Gaba colecistectomia cochrane 2014

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
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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)

[Intervention Review]
Pharmacological interventions for prevention or treatment of
postoperative pain in people undergoing laparoscopic
cholecystectomy
Kurinchi Selvan Gurusamy1, Jessica Vaughan1, Clare D Toon2, Brian R Davidson1
1
Department of Surgery, Royal Free Campus, UCL Medical School, London, UK. 2
Public 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. k.gurusamy@ucl.ac.uk.
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.
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)

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.
Participantswere allowedtotake additional analgesics as requiredin 24of 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
(Review)

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.
(Review)

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
2.2 cm VAS
0.5 lower
(0.67 to 0.33 lower)
- 707
(9 studies)
⊕
very low1,4
4Pharmacologicalinterventionsforpreventionortreatmentofpostoperativepaininpeopleundergoinglaparoscopiccholecystectomy
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Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.

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
4.00 cm VAS
2.51 lower
(3.02 to 2.01 lower)
- 425
(3 studies)
⊕⊕
low1
2.76 cm VAS
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
(13 to 1000)
RR 3
(0.33 to 26.92)
50
(1 study)
⊕
very low1,2
4 cm VAS
2.52 lower
(2.95 to 2.09 lower)
- 402
(3 studies)
⊕
very low1,4
3 cm VAS
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
(Review)

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
(8 to 829)
RR 2.16
(0.21 to 22.38)
52
(1 study)
⊕
very low1,2
4.3 cm VAS
2.5 lower
(2.84 to 2.16 lower)
- 60
(1 study)
⊕
very low1,3
2.1 cm VAS
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
2.97 VAS
0.32 lower
(0.92 lower to 0.28 higher)
- 306
(1 study)
⊕
very low1,3
0.87 VAS
0.22 lower
(0.34 to 0.1 lower)
- 306
(1 study)
⊕
very low1,3
(Review)

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).
(Review)

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 (Kehlet2005).
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
(Review)

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 excludedquasi-randomisedtrials(where the methodof 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-
gesicsbyintraperitoneal, intrathecal,orintrapleural 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 propertyto 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.
(Review)

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 Handbook
for 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.
(Review)

• 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.
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.
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 (
Newell1992). We imputed data for binary outcomes using various
scenariossuch asbest-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 Reviews
of 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.
(Review)

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 identified1238referencesthrough electronicsearchesof CEN-
TRAL (n = 274), MEDLINE (n = 269), EMBASE (n = 302), and
(Review)

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.
(Review)

Figure 1. Study ﬂow diagram.
(Review)

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; Zhu2011; 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; Sandhu2011; Zhu2011; Abdulla2012; 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,
(Review)

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.
(Review)

Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
(Review)

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%))reportedthatthe 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).
(Review)

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.
(Review)

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 analysiswasnotperformedbecause 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).
(Review)

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.
(Review)

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).
(Review)

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
(Review)

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
thatthere were nosignificantdifferencesinthe time takentoreturn
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).
Hospital stay
None of the trials reported the proportion of people discharged as
day-surgery or the length of hospital stay.
Pain
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
(Review)

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
(Review)

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
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).
(Review)

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.
(Review)

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 (123participants)reportedmortality(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).
Hospital stay
Proportion discharged as day-surgery
day surgery or the length of hospital stay.
Pain
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.
(Review)

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.
(Review)

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).
(Review)

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.
(Review)

Return to work
Subgroup analysis
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.
Hospital stay
day-surgery or the length of hospital stay.
Pain
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.
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
qualityevidence)(Analysis 4.3). Neitherthe meannorthe standard
deviation was imputed in this trial. Trial sequential analysis was
not performed because of the presence of only one trial.
(Review)

Return to work
Subgroup analysis
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-
(Review)

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 of
evidence
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 other
studies 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
(Review)

Gaba colecistectomia cochrane 2014

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