectomy.
8. Administration of analgesics within 48 h of scheduled surgery.
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: gabapentin 300 mg orally 2 h before surgery (n = 153).
Group 2: tramadol 100 mg orally 2 h before surgery (n = 153).
Group 3: placebo 2 h before surgery (n = 153).
Outcomes Pain.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
70Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pandey 2004 (Continued)
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer generated table of random numbers
used”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Quote: “A senior resident, who was not part of the anesthe-
sia team recorded the pain score”.
Comment: Further details were not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Peng 2010
Methods Randomised clinical trial.
Participants Country: Canada.
Number randomised: 165.
Post-randomisation drop-outs: 42 (25.5%).
Revised sample size: 123.
Mean age: 45 years.
Females: 95 (77.2%).
Inclusion criteria:
1. Aged 18 to 65 years.
2. ASA physical status I to III.
3. Laparoscopic cholecystectomy.
Exclusion criteria:
1. Urgent or emergent cholecystectomy.
2. Analgesics in 24 h before surgery.
3. Body mass index > 40.
4. Clinical diagnosis of acute pancreatitis.
5. Contraindication to gabapentin, pregabalin, NSAIDs, codeine, or paracetamol
(acetaminophen).
6. Serious organ disease or dysfunction.
7. Severe psychiatric disease.
8. Drug addiction.
9. Pregnancy.
10. Unable to communicate in English.
71Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Peng 2010 (Continued)
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: pregabalin 50 mg orally 1 h before surgery and then every 12 h after operation
for 3 doses (n = 42).
Group 2: pregabalin 75 mg orally 1 h before surgery and then every 12 h after operation
for 3 doses. (n = 40).
Group 3: placebo 1 h before surgery and then every 12 h after operation for 3 doses (n
= 41)
Outcomes Mortality.
Notes Reasons for post-randomisation drop-outs: protocol violation (n = 23), questionnaire
not completed or returned (n = 19)
Attempts were made to contact authors in August 2013. Authors provided replies
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “According to a computer-generated randomization
list”
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “The study medications were prepared in capsules
of identical colour and appearance and were packaged by
the hospital pharmacy”
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Morbidity was not reported.
For-profit bias High risk Quote: “This research was funded by the Pfizer Global In-
vestigator Initiated Grant. The medications in this study
were provided by Pfizer Inc”
Puura 2006
Methods Randomised clinical trial.
Participants Country: Finland.
Number randomised: 75.
Post-randomisation drop-outs: 3 (4%).
Revised sample size: 72.
72Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Puura 2006 (Continued)
Mean age: 46 years.
Females: not stated
Inclusion criteria:
1. Aged 16 to 70 years.
2. ASA physiological status I to III.
3. Elective laparoscopic cholecystectomy.
Exclusion criteria:
1. Allergy to NSAIDs.
2. Chronic pain syndrome.
3. Psychiatric disorder.
4. Substance abuse.
5. Gastrointestinal bleeding.
6. Any disease of the liver or the kidneys.
7. Pregnancy.
8. Congestive heart disease.
9. Angina pectoris.
10. Cerebrovascular circulatory symptoms.
11. Body mass index > 40.
Interventions Participants were randomly assigned to 1 of 3 groups.
Group 1: etoricoxib 120 mg plus paracetamol (acetaminophen) 1 g orally 1.5 h before
surgery (n = 25).
Group 2: etoricoxib 120 mg orally 1.5 h before surgery (n = 24).
Group 3: placebo 1.5 h before surgery (n = 23).
Outcomes No outcomes of interest were reported.
Notes Reasons for post-randomisation drop-outs: cirrhosis (n = 1), needed open cholecystec-
tomy (n = 2)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Using a random number table”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Quote: “Drug-containing bags used”.
Comment: Further details were not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
73Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Puura 2006 (Continued)
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Low risk Quote: “This study was supported by a grant from the Med-
ical Research Fund of Tampere University Hospital”
Salihoglu 2009
Methods Randomised clinical trial.
Participants Country: Turkey.
Number randomised: 40.
Post-randomisation drop-outs: 0 (0%).
Revised sample size: 40.
Mean age: 42 years.
Females: 31 (77.5%).
Inclusion criteria:
1. ASA status I or II.
Exclusion criteria:
1. Chronic analgesic or alcohol intake.
2. Hypersensitivity to the drugs used in the study.
3. Body mass index > 35.
4. Diminished liver and kidney functions.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: paracetamol (acetaminophen) 1 g IV after intubation (n = 20).
Group 2: saline IV after intubation (n = 20).
Outcomes Serious adverse events.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Random number generator”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “The anaesthetist who intubated and followed the
patient during surgery, and the surgical team were also un-
aware about which patient received paracetamol or not”
74Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Salihoglu 2009 (Continued)
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Quote: “The researchers were unaware about the patients
or the anaesthetists, who were taken into the study while
the study was going on”
Comment: Further details not available.
Incomplete outcome data (attrition bias)
All outcomes
Low risk Comment: There were no post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality was not reported.
For-profit bias Unclear risk Comment: This information was not available.
Sandhu 2011
Methods Randomised clinical trial.
Participants Country: Thailand.
Number randomised: 120.
Post-randomisation drop-outs: 1 (0.8%).
Revised sample size: 119.
Mean age: 53 years.
Females: 78 (65.5%).
Inclusion criteria:
1. ASA I or II.
2. Aged 18 to 75 years.
3. Elective laparoscopic cholecystectomy.
Exclusion criteria:
1. Acute pre-operative pain other than biliary colic.
2. Chronic pain treatment.
3. Advanced renal disease, heart failure, or fluid retention.
4. Use of pre-operative NSAIDs or opioids within 24 h of the scheduled operation.
5. Known hypersensitivity to NSAIDs.
6. Pregnancy.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: etoricoxib 120 mg (route not stated) 1 h before surgery (n = 60).
Group 2: placebo 1 h (route not stated) before surgery (n = 59)
Outcomes Length of hospital stay.
Notes Reasons for post-randomisation drop-outs: conversion to open cholecystectomy (n = 1)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
75Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sandhu 2011 (Continued)
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There was one post-randomisation drop-out.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Low risk Quote: “This study was supported by the Prasert Prasart-
tong-Osoth Research Fund, Medical Association of Thai-
land”
Sarakatsianou 2013
Methods Randomised clinical trial.
Participants Country: Greece.
Number randomised: 50.
Post-randomisation drop-outs: 10 (20%).
Revised sample size: 40.
Mean age: 54 years.
Females: 24 (60%).
Inclusion criteria:
1. ASA physical status I or II.
2. Elective laparoscopic cholecystectomy under general anaesthesia.
Exclusion criteria:
1. History of chronic pain or daily use of analgesics.
2. Renal or hepatic insufficiency.
3. Uncontrolled medical diseases.
4. Psychiatric disorders.
5. History of alcohol or drug abuse.
6. Inability of person to use patient-controlled analgesia pump.
7. Administration of NSAIDs within 24 h before surgery.
8. Use of drainage at the end of the procedure.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: pregabalin 600 mg orally divided in 2 doses, the night before surgery and 1 h
preoperatively (n = 20).
76Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sarakatsianou 2013 (Continued)
Group 2: placebo divided in 2 doses, the night before surgery and 1 h preoperatively (n
= 20)
Outcomes Pain.
Notes Reasons for post-randomisation drop-outs: converted to open cholecystectomy (n = 4),
use of drain (n = 6)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated table of random numbers
with sex stratification”
Allocation concealment (selection bias) Unclear risk Quote: “Patients were randomised by a computer-gener-
ated, blinded randomisation list”.
Comment: Further details were not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “All medications were provided by the hospital
pharmacy, and they were identical in shape and colour”
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Schuster 2005
Methods Randomised clinical trial.
Participants Country: USA.
Number randomised: 80.
Post-randomisation drop-outs: 8 (10%).
Revised sample size: 72.
Mean age: not stated.
Females: not stated.
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy.
2. Aged ≥ 18.
Exclusion criteria:
77Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Schuster 2005 (Continued)
1. Acute cholecystitis.
2. Conversion to open cholecystectomy.
3. Renal insufficiency or failure.
4. History of gastrointestinal bleeding.
5. Allergy to NSAIDs or cyclo-oxygenase-2 inhibitors.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: rofecoxib 25 mg orally presurgically (n = not stated).
Group 2: placebo (n = not stated).
Outcomes Serious adverse events, hospital stay, and pain.
Notes Reasons for post-randomisation drop-outs: converted to open cholecystectomy (n = 2),
refused (n = 2), acute cholecystitis (n = 3), postoperative NSAID use (n = 1)
Attempts were made to contact authors in August 2013.
There were no serious adverse events in either group. There was no significant difference
in the length of hospital stay and pain in either group
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Quote: “Random card pull design method”.
Comment: Further details were not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Quote: “The patient, surgeon and researcher were all
blinded to the patient’s treatment group”.
Comment: Further details were not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Quote: “The patient, surgeon and researcher were all
blinded to the patient’s treatment group”.
Comment: Further details were not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
78Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sen 2010
Methods Randomised clinical trial.
Participants Country: Turkey.
Number randomised: 120.
Post-randomisation drop-outs: 2 (1.7%).
Revised sample size: 118.
Mean age: 54 years.
Females: 81 (68.6%).
Inclusion criteria:
1. ASA physical status I or II.
2. Elective laparoscopic cholecystectomy under general anaesthesia.
Exclusion criteria:
1. Acute cholecystitis.
2. Acute pancreatitis.
3. Known history of hypersensitivity to any drug.
4. Uncontrolled concomitant medical diseases.
5. Chronic opioid therapy.
6. Cholelithiasis with known bile duct pathology.
7. Administration of analgesics within 48 h of the day before surgery.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: etofenomate 1 g (2 mL) IM 1 h before surgery (n = 59).
Group 2: saline IM 1 h before surgery (n = 59).
Outcomes Pain.
Notes Reasons for post-randomisation drop-outs: protocol violation (n = 2)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated, blinded randomisation list”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
79Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sen 2010 (Continued)
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Wilson 1994
Methods Randomised clinical trial.
Participants Country: England.
Number randomised: 55.
Post-randomisation drop-outs: 6 (10.9%).
Revised sample size: 49.
Mean age: 48 years.
Females: 40 (81.6%).
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy.
Exclusion criteria:
1. Peptic ulcer disease.
2. Hepatic or renal insufficiency.
3. History of haemorrhagic diathesis.
4. Hypersensitivity to diclofenac.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: diclofenac 75 mg IM (n = 26).
Group 2: placebo (n = 23).
Outcomes Pain.
Notes Reasons for post-randomisation drop-outs: incomplete data extraction (n = 3), conver-
sion to open (n = 3)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer random number generation”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “Pharmacy provided identical pre-packed syringes”.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
80Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Wilson 1994 (Continued)
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There were post-randomisation drop-outs.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Yeh 2004
Methods Randomised clinical trial.
Participants Country: Taiwan.
Number randomised: 44.
Post-randomisation drop-outs: 1 (2.3%).
Revised sample size: 43.
Mean age: 49 years.
Females: 27 (62.8%).
Inclusion criteria:
1. ASA physical status I or II.
2. Elective laparoscopic cholecystectomy.
Exclusion criteria:
1. NSAIDs contraindicated.
2. Received opioids or NSAIDs less than 1 week before the study.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: tenoxicam 40 mg IV 30 min before incision (n = 21).
Group 2: saline 30 min before incision (n = 22).
Outcomes Pain.
Notes Reasons for post-randomisation drop-outs: ineligibility for laparoscopic cholecystectomy
(n = 1)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Comment: This information was not available.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Quote: “The study drugs were prepared by the hospital
pharmacy in identical, consecutively numbered containers
marked with the name of the project, the investigator’s name
and route of administration”
81Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Yeh 2004 (Continued)
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There was one post-randomisation drop-out.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Zajaczkowska 2004
Methods Randomised clinical trial.
Participants Country: Poland.
Number randomised: 60.
Post-randomisation drop-outs: not stated.
Revised sample size: 60.
Mean age: 51 years.
Females: 44 (73.3%).
Inclusion criteria:
1. Symptomatic gallstone disease.
2. ASA I or II.
3. Age > 18 years.
Exclusion criteria:
1. Acute cholecystitis.
2. Significant cardiac, respiratory, hepatic, renal, or neurological disease.
3. Local anaesthetic and morphine allergies.
4. Analgesics for non-biliary complaints.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: morphine SC (n = 30).
Group 2: no intervention (n = 30).
Outcomes Pain.
Notes Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated random-number table”.
Allocation concealment (selection bias) Unclear risk Quote: “Sealed envelope method used”.
Comment: Further details not available.
82Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Zajaczkowska 2004 (Continued)
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Comment: This information was not available.
Selective reporting (reporting bias) High risk Comment: Mortality and morbidity were not reported.
For-profit bias Unclear risk Comment: This information was not available.
Zhu 2011
Methods Randomised clinical trial.
Participants Country: China.
Number randomised: 60.
Post-randomisation drop-outs: 1 (1.7%).
Revised sample size: 59.
Mean age: 44 years.
Females: 25 (42.4%).
Inclusion criteria:
1. ASA physical status I or II.
2. Scheduled for laparoscopic cholecystectomy.
3. Aged 33 to 65 years.
Exclusion criteria:
1. History of chronic pain or daily intake of analgesics.
2. Uncontrolled medical disease.
3. Inability to operated patient-controlled analgesia.
Interventions Participants were randomly assigned to 1 of 2 groups.
Group 1: dezocine 0.1 mg/kg IM 10 min before induction (n = 30).
Group 2: saline IM 10 min before induction (n = 29).
Outcomes Pain.
Notes Reasons for post-randomisation drop-outs: conversion to open cholecystectomy (n = 1)
Attempts were made to contact authors in August 2013.
Risk of bias
Bias Authors’ judgement Support for judgement
83Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Zhu 2011 (Continued)
Random sequence generation (selection
bias)
Low risk Quote: “Computer-generated table used”.
Allocation concealment (selection bias) Unclear risk Comment: This information was not available.
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Comment: This information was not available.
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Comment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High risk Comment: There was one post-randomisation drop-out.
Selective reporting (reporting bias) High risk Comment: Some important outcomes which will generally
be assessed were not reported
For-profit bias Unclear risk Comment: This information was not available.
ASA: American Society of Anesthesiologists; h: hour; IM: intramuscular; IV: intravenous; min: minute; NSAID: non-steroidal anti-
inflammatory drug; SC: subcutaneous.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Aftab 2008 Quasi-randomisation used.
Akca 2004 Separate data for laparoscopic cholecystectomy not available
Bajaj 2004 Separate data for laparoscopic cholecystectomy not available
Boccara 2005 Compares different NSAIDs.
Collard 2007 Compares different opioids.
Elhakim 2000 Compares different routes of administration of NSAIDs.
Gan 2004 Combination of ≥ 2 classes of drug used.
Hernandez-Palazon 2003 Trial features intraperitoneal installation of local anaesthetics
84Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Kocaayan 2007 Compares different NSAIDs.
Koch 2008 Compares different NSAIDs.
Kokki 2012 Combination of ≥ 2 classes of drug used.
Matkap 2011 Compares different routes of administration of opioids.
Naguib 1998 Compares different opioids.
O’Hanlon 2002 Compares different routes of administration of opioids.
Ozkocak 2002 Trial features intraperitoneal installation of local anaesthetics
Sanchez-Rodriguez 2010 Comparison of steroids not included in this review.
Sozbilen 2007 Trial features local anaesthetics.
Stempin 2007 Trial features intraperitoneal installation of local anaesthetics
Tiippana 2008 Not a randomised clinical trial.
Wininger 2010 Separate data for laparoscopic cholecystectomy not available
Wu 1999 Intervention not intended primarily for analgesia.
Wu 2005 Intervention not intended primarily for analgesia.
Yamazaki 2003 Not a randomised clinical trial.
Zambouri 2002 Comparison of 2 opioids.
Zghidi 2011 Comparison of steroids not included in this review.
NSAID: non-steroidal anti-inflammatory drug.
Characteristics of studies awaiting assessment [ordered by study ID]
85Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Gan 2003
Methods
Participants
Interventions
Outcomes
Notes Full text unavailable.
86Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. NSAID versus control
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Morbidity 5 543 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.37, 1.53]
2 Proportion discharged as
day-surgery
1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
3 Length of hospital stay 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
4 Pain (4 to 8 hours) 11 999 Mean Difference (IV, Fixed, 95% CI) -0.88 [-1.07, -0.70]
5 Pain (9 to 24 hours) 9 707 Mean Difference (IV, Fixed, 95% CI) -0.50 [-0.67, -0.33]
6 Morbidity (sensitivity analysis) 5 2268 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.59, 1.07]
6.1 Best-best 5 567 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.36, 1.53]
6.2 Best-worst 5 567 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.23, 0.82]
6.3 Worst-best 5 567 Risk Ratio (M-H, Fixed, 95% CI) 1.46 [0.79, 2.67]
6.4 Worst-worst 5 567 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.50, 1.36]
7 Proportion discharged as
day-surgery (sensitivity
analysis)
1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
7.1 Best-best 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7.2 Best-worst 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7.3 Worst-best 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7.4 Best-worst 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8 Pain (4 to 8 hours) sensitivity
analysis
4 433 Mean Difference (IV, Fixed, 95% CI) -0.91 [-1.10, -0.71]
9 Pain (9 to 24 hours) sensitivity
analysis
4 433 Mean Difference (IV, Fixed, 95% CI) -0.50 [-0.67, -0.33]
10 Pain (4 to 8 hours) stratified by
drug
11 999 Mean Difference (IV, Fixed, 95% CI) -0.88 [-1.07, -0.70]
10.1 Celecoxib 1 38 Mean Difference (IV, Fixed, 95% CI) -1.03 [-7.01, 4.95]
10.2 Diclofenac 1 49 Mean Difference (IV, Fixed, 95% CI) -2.50 [-7.56, 2.56]
10.3 Etofenomate 1 118 Mean Difference (IV, Fixed, 95% CI) -0.34 [-0.60, -0.08]
10.4 Flurbiprofen 1 23 Mean Difference (IV, Fixed, 95% CI) -2.26 [-3.26, -1.26]
10.5 Lornoxicam 1 150 Mean Difference (IV, Fixed, 95% CI) -2.70 [-3.13, -2.26]
10.6 Metamizol 1 40 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.74, 1.14]
10.7 Paracetamol 3 146 Mean Difference (IV, Fixed, 95% CI) -0.10 [-1.02, 0.82]
10.8 Parecoxib 4 355 Mean Difference (IV, Fixed, 95% CI) -0.76 [-1.21, -0.31]
10.9 Tenoxicam 2 80 Mean Difference (IV, Fixed, 95% CI) -0.46 [-4.42, 3.51]
11 Pain (4 to 8 hours) stratified by
time
11 999 Mean Difference (IV, Fixed, 95% CI) -0.88 [-1.07, -0.70]
11.1 Before 4 285 Mean Difference (IV, Fixed, 95% CI) -0.35 [-0.60, -0.09]
11.2 During 1 150 Mean Difference (IV, Fixed, 95% CI) -2.70 [-3.13, -2.26]
11.3 After 4 271 Mean Difference (IV, Fixed, 95% CI) -0.73 [-1.17, -0.29]
11.4 Before and after 2 293 Mean Difference (IV, Fixed, 95% CI) -0.69 [-1.28, -0.11]
12 Pain (9 to 24 hours) stratified
by drug
9 707 Mean Difference (IV, Fixed, 95% CI) -0.50 [-0.67, -0.33]
12.1 Celecoxib 1 38 Mean Difference (IV, Fixed, 95% CI) -0.37 [-5.52, 4.78]
12.2 Diclofenac 1 49 Mean Difference (IV, Fixed, 95% CI) 0.5 [-3.94, 4.94]
87Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
12.3 Etofenomate 1 118 Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.22, 0.24]
12.4 Flurbiprofen 1 23 Mean Difference (IV, Fixed, 95% CI) -0.98 [-2.08, 0.12]
12.5 Lornoxicam 1 150 Mean Difference (IV, Fixed, 95% CI) -2.07 [-2.42, -1.72]
12.6 Metamizol 1 40 Mean Difference (IV, Fixed, 95% CI) 0.40 [-0.35, 1.15]
12.7 Paracetamol 2 77 Mean Difference (IV, Fixed, 95% CI) 0.21 [-0.48, 0.90]
12.8 Parecoxib 3 132 Mean Difference (IV, Fixed, 95% CI) -0.50 [-1.08, 0.08]
12.9 Tenoxicam 2 80 Mean Difference (IV, Fixed, 95% CI) -0.60 [-4.10, 2.89]
13 Pain (9 to 24 hours) stratified
by time
9 707 Mean Difference (IV, Fixed, 95% CI) -0.50 [-0.67, -0.33]
13.1 Before 4 285 Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.22, 0.24]
13.2 During 1 150 Mean Difference (IV, Fixed, 95% CI) -2.07 [-2.42, -1.72]
13.3 After 3 202 Mean Difference (IV, Fixed, 95% CI) -0.16 [-0.53, 0.20]
13.4 Before and after 1 70 Mean Difference (IV, Fixed, 95% CI) 0.09 [-3.62, 3.80]
Comparison 2. Opioid versus control
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Pain (4 to 8 hours) 3 425 Mean Difference (IV, Fixed, 95% CI) -2.51 [-3.02, -2.01]
2 Pain (9 to 24 hours) 3 425 Mean Difference (IV, Fixed, 95% CI) -0.32 [-0.44, -0.20]
3 Pain (4 to 8 hours) (sensitivity
analysis)
1 306 Mean Difference (IV, Fixed, 95% CI) -2.56 [-3.07, -2.05]
4 Pain (9 to 24 hours) (sensitivity
analysis)
1 306 Mean Difference (IV, Fixed, 95% CI) -0.32 [-0.44, -0.20]
Comparison 3. Anticonvulsant analgesic versus control
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Morbidity 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
2 Pain (4 to 8 hours) 3 402 Mean Difference (IV, Fixed, 95% CI) -2.52 [-2.95, -2.09]
3 Pain (9 to 24 hours) 3 402 Mean Difference (IV, Fixed, 95% CI) -0.55 [-0.68, -0.42]
4 Morbidity (sensitivity analysis) 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
4.1 Best-best 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.2 Best-worst 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.3 Worst-best 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.4 Worst-worst 1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
5 Pain (4 to 8 hours) sensitivity
analysis
1 306 Mean Difference (IV, Fixed, 95% CI) -2.88 [-3.36, -2.40]
6 Pain (9 to 24 hours) sensitivity
analysis
1 306 Mean Difference (IV, Fixed, 95% CI) -0.54 [-0.67, -0.41]
88Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 4. Anticonvulsant analgesic versus NSAID
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Morbidity 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
2 Pain (4 to 8 hours) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
3 Pain (9 to 24 hours) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
4 Morbidity (sensitivity analysis) 1 240 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.50, 2.01]
4.1 Best-best 1 60 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [0.19, 20.90]
4.2 Best-worst 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.07, 1.52]
4.3 Worst-best 1 60 Risk Ratio (M-H, Fixed, 95% CI) 5.0 [0.62, 40.28]
4.4 Worst-worst 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.28, 2.44]
Comparison 5. Anticonvulsant analgesic versus opioid
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Pain (4 to 8 hours) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
2 Pain (9 to 24 hours) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
89Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.1. Comparison 1 NSAID versus control, Outcome 1 Morbidity.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 1 Morbidity
Study or subgroup NSAID Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Chung 2004 2/33 1/36 5.9 % 2.18 [ 0.21, 22.96 ]
Gilron 2009 3/25 2/27 11.9 % 1.62 [ 0.29, 8.91 ]
Joshi 2004 7/134 13/129 82.1 % 0.52 [ 0.21, 1.26 ]
Salihoglu 2009 0/20 0/20 Not estimable
Sandhu 2011 0/60 0/59 Not estimable
Total (95% CI) 272 271 100.0 % 0.75 [ 0.37, 1.53 ]
Total events: 12 (NSAID), 16 (Control)
Heterogeneity: Chi2 = 2.24, df = 2 (P = 0.33); I2 =11%
Test for overall effect: Z = 0.79 (P = 0.43)
Test for subgroup differences: Not applicable
0.05 0.2 1 5 20
Favours NSAID Favours control
Analysis 1.2. Comparison 1 NSAID versus control, Outcome 2 Proportion discharged as day-surgery.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 2 Proportion discharged as day-surgery
Study or subgroup NSAID Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Horattas 2004 35/58 35/58 1.00 [ 0.74, 1.34 ]
0.5 0.7 1 1.5 2
Favours control Favours NSAID
90Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.3. Comparison 1 NSAID versus control, Outcome 3 Length of hospital stay.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 3 Length of hospital stay
Study or subgroup NSAID ControlMean
DifferenceMean
Difference
N Mean(SD)[days] N Mean(SD)[days] IV,Fixed,95% CI IV,Fixed,95% CI
Sandhu 2011 60 1 (0.77) 59 1.1 (2.3) -0.10 [ -0.72, 0.52 ]
-0.5 -0.25 0 0.25 0.5
Favours NSAID Favours control
Analysis 1.4. Comparison 1 NSAID versus control, Outcome 4 Pain (4 to 8 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 4 Pain (4 to 8 hours)
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Abdulla 2012 30 1.8 (1.2) 10 2.2 (1.4) 3.7 % -0.40 [ -1.37, 0.57 ]
Abdulla 2012 30 2.1 (1.1) 10 2.2 (1.4) 3.8 % -0.10 [ -1.05, 0.85 ]
Abdulla 2012 30 2.4 (1) 10 2.2 (1.4) 3.9 % 0.20 [ -0.74, 1.14 ]
Akaraviputh 2009 40 2.9 (9.41) 30 3.3 (8.67) 0.2 % -0.40 [ -4.66, 3.86 ]
Chung 2004 33 3.68 (9.41) 36 3.68 (8.67) 0.2 % 0.0 [ -4.28, 4.28 ]
Dong 2003 50 2.2 (0.6) 25 4.7 (1.5) 9.3 % -2.50 [ -3.11, -1.89 ]
Dong 2003 50 1.8 (0.7) 25 4.7 (1.5) 9.0 % -2.90 [ -3.52, -2.28 ]
Ji 2010 15 2.3 (1.22) 8 4.56 (1.13) 3.5 % -2.26 [ -3.26, -1.26 ]
Ji 2010 15 3.12 (1.36) 7 4.56 (1.13) 3.0 % -1.44 [ -2.52, -0.36 ]
Joshi 2004 119 2.1 (2.23) 104 2.8 (2.23) 10.1 % -0.70 [ -1.29, -0.11 ]
-4 -2 0 2 4
Favours NSAID Favours control
(Continued . . . )
91Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Mebazaa 2008 25 2.65 (9.41) 13 3.68 (8.67) 0.1 % -1.03 [ -7.01, 4.95 ]
Mebazaa 2008 24 3.39 (9.41) 13 3.68 (8.67) 0.1 % -0.29 [ -6.32, 5.74 ]
Munro 1998 19 1.7 (9.41) 18 2.5 (8.67) 0.1 % -0.80 [ -6.63, 5.03 ]
Sen 2010 59 2.28 (0.58) 59 2.62 (0.82) 52.8 % -0.34 [ -0.60, -0.08 ]
Wilson 1994 26 1.6 (9.41) 23 4.1 (8.67) 0.1 % -2.50 [ -7.56, 2.56 ]
Yeh 2004 21 3.04 (9.41) 22 3.2 (8.67) 0.1 % -0.16 [ -5.58, 5.26 ]
Total (95% CI) 586 413 100.0 % -0.88 [ -1.07, -0.70 ]
Heterogeneity: Chi2 = 103.00, df = 15 (P<0.00001); I2 =85%
Test for overall effect: Z = 9.29 (P < 0.00001)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours NSAID Favours control
92Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.5. Comparison 1 NSAID versus control, Outcome 5 Pain (9 to 24 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 5 Pain (9 to 24 hours)
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Abdulla 2012 30 1.5 (1.2) 10 1.1 (1) 5.0 % 0.40 [ -0.35, 1.15 ]
Abdulla 2012 30 0.7 (0.7) 10 1.1 (1) 6.4 % -0.40 [ -1.07, 0.27 ]
Abdulla 2012 30 1.3 (0.9) 10 1.1 (1) 5.8 % 0.20 [ -0.50, 0.90 ]
Akaraviputh 2009 40 0.81 (8.79) 30 0.72 (7.05) 0.2 % 0.09 [ -3.62, 3.80 ]
Dong 2003 50 2.5 (0.4) 25 4.2 (1.2) 12.2 % -1.70 [ -2.18, -1.22 ]
Dong 2003 50 1.7 (0.8) 25 4.2 (1.2) 10.5 % -2.50 [ -3.02, -1.98 ]
Ji 2010 15 1.31 (0.99) 7 2.2 (1.47) 2.0 % -0.89 [ -2.09, 0.31 ]
Ji 2010 15 1.22 (0.8) 8 2.2 (1.47) 2.4 % -0.98 [ -2.08, 0.12 ]
Mebazaa 2008 25 2.21 (8.79) 13 2.58 (7.05) 0.1 % -0.37 [ -5.52, 4.78 ]
Mebazaa 2008 24 3.46 (8.79) 13 2.58 (7.05) 0.1 % 0.88 [ -4.32, 6.08 ]
Munro 1998 19 1.5 (8.79) 18 2.5 (7.05) 0.1 % -1.00 [ -6.12, 4.12 ]
Sen 2010 59 1.01 (0.6) 59 1 (0.66) 54.9 % 0.01 [ -0.22, 0.24 ]
Wilson 1994 26 2.6 (8.79) 23 2.1 (7.05) 0.1 % 0.50 [ -3.94, 4.94 ]
Yeh 2004 21 2.63 (8.79) 22 2.89 (7.05) 0.1 % -0.26 [ -5.04, 4.52 ]
Total (95% CI) 434 273 100.0 % -0.50 [ -0.67, -0.33 ]
Heterogeneity: Chi2 = 110.96, df = 13 (P<0.00001); I2 =88%
Test for overall effect: Z = 5.80 (P < 0.00001)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours NSAID Favours control
93Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.6. Comparison 1 NSAID versus control, Outcome 6 Morbidity (sensitivity analysis).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 6 Morbidity (sensitivity analysis)
Study or subgroup NSAID Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Best-best
Chung 2004 2/40 1/45 1.0 % 2.25 [ 0.21, 23.89 ]
Gilron 2009 3/29 2/30 2.2 % 1.55 [ 0.28, 8.62 ]
Joshi 2004 7/134 13/129 14.6 % 0.52 [ 0.21, 1.26 ]
Salihoglu 2009 0/20 0/20 Not estimable
Sandhu 2011 0/60 0/60 Not estimable
Subtotal (95% CI) 283 284 17.9 % 0.75 [ 0.36, 1.53 ]
Total events: 12 (NSAID), 16 (Control)
Heterogeneity: Chi2 = 2.19, df = 2 (P = 0.33); I2 =9%
Test for overall effect: Z = 0.80 (P = 0.42)
2 Best-worst
Chung 2004 2/40 10/45 10.4 % 0.23 [ 0.05, 0.97 ]
Gilron 2009 3/29 5/30 5.4 % 0.62 [ 0.16, 2.36 ]
Joshi 2004 7/134 13/129 14.6 % 0.52 [ 0.21, 1.26 ]
Salihoglu 2009 0/20 0/20 Not estimable
Sandhu 2011 0/60 1/60 1.7 % 0.33 [ 0.01, 8.02 ]
Subtotal (95% CI) 283 284 32.1 % 0.43 [ 0.23, 0.82 ]
Total events: 12 (NSAID), 29 (Control)
Heterogeneity: Chi2 = 1.24, df = 3 (P = 0.74); I2 =0.0%
Test for overall effect: Z = 2.59 (P = 0.0097)
3 Worst-best
Chung 2004 9/40 1/45 1.0 % 10.13 [ 1.34, 76.45 ]
Gilron 2009 7/29 2/30 2.2 % 3.62 [ 0.82, 16.01 ]
Joshi 2004 7/134 13/129 14.6 % 0.52 [ 0.21, 1.26 ]
Salihoglu 2009 0/20 0/20 Not estimable
Sandhu 2011 0/60 0/60 Not estimable
Subtotal (95% CI) 283 284 17.9 % 1.46 [ 0.79, 2.67 ]
Total events: 23 (NSAID), 16 (Control)
Heterogeneity: Chi2 = 10.19, df = 2 (P = 0.01); I2 =80%
Test for overall effect: Z = 1.22 (P = 0.22)
0.02 0.1 1 10 50
Favours NSAID Favours control
(Continued . . . )
94Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup NSAID Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
4 Worst-worst
Chung 2004 9/40 10/45 10.4 % 1.01 [ 0.46, 2.24 ]
Gilron 2009 7/29 5/30 5.4 % 1.45 [ 0.52, 4.05 ]
Joshi 2004 7/134 13/129 14.6 % 0.52 [ 0.21, 1.26 ]
Salihoglu 2009 0/20 0/20 Not estimable
Sandhu 2011 0/60 1/60 1.7 % 0.33 [ 0.01, 8.02 ]
Subtotal (95% CI) 283 284 32.1 % 0.83 [ 0.50, 1.36 ]
Total events: 23 (NSAID), 29 (Control)
Heterogeneity: Chi2 = 2.77, df = 3 (P = 0.43); I2 =0.0%
Test for overall effect: Z = 0.75 (P = 0.45)
Total (95% CI) 1132 1136 100.0 % 0.80 [ 0.59, 1.07 ]
Total events: 70 (NSAID), 90 (Control)
Heterogeneity: Chi2 = 20.25, df = 13 (P = 0.09); I2 =36%
Test for overall effect: Z = 1.52 (P = 0.13)
Test for subgroup differences: Chi2 = 7.42, df = 3 (P = 0.06), I2 =60%
0.02 0.1 1 10 50
Favours NSAID Favours control
95Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.7. Comparison 1 NSAID versus control, Outcome 7 Proportion discharged as day-surgery
(sensitivity analysis).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 7 Proportion discharged as day-surgery (sensitivity analysis)
Study or subgroup NSAID Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Best-best
Horattas 2004 37/60 37/60 1.00 [ 0.75, 1.33 ]
2 Best-worst
Horattas 2004 37/60 35/60 1.06 [ 0.79, 1.42 ]
3 Worst-best
Horattas 2004 35/60 37/60 0.95 [ 0.71, 1.27 ]
4 Best-worst
Horattas 2004 35/60 35/60 1.00 [ 0.74, 1.35 ]
0.5 0.7 1 1.5 2
Favours control Favours NSAID
96Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.8. Comparison 1 NSAID versus control, Outcome 8 Pain (4 to 8 hours) sensitivity analysis.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 8 Pain (4 to 8 hours) sensitivity analysis
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Abdulla 2012 30 2.1 (1.1) 10 2.2 (1.4) 4.3 % -0.10 [ -1.05, 0.85 ]
Abdulla 2012 30 1.8 (1.2) 10 2.2 (1.4) 4.2 % -0.40 [ -1.37, 0.57 ]
Abdulla 2012 30 2.4 (1) 10 2.2 (1.4) 4.4 % 0.20 [ -0.74, 1.14 ]
Dong 2003 50 1.8 (0.7) 25 4.7 (1.5) 10.2 % -2.90 [ -3.52, -2.28 ]
Dong 2003 50 2.2 (0.6) 25 4.7 (1.5) 10.4 % -2.50 [ -3.11, -1.89 ]
Ji 2010 15 2.3 (1.22) 8 4.56 (1.13) 3.9 % -2.26 [ -3.26, -1.26 ]
Ji 2010 15 3.12 (1.36) 7 4.56 (1.13) 3.3 % -1.44 [ -2.52, -0.36 ]
Sen 2010 59 2.28 (0.58) 59 2.62 (0.82) 59.3 % -0.34 [ -0.60, -0.08 ]
Total (95% CI) 279 154 100.0 % -0.91 [ -1.10, -0.71 ]
Heterogeneity: Chi2 = 101.86, df = 7 (P<0.00001); I2 =93%
Test for overall effect: Z = 8.99 (P < 0.00001)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours NSAID Favours control
97Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.9. Comparison 1 NSAID versus control, Outcome 9 Pain (9 to 24 hours) sensitivity analysis.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 9 Pain (9 to 24 hours) sensitivity analysis
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Abdulla 2012 30 0.7 (0.7) 10 1.1 (1) 6.4 % -0.40 [ -1.07, 0.27 ]
Abdulla 2012 30 1.3 (0.9) 10 1.1 (1) 5.9 % 0.20 [ -0.50, 0.90 ]
Abdulla 2012 30 1.5 (1.2) 10 1.1 (1) 5.0 % 0.40 [ -0.35, 1.15 ]
Dong 2003 50 1.7 (0.8) 25 4.2 (1.2) 10.6 % -2.50 [ -3.02, -1.98 ]
Dong 2003 50 2.5 (0.4) 25 4.2 (1.2) 12.3 % -1.70 [ -2.18, -1.22 ]
Ji 2010 15 1.31 (0.99) 7 2.2 (1.47) 2.0 % -0.89 [ -2.09, 0.31 ]
Ji 2010 15 1.22 (0.8) 8 2.2 (1.47) 2.4 % -0.98 [ -2.08, 0.12 ]
Sen 2010 59 1.01 (0.6) 59 1 (0.66) 55.4 % 0.01 [ -0.22, 0.24 ]
Total (95% CI) 279 154 100.0 % -0.50 [ -0.67, -0.33 ]
Heterogeneity: Chi2 = 110.35, df = 7 (P<0.00001); I2 =94%
Test for overall effect: Z = 5.82 (P < 0.00001)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours NSAID Favours control
98Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.10. Comparison 1 NSAID versus control, Outcome 10 Pain (4 to 8 hours) stratified by drug.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 10 Pain (4 to 8 hours) stratified by drug
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
1 Celecoxib
Mebazaa 2008 25 2.65 (9.41) 13 3.68 (8.67) 0.1 % -1.03 [ -7.01, 4.95 ]
Subtotal (95% CI) 25 13 0.1 % -1.03 [ -7.01, 4.95 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.34 (P = 0.74)
2 Diclofenac
Wilson 1994 26 1.6 (9.41) 23 4.1 (8.67) 0.1 % -2.50 [ -7.56, 2.56 ]
Subtotal (95% CI) 26 23 0.1 % -2.50 [ -7.56, 2.56 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.97 (P = 0.33)
3 Etofenomate
Sen 2010 59 2.28 (0.58) 59 2.62 (0.82) 52.8 % -0.34 [ -0.60, -0.08 ]
Subtotal (95% CI) 59 59 52.8 % -0.34 [ -0.60, -0.08 ]
Heterogeneity: not applicable
Test for overall effect: Z = 2.60 (P = 0.0093)
4 Flurbiprofen
Ji 2010 15 2.3 (1.22) 8 4.56 (1.13) 3.5 % -2.26 [ -3.26, -1.26 ]
Subtotal (95% CI) 15 8 3.5 % -2.26 [ -3.26, -1.26 ]
Heterogeneity: not applicable
Test for overall effect: Z = 4.44 (P < 0.00001)
5 Lornoxicam
Dong 2003 50 1.8 (0.7) 25 4.7 (1.5) 9.0 % -2.90 [ -3.52, -2.28 ]
Dong 2003 50 2.2 (0.6) 25 4.7 (1.5) 9.3 % -2.50 [ -3.11, -1.89 ]
Subtotal (95% CI) 100 50 18.3 % -2.70 [ -3.13, -2.26 ]
Heterogeneity: Chi2 = 0.81, df = 1 (P = 0.37); I2 =0.0%
Test for overall effect: Z = 12.16 (P < 0.00001)
6 Metamizol
Abdulla 2012 30 2.4 (1) 10 2.2 (1.4) 3.9 % 0.20 [ -0.74, 1.14 ]
Subtotal (95% CI) 30 10 3.9 % 0.20 [ -0.74, 1.14 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.42 (P = 0.68)
7 Paracetamol
-4 -2 0 2 4
Favours NSAID Favours control
(Continued . . . )
99Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Abdulla 2012 30 2.1 (1.1) 10 2.2 (1.4) 3.8 % -0.10 [ -1.05, 0.85 ]
Chung 2004 33 3.68 (9.41) 36 3.68 (8.67) 0.2 % 0.0 [ -4.28, 4.28 ]
Mebazaa 2008 24 3.39 (9.41) 13 3.68 (8.67) 0.1 % -0.29 [ -6.32, 5.74 ]
Subtotal (95% CI) 87 59 4.1 % -0.10 [ -1.02, 0.82 ]
Heterogeneity: Chi2 = 0.01, df = 2 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 0.21 (P = 0.83)
8 Parecoxib
Abdulla 2012 30 1.8 (1.2) 10 2.2 (1.4) 3.7 % -0.40 [ -1.37, 0.57 ]
Akaraviputh 2009 40 2.9 (9.41) 30 3.3 (8.67) 0.2 % -0.40 [ -4.66, 3.86 ]
Ji 2010 15 3.12 (1.36) 7 4.56 (1.13) 3.0 % -1.44 [ -2.52, -0.36 ]
Joshi 2004 119 2.1 (2.23) 104 2.8 (2.23) 10.1 % -0.70 [ -1.29, -0.11 ]
Subtotal (95% CI) 204 151 16.9 % -0.76 [ -1.21, -0.31 ]
Heterogeneity: Chi2 = 2.11, df = 3 (P = 0.55); I2 =0.0%
Test for overall effect: Z = 3.29 (P = 0.0010)
9 Tenoxicam
Munro 1998 19 1.7 (9.41) 18 2.5 (8.67) 0.1 % -0.80 [ -6.63, 5.03 ]
Yeh 2004 21 3.04 (9.41) 22 3.2 (8.67) 0.1 % -0.16 [ -5.58, 5.26 ]
Subtotal (95% CI) 40 40 0.2 % -0.46 [ -4.42, 3.51 ]
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.87); I2 =0.0%
Test for overall effect: Z = 0.23 (P = 0.82)
Total (95% CI) 586 413 100.0 % -0.88 [ -1.07, -0.70 ]
Heterogeneity: Chi2 = 103.00, df = 15 (P<0.00001); I2 =85%
Test for overall effect: Z = 9.29 (P < 0.00001)
Test for subgroup differences: Chi2 = 100.05, df = 8 (P = 0.0), I2 =92%
-4 -2 0 2 4
Favours NSAID Favours control
100Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.11. Comparison 1 NSAID versus control, Outcome 11 Pain (4 to 8 hours) stratified by time.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 11 Pain (4 to 8 hours) stratified by time
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
1 Before
Mebazaa 2008 25 2.65 (9.41) 13 3.68 (8.67) 0.1 % -1.03 [ -7.01, 4.95 ]
Mebazaa 2008 24 3.39 (9.41) 13 3.68 (8.67) 0.1 % -0.29 [ -6.32, 5.74 ]
Sen 2010 59 2.28 (0.58) 59 2.62 (0.82) 52.8 % -0.34 [ -0.60, -0.08 ]
Wilson 1994 26 1.6 (9.41) 23 4.1 (8.67) 0.1 % -2.50 [ -7.56, 2.56 ]
Yeh 2004 21 3.04 (9.41) 22 3.2 (8.67) 0.1 % -0.16 [ -5.58, 5.26 ]
Subtotal (95% CI) 155 130 53.2 % -0.35 [ -0.60, -0.09 ]
Heterogeneity: Chi2 = 0.75, df = 4 (P = 0.94); I2 =0.0%
Test for overall effect: Z = 2.66 (P = 0.0078)
2 During
Dong 2003 50 1.8 (0.7) 25 4.7 (1.5) 9.0 % -2.90 [ -3.52, -2.28 ]
Dong 2003 50 2.2 (0.6) 25 4.7 (1.5) 9.3 % -2.50 [ -3.11, -1.89 ]
Subtotal (95% CI) 100 50 18.3 % -2.70 [ -3.13, -2.26 ]
Heterogeneity: Chi2 = 0.81, df = 1 (P = 0.37); I2 =0.0%
Test for overall effect: Z = 12.16 (P < 0.00001)
3 After
Abdulla 2012 30 1.8 (1.2) 10 2.2 (1.4) 3.7 % -0.40 [ -1.37, 0.57 ]
Abdulla 2012 30 2.4 (1) 10 2.2 (1.4) 3.9 % 0.20 [ -0.74, 1.14 ]
Abdulla 2012 30 2.1 (1.1) 10 2.2 (1.4) 3.8 % -0.10 [ -1.05, 0.85 ]
Chung 2004 33 3.68 (9.41) 36 3.68 (8.67) 0.2 % 0.0 [ -4.28, 4.28 ]
Ji 2010 15 2.3 (1.22) 8 4.56 (1.13) 3.5 % -2.26 [ -3.26, -1.26 ]
Ji 2010 15 3.12 (1.36) 7 4.56 (1.13) 3.0 % -1.44 [ -2.52, -0.36 ]
Munro 1998 19 1.7 (9.41) 18 2.5 (8.67) 0.1 % -0.80 [ -6.63, 5.03 ]
Subtotal (95% CI) 172 99 18.2 % -0.73 [ -1.17, -0.29 ]
Heterogeneity: Chi2 = 16.70, df = 6 (P = 0.01); I2 =64%
Test for overall effect: Z = 3.28 (P = 0.0010)
4 Before and after
Akaraviputh 2009 40 2.9 (9.41) 30 3.3 (8.67) 0.2 % -0.40 [ -4.66, 3.86 ]
-4 -2 0 2 4
Favours NSAID Favours control
(Continued . . . )
101Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Joshi 2004 119 2.1 (2.23) 104 2.8 (2.23) 10.1 % -0.70 [ -1.29, -0.11 ]
Subtotal (95% CI) 159 134 10.3 % -0.69 [ -1.28, -0.11 ]
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 2.34 (P = 0.019)
Total (95% CI) 586 413 100.0 % -0.88 [ -1.07, -0.70 ]
Heterogeneity: Chi2 = 103.00, df = 15 (P<0.00001); I2 =85%
Test for overall effect: Z = 9.29 (P < 0.00001)
Test for subgroup differences: Chi2 = 84.72, df = 3 (P = 0.00), I2 =96%
-4 -2 0 2 4
Favours NSAID Favours control
Analysis 1.12. Comparison 1 NSAID versus control, Outcome 12 Pain (9 to 24 hours) stratified by drug.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 12 Pain (9 to 24 hours) stratified by drug
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
1 Celecoxib
Mebazaa 2008 25 2.21 (8.79) 13 2.58 (7.05) 0.1 % -0.37 [ -5.52, 4.78 ]
Subtotal (95% CI) 25 13 0.1 % -0.37 [ -5.52, 4.78 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.14 (P = 0.89)
2 Diclofenac
Wilson 1994 26 2.6 (8.79) 23 2.1 (7.05) 0.1 % 0.50 [ -3.94, 4.94 ]
Subtotal (95% CI) 26 23 0.1 % 0.50 [ -3.94, 4.94 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.22 (P = 0.83)
3 Etofenomate
-4 -2 0 2 4
Favours NSAID Favours control
(Continued . . . )
102Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Sen 2010 59 1.01 (0.6) 59 1 (0.66) 54.9 % 0.01 [ -0.22, 0.24 ]
Subtotal (95% CI) 59 59 54.9 % 0.01 [ -0.22, 0.24 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.09 (P = 0.93)
4 Flurbiprofen
Ji 2010 15 1.22 (0.8) 8 2.2 (1.47) 2.4 % -0.98 [ -2.08, 0.12 ]
Subtotal (95% CI) 15 8 2.4 % -0.98 [ -2.08, 0.12 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.75 (P = 0.080)
5 Lornoxicam
Dong 2003 50 2.5 (0.4) 25 4.2 (1.2) 12.2 % -1.70 [ -2.18, -1.22 ]
Dong 2003 50 1.7 (0.8) 25 4.2 (1.2) 10.5 % -2.50 [ -3.02, -1.98 ]
Subtotal (95% CI) 100 50 22.7 % -2.07 [ -2.42, -1.72 ]
Heterogeneity: Chi2 = 4.88, df = 1 (P = 0.03); I2 =79%
Test for overall effect: Z = 11.46 (P < 0.00001)
6 Metamizol
Abdulla 2012 30 1.5 (1.2) 10 1.1 (1) 5.0 % 0.40 [ -0.35, 1.15 ]
Subtotal (95% CI) 30 10 5.0 % 0.40 [ -0.35, 1.15 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.04 (P = 0.30)
7 Paracetamol
Abdulla 2012 30 1.3 (0.9) 10 1.1 (1) 5.8 % 0.20 [ -0.50, 0.90 ]
Mebazaa 2008 24 3.46 (8.79) 13 2.58 (7.05) 0.1 % 0.88 [ -4.32, 6.08 ]
Subtotal (95% CI) 54 23 5.9 % 0.21 [ -0.48, 0.90 ]
Heterogeneity: Chi2 = 0.06, df = 1 (P = 0.80); I2 =0.0%
Test for overall effect: Z = 0.60 (P = 0.55)
8 Parecoxib
Abdulla 2012 30 0.7 (0.7) 10 1.1 (1) 6.4 % -0.40 [ -1.07, 0.27 ]
Akaraviputh 2009 40 0.81 (8.79) 30 0.72 (7.05) 0.2 % 0.09 [ -3.62, 3.80 ]
Ji 2010 15 1.31 (0.99) 7 2.2 (1.47) 2.0 % -0.89 [ -2.09, 0.31 ]
Subtotal (95% CI) 85 47 8.6 % -0.50 [ -1.08, 0.08 ]
Heterogeneity: Chi2 = 0.59, df = 2 (P = 0.74); I2 =0.0%
Test for overall effect: Z = 1.70 (P = 0.088)
9 Tenoxicam
Munro 1998 19 1.5 (8.79) 18 2.5 (7.05) 0.1 % -1.00 [ -6.12, 4.12 ]
Yeh 2004 21 2.63 (8.79) 22 2.89 (7.05) 0.1 % -0.26 [ -5.04, 4.52 ]
Subtotal (95% CI) 40 40 0.2 % -0.60 [ -4.10, 2.89 ]
Heterogeneity: Chi2 = 0.04, df = 1 (P = 0.84); I2 =0.0%
-4 -2 0 2 4
Favours NSAID Favours control
(Continued . . . )
103Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Test for overall effect: Z = 0.34 (P = 0.73)
Total (95% CI) 434 273 100.0 % -0.50 [ -0.67, -0.33 ]
Heterogeneity: Chi2 = 110.96, df = 13 (P<0.00001); I2 =88%
Test for overall effect: Z = 5.80 (P < 0.00001)
Test for subgroup differences: Chi2 = 105.39, df = 8 (P = 0.00), I2 =92%
-4 -2 0 2 4
Favours NSAID Favours control
Analysis 1.13. Comparison 1 NSAID versus control, Outcome 13 Pain (9 to 24 hours) stratified by time.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 1 NSAID versus control
Outcome: 13 Pain (9 to 24 hours) stratified by time
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
1 Before
Mebazaa 2008 25 2.21 (8.79) 13 2.58 (7.05) 0.1 % -0.37 [ -5.52, 4.78 ]
Mebazaa 2008 24 3.46 (8.79) 13 2.58 (7.05) 0.1 % 0.88 [ -4.32, 6.08 ]
Sen 2010 59 1.01 (0.6) 59 1 (0.66) 54.9 % 0.01 [ -0.22, 0.24 ]
Wilson 1994 26 2.6 (8.79) 23 2.1 (7.05) 0.1 % 0.50 [ -3.94, 4.94 ]
Yeh 2004 21 2.63 (8.79) 22 2.89 (7.05) 0.1 % -0.26 [ -5.04, 4.52 ]
Subtotal (95% CI) 155 130 55.4 % 0.01 [ -0.22, 0.24 ]
Heterogeneity: Chi2 = 0.19, df = 4 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 0.10 (P = 0.92)
2 During
Dong 2003 50 2.5 (0.4) 25 4.2 (1.2) 12.2 % -1.70 [ -2.18, -1.22 ]
Dong 2003 50 1.7 (0.8) 25 4.2 (1.2) 10.5 % -2.50 [ -3.02, -1.98 ]
-4 -2 0 2 4
Favours NSAID Favours control
(Continued . . . )
104Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)
Study or subgroup NSAID ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Subtotal (95% CI) 100 50 22.7 % -2.07 [ -2.42, -1.72 ]
Heterogeneity: Chi2 = 4.88, df = 1 (P = 0.03); I2 =79%
Test for overall effect: Z = 11.46 (P < 0.00001)
3 After
Abdulla 2012 30 1.5 (1.2) 10 1.1 (1) 5.0 % 0.40 [ -0.35, 1.15 ]
Abdulla 2012 30 1.3 (0.9) 10 1.1 (1) 5.8 % 0.20 [ -0.50, 0.90 ]
Abdulla 2012 30 0.7 (0.7) 10 1.1 (1) 6.4 % -0.40 [ -1.07, 0.27 ]
Ji 2010 15 1.31 (0.99) 7 2.2 (1.47) 2.0 % -0.89 [ -2.09, 0.31 ]
Ji 2010 15 1.22 (0.8) 8 2.2 (1.47) 2.4 % -0.98 [ -2.08, 0.12 ]
Munro 1998 19 1.5 (8.79) 18 2.5 (7.05) 0.1 % -1.00 [ -6.12, 4.12 ]
Subtotal (95% CI) 139 63 21.7 % -0.16 [ -0.53, 0.20 ]
Heterogeneity: Chi2 = 7.31, df = 5 (P = 0.20); I2 =32%
Test for overall effect: Z = 0.89 (P = 0.37)
4 Before and after
Akaraviputh 2009 40 0.81 (8.79) 30 0.72 (7.05) 0.2 % 0.09 [ -3.62, 3.80 ]
Subtotal (95% CI) 40 30 0.2 % 0.09 [ -3.62, 3.80 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.05 (P = 0.96)
Total (95% CI) 434 273 100.0 % -0.50 [ -0.67, -0.33 ]
Heterogeneity: Chi2 = 110.96, df = 13 (P<0.00001); I2 =88%
Test for overall effect: Z = 5.80 (P < 0.00001)
Test for subgroup differences: Chi2 = 98.59, df = 3 (P = 0.00), I2 =97%
-4 -2 0 2 4
Favours NSAID Favours control
105Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.1. Comparison 2 Opioid versus control, Outcome 1 Pain (4 to 8 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 2 Opioid versus control
Outcome: 1 Pain (4 to 8 hours)
Study or subgroup Opioid ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Pandey 2004 153 2.97 (2.35) 153 5.53 (2.22) 97.6 % -2.56 [ -3.07, -2.05 ]
Zajaczkowska 2004 30 3.23 (9.41) 30 3.15 (8.67) 1.2 % 0.08 [ -4.50, 4.66 ]
Zhu 2011 30 2.61 (9.41) 29 4 (8.67) 1.2 % -1.39 [ -6.00, 3.22 ]
Total (95% CI) 213 212 100.0 % -2.51 [ -3.02, -2.01 ]
Heterogeneity: Chi2 = 1.49, df = 2 (P = 0.47); I2 =0.0%
Test for overall effect: Z = 9.74 (P < 0.00001)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours opioid Favours control
106Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.2. Comparison 2 Opioid versus control, Outcome 2 Pain (9 to 24 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 2 Opioid versus control
Outcome: 2 Pain (9 to 24 hours)
Study or subgroup Opioid ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Pandey 2004 153 0.87 (0.5) 153 1.19 (0.56) 99.8 % -0.32 [ -0.44, -0.20 ]
Zajaczkowska 2004 30 2.44 (8.79) 30 2.76 (7.05) 0.1 % -0.32 [ -4.35, 3.71 ]
Zhu 2011 30 2.33 (8.79) 29 3.17 (7.05) 0.1 % -0.84 [ -4.90, 3.22 ]
Total (95% CI) 213 212 100.0 % -0.32 [ -0.44, -0.20 ]
Heterogeneity: Chi2 = 0.06, df = 2 (P = 0.97); I2 =0.0%
Test for overall effect: Z = 5.28 (P < 0.00001)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours opioid Favours control
Analysis 2.3. Comparison 2 Opioid versus control, Outcome 3 Pain (4 to 8 hours) (sensitivity analysis).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 2 Opioid versus control
Outcome: 3 Pain (4 to 8 hours) (sensitivity analysis)
Study or subgroup Opioid ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Pandey 2004 153 2.97 (2.35) 153 5.53 (2.22) 100.0 % -2.56 [ -3.07, -2.05 ]
Total (95% CI) 153 153 100.0 % -2.56 [ -3.07, -2.05 ]
Heterogeneity: not applicable
Test for overall effect: Z = 9.80 (P < 0.00001)
Test for subgroup differences: Not applicable
-2 -1 0 1 2
Favours opioid Favours control
107Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.4. Comparison 2 Opioid versus control, Outcome 4 Pain (9 to 24 hours) (sensitivity analysis).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 2 Opioid versus control
Outcome: 4 Pain (9 to 24 hours) (sensitivity analysis)
Study or subgroup Opioid ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Pandey 2004 153 0.87 (0.5) 153 1.19 (0.56) 100.0 % -0.32 [ -0.44, -0.20 ]
Total (95% CI) 153 153 100.0 % -0.32 [ -0.44, -0.20 ]
Heterogeneity: not applicable
Test for overall effect: Z = 5.27 (P < 0.00001)
Test for subgroup differences: Not applicable
-0.5 -0.25 0 0.25 0.5
Favours opioid Favours control
Analysis 3.1. Comparison 3 Anticonvulsant analgesic versus control, Outcome 1 Morbidity.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 3 Anticonvulsant analgesic versus control
Outcome: 1 Morbidity
Study or subgroup Anticonvulsant Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Gilron 2009 3/25 1/25 3.00 [ 0.33, 26.92 ]
0.05 0.2 1 5 20
Favours anticonvulsant Favours control
108Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.2. Comparison 3 Anticonvulsant analgesic versus control, Outcome 2 Pain (4 to 8 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 3 Anticonvulsant analgesic versus control
Outcome: 2 Pain (4 to 8 hours)
Study or subgroup Anticonvulsant ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Agarwal 2008 27 3 (1.87) 29 4 (1.87) 19.0 % -1.00 [ -1.98, -0.02 ]
Pandey 2004 153 2.65 (3) 153 5.53 (0.22) 80.4 % -2.88 [ -3.36, -2.40 ]
Sarakatsianou 2013 20 1.5 (9.41) 20 4 (8.67) 0.6 % -2.50 [ -8.11, 3.11 ]
Total (95% CI) 200 202 100.0 % -2.52 [ -2.95, -2.09 ]
Heterogeneity: Chi2 = 11.43, df = 2 (P = 0.003); I2 =83%
Test for overall effect: Z = 11.56 (P < 0.00001)
Test for subgroup differences: Not applicable
-10 -5 0 5 10
Favours anticonvulsant Favours control
109Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.3. Comparison 3 Anticonvulsant analgesic versus control, Outcome 3 Pain (9 to 24 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 3 Anticonvulsant analgesic versus control
Outcome: 3 Pain (9 to 24 hours)
Study or subgroup Anticonvulsant ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Agarwal 2008 27 2 (1.87) 29 3 (1.87) 1.8 % -1.00 [ -1.98, -0.02 ]
Pandey 2004 153 0.65 (0.61) 153 1.19 (0.56) 98.2 % -0.54 [ -0.67, -0.41 ]
Sarakatsianou 2013 20 1 (8.79) 20 3 (7.05) 0.1 % -2.00 [ -6.94, 2.94 ]
Total (95% CI) 200 202 100.0 % -0.55 [ -0.68, -0.42 ]
Heterogeneity: Chi2 = 1.16, df = 2 (P = 0.56); I2 =0.0%
Test for overall effect: Z = 8.28 (P < 0.00001)
Test for subgroup differences: Not applicable
-10 -5 0 5 10
Favours anticonvulsant Favours control
110Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.4. Comparison 3 Anticonvulsant analgesic versus control, Outcome 4 Morbidity (sensitivity
analysis).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 3 Anticonvulsant analgesic versus control
Outcome: 4 Morbidity (sensitivity analysis)
Study or subgroup Anticonvulsant Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Best-best
Gilron 2009 3/29 1/30 3.10 [ 0.34, 28.15 ]
2 Best-worst
Gilron 2009 3/29 6/30 0.52 [ 0.14, 1.88 ]
3 Worst-best
Gilron 2009 7/29 1/30 7.24 [ 0.95, 55.26 ]
4 Worst-worst
Gilron 2009 7/29 6/30 1.21 [ 0.46, 3.16 ]
0.02 0.1 1 10 50
Favours anticonvulsant Favours control
Analysis 3.5. Comparison 3 Anticonvulsant analgesic versus control, Outcome 5 Pain (4 to 8 hours)
sensitivity analysis.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 3 Anticonvulsant analgesic versus control
Outcome: 5 Pain (4 to 8 hours) sensitivity analysis
Study or subgroup Anticonvulsant ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Pandey 2004 153 2.65 (3) 153 5.53 (0.22) 100.0 % -2.88 [ -3.36, -2.40 ]
Total (95% CI) 153 153 100.0 % -2.88 [ -3.36, -2.40 ]
Heterogeneity: not applicable
Test for overall effect: Z = 11.84 (P < 0.00001)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours anticonvulsant Favours control
111Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.6. Comparison 3 Anticonvulsant analgesic versus control, Outcome 6 Pain (9 to 24 hours)
sensitivity analysis.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 3 Anticonvulsant analgesic versus control
Outcome: 6 Pain (9 to 24 hours) sensitivity analysis
Study or subgroup Anticonvulsant ControlMean
Difference WeightMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Pandey 2004 153 0.65 (0.61) 153 1.19 (0.56) 100.0 % -0.54 [ -0.67, -0.41 ]
Total (95% CI) 153 153 100.0 % -0.54 [ -0.67, -0.41 ]
Heterogeneity: not applicable
Test for overall effect: Z = 8.07 (P < 0.00001)
Test for subgroup differences: Not applicable
-4 -2 0 2 4
Favours anticonvulsant Favours control
Analysis 4.1. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 1 Morbidity.
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 4 Anticonvulsant analgesic versus NSAID
Outcome: 1 Morbidity
Study or subgroup Anticonvulsant Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Gilron 2009 2/25 1/27 2.16 [ 0.21, 22.38 ]
0.05 0.2 1 5 20
Favours anticonvulsant Favours control
112Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.2. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 2 Pain (4 to 8 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 4 Anticonvulsant analgesic versus NSAID
Outcome: 2 Pain (4 to 8 hours)
Study or subgroupAnticonvulsant
analgesic NSAIDMean
DifferenceMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Akarsu 2012 30 1.8 (0.5) 30 4.3 (0.8) -2.50 [ -2.84, -2.16 ]
-2 -1 0 1 2
Favours anticonvulsant Favours NSAID
Analysis 4.3. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 3 Pain (9 to 24 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 4 Anticonvulsant analgesic versus NSAID
Outcome: 3 Pain (9 to 24 hours)
Study or subgroupAnticonvulsant
analgesic NSAIDMean
DifferenceMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Akarsu 2012 30 1.6 (0.5) 30 2.1 (0.8) -0.50 [ -0.84, -0.16 ]
-0.5 -0.25 0 0.25 0.5
Favours anticonvulsant Favours NSAID
113Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.4. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 4 Morbidity (sensitivity
analysis).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 4 Anticonvulsant analgesic versus NSAID
Outcome: 4 Morbidity (sensitivity analysis)
Study or subgroupAnticonvulsant
analgesic NSAID Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Best-best
Gilron 2009 2/30 1/30 7.1 % 2.00 [ 0.19, 20.90 ]
Subtotal (95% CI) 30 30 7.1 % 2.00 [ 0.19, 20.90 ]
Total events: 2 (Anticonvulsant analgesic), 1 (NSAID)
Heterogeneity: not applicable
Test for overall effect: Z = 0.58 (P = 0.56)
2 Best-worst
Gilron 2009 2/30 6/30 42.9 % 0.33 [ 0.07, 1.52 ]
Subtotal (95% CI) 30 30 42.9 % 0.33 [ 0.07, 1.52 ]
Total events: 2 (Anticonvulsant analgesic), 6 (NSAID)
Heterogeneity: not applicable
Test for overall effect: Z = 1.42 (P = 0.16)
3 Worst-best
Gilron 2009 5/30 1/30 7.1 % 5.00 [ 0.62, 40.28 ]
Subtotal (95% CI) 30 30 7.1 % 5.00 [ 0.62, 40.28 ]
Total events: 5 (Anticonvulsant analgesic), 1 (NSAID)
Heterogeneity: not applicable
Test for overall effect: Z = 1.51 (P = 0.13)
4 Worst-worst
Gilron 2009 5/30 6/30 42.9 % 0.83 [ 0.28, 2.44 ]
Subtotal (95% CI) 30 30 42.9 % 0.83 [ 0.28, 2.44 ]
Total events: 5 (Anticonvulsant analgesic), 6 (NSAID)
Heterogeneity: not applicable
Test for overall effect: Z = 0.33 (P = 0.74)
Total (95% CI) 120 120 100.0 % 1.00 [ 0.50, 2.01 ]
Total events: 14 (Anticonvulsant analgesic), 14 (NSAID)
Heterogeneity: Chi2 = 4.74, df = 3 (P = 0.19); I2 =37%
Test for overall effect: Z = 0.0 (P = 1.0)
Test for subgroup differences: Chi2 = 4.70, df = 3 (P = 0.20), I2 =36%
0.02 0.1 1 10 50
Favours anticonvulsant Favours NSAID
114Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 5.1. Comparison 5 Anticonvulsant analgesic versus opioid, Outcome 1 Pain (4 to 8 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 5 Anticonvulsant analgesic versus opioid
Outcome: 1 Pain (4 to 8 hours)
Study or subgroupAnticonvulsant
analgesic NSAIDMean
DifferenceMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Pandey 2004 153 2.65 (3) 153 2.97 (2.35) -0.32 [ -0.92, 0.28 ]
-1 -0.5 0 0.5 1
Favours anticonvulsant Favours NSAID
Analysis 5.2. Comparison 5 Anticonvulsant analgesic versus opioid, Outcome 2 Pain (9 to 24 hours).
Review: Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
Comparison: 5 Anticonvulsant analgesic versus opioid
Outcome: 2 Pain (9 to 24 hours)
Study or subgroupAnticonvulsant
analgesic NSAIDMean
DifferenceMean
Difference
NMean(SD)[cm
VAS] NMean(SD)[cm
VAS] IV,Fixed,95% CI IV,Fixed,95% CI
Pandey 2004 153 0.65 (0.61) 153 0.87 (0.5) -0.22 [ -0.34, -0.10 ]
-0.2 -0.1 0 0.1 0.2
Favours anticonvulsant Favours NSAID
115Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A P P E N D I C E S
Appendix 1. Search strategies for identification of studies
Database Period of search Search strategy
Cochrane Central Register of Controlled
Trials (CENTRAL) (Wiley)
Issue 3 of 12, 2013. #1 laparoscop* OR coelioscop* OR celioscop* OR peritoneo-
scop*
#2 cholecystectom*
#3 MeSH descriptor Cholecystectomy, Laparoscopic explode
all trees
#4 (( #1 AND #2) OR #3)
#5 MeSH descriptor Pain explode all trees
#6 MeSH descriptor Anesthetics, Local explode all trees
#7 Intraperitoneal morphine OR intraperitoneal meperidine
OR NSAID OR Ketorolac OR diclofenac OR Indomethacine
OR Paracetamolo OR tenoxicam OR parecoxib OR valecoxib
intraperitoneal bupivacaine OR thoracic epidural analgesia OR
opioids analgesia OR preemptive gabapentin OR clonidine OR
ketamine OR esmolol
#8 (#4 OR #5 OR #6 )
#9 pain OR ache* OR suffering*
#10 (#8 OR #9)
#11 (#4 AND #5 AND #6 AND #10)
MEDLINE (PubMed) 1987 to March 2013. laparoscop* OR coelioscop* OR celioscop* OR peritoneo-
scop*) AND (cholecystectom* OR “cholecystectomy, laparo-
scopic”[MeSH]) AND (Analgesia OR bupivacain* OR buva-
caina OR sensorcaine OR marcain* OR svedocain* OR lev-
obupivacaine OR ropivacaine OR Ketorolac OR diclofenac OR
Indomethacine OR Paracetamolo OR tenoxicam OR parecoxib
OR valecoxib OR ntraperitoneal morphine OR intraperitoneal
meperidine OR intraperitoneal bupivacaine OR thoracic epidu-
ral analgesia OR opioids analgesia OR preemptive gabapentin
OR clonidine OR ketamine OR esmolol AND (“Pain”[Mesh]
OR pain OR ache* OR suffering*) AND (((randomized con-
trolled trial [pt] OR controlled clinical trial [pt] OR randomized
controlled trials [mh] OR random allocation [mh] OR double-
blind method [mh] OR single-blind method [mh] OR clinical
trial [pt] OR clinical trials [mh] OR (“clinical trial” [tw]) OR
((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw])
AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR
placebo* [tw] OR random* [tw] OR research design [mh:no-
exp]) NOT (animals [mh] NOT human [mh]))))
EMBASE (OvidSP) 1987 to March 2013. 1. exp crossover-procedure/ or exp double-blind procedure/ or
exp randomized controlled trial/ or single-blind procedure/
2. (((((random* or factorial* or crossover* or cross over* or cross-
over* or placebo* or double*) adj blind*) or single*) adj blind*)
or assign* or allocat* or volunteer*).af
116Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
3. 1 or 2
4. (laparoscop* or coelioscop* or celioscop*OR peritoneoscop*)
.af
5. exp laparoscopic surgery/
6. 4 or 5
7. cholecystectom*.af.
8. exp cholecystectomy/
9. 7 or 8
10. (analgesia or ketorolac or diclofenac or indomethacin or
paracetamol or tenoxicam or parecoxib or valdecoxib or mor-
phine or meperidine or opioid or opiate).af
11. exp analgesia/
12. 10 or 11
13. (pain or ache* or suffering*).af.
14. exp pain/
15. 13 or 14
16. 3 and 6 and 9 and 12 and 15
Science Citation Index Expanded (Web of
Knowledge)
1987 to March 2013. #1 TS=(laparoscop* OR coelioscop* OR celioscop* OR peri-
toneoscop*)
#2 TS=(cholecystectom*)
#3 TS=(pain OR ache* OR suffering* OR Preemptive analgesia
OR pain control OR Multimodal analgesia)
#4 TS=(NSAID OR Ketorolac OR diclofenac OR In-
domethacine OR Paracetamolo OR tenoxicam OR parecoxib
OR valecoxib OR intraperitoneal morphine OR intraperitoneal
meperidine OR intraperitoneal bupivacaine OR thoracic epidu-
ral analgesia OR opioids analgesia OR preemptive gabapentin
OR clonidine OR ketamine OR esmolol)
#5 #3 OR #4
#6 #5 AND #4 AND #3 AND #2 AND #1
C O N T R I B U T I O N S O F A U T H O R S
KS Gurusamy performed the analysis, interpreted the information, and wrote the review.
J Vaughan and C Toon independently assessed the trials for inclusion and extracted data on included trials.
BR Davidson critically commented on the review.
All authors agreed on the final version of the review.
117Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D E C L A R A T I O N S O F I N T E R E S T
None known.
S O U R C E S O F S U P P O R T
Internal sources
• None, Other.
External sources
• None, Other.
D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
1. The outcomes have been revised based on importance to the participants and not according to the expected treatment effect. As
a result, pain was moved to a secondary outcome as mortality was considered more important than pain. With regards to quality of
life, we accepted only validated scales of quality of life such as Euro-QoL, SF-36 since using unvalidated other scales may be
misleading. With regards to pain, we limited pain to 4 to 8 hours and 9 to 24 hours since this is the time period that most people are
discharged. We also included only trials that reported pain on the visual analogue scale. Even this is difficult to interpret (see
Discussion) but using other scales would make it even more difficult to interpret. We added other outcomes such as return to normal
activity and return to work, which are very important to the patient. We have excluded analgesic requirement, which was considered a
surrogate to pain. Any clinically significant differences in pain would be captured by quality of life, return to normal activity, and
return to work. By altering the outcomes, we have harmonised the outcomes in this review with other reviews aimed at decreasing
pain in people undergoing laparoscopic cholecystectomy.
2. We have added a section on trial sequential analysis to control for random errors.
3. We have restricted the comparisons to six main comparisons to ensure that the review is readable.
N O T E S
Change in review’s author team. It is as follows: Kurinchi Selvan Gurusamy, Jessica Vaughan, Clare D Toon, Brian R Davidson.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Ambulatory Surgical Procedures; Analgesics [∗therapeutic use]; Analgesics, Opioid [therapeutic use]; Anti-Inflammatory Agents, Non-
Steroidal [therapeutic use]; Anticonvulsants [therapeutic use]; Cholecystectomy, Laparoscopic [∗adverse effects]; Elective Surgical Pro-
cedures; Length of Stay; Pain Measurement [methods]; Pain, Postoperative [etiology; ∗prevention & control]; Randomized Controlled
Trials as Topic; Time Factors
118Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
MeSH check words
Humans
119Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy
(Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.