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.

http://www.cochranelibrary.com

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)


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 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.


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)


mailto:[email protected]

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


(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

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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

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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

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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

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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).

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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


(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 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.


(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 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.


(Review)


http://apps.who.int/trialsearch/

http://apps.who.int/trialsearch/

• 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 (

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.


(Review)


http://www.clinicaltrials.gov

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


(Review)


http://ims.cochrane.org/revman/gradepro



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; 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,


(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%)) 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).


(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 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).


(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

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).



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 (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).



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

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.




(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 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


(Review)


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

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Agarwal 2008 {published data only}

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Singh U. Evaluation of a single preoperative dose of

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Akaraviputh 2009 {published data only}

Akaraviputh T, Leelouhapong C, Lohsiriwat V,

Aroonpruksakul S. Efficacy of perioperative parecoxib

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Abbasoglu O, et al. The postoperative analgesic efficacy

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Balaban F, Yagar S, Ozgok A, Koc M, Gullapoglu H.

A randomized, placebo-controlled study of pregabalin

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Belzarena 1998 {published data only}

Belzarena SD. Intravenous tenoxicam for postoperative pain

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Cheng PGB, Lim MJ, Onsiong MK, Chiu KYW, Chan

MK, Li KWM, et al. Celecoxib premedication in post-

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Chung 2004 {published data only}

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Dong 2003 {published data only}

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C, et al. Preoperative administration of controlled-

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Gilron 2009 {published data only}

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randomized, double-blind, controlled trial of perioperative

administration of gabapentin, meloxicam and their

combination for spontaneous and movement-evoked pain

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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

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Horattas 2004 {published data only}

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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

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(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

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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

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(Review)


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.

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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

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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.

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Wilson 1994 {published data only}

Wilson YG, Rhodes M, Ahmed R, Daugherty M, Cawthorn

SJ, Armstrong CP. Intramuscular diclofenac sodium for

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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

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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:

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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

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Fried GM, et al. Intraoperative esmolol infusion in the

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Elhakim 2000 {published data only}

Elhakim M, Amine H, Kamel S, Saad F. Effects of

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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

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Kocaayan E, Ozkardeler S, Ozzeybek D, Bayindir S, Akan

M. Comparison of effects of preoperatively administered

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RY, Breitmeyer JB, et al. A randomized, double-blind,

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al. The interaction effect of perioperative cotreatment

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Yamazaki 2003 {published data only}

Yamazaki E, Murao K, Asai T, Matsumoto S, Shingu K.

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∗ Indicates the major publication for the study


(Review)


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”


(performance bias)

All outcomes

Low risk Quote: “Group assignment code retained until the conclu-



(Review)


Abdulla 2012 (Continued)

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk Quote: “Group assignment code retained until the conclu-


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


Participants Country: India.


Post-randomisation drop-outs: 4 (6.7%).


Mean age: 46 years.

Females: 19 (33.9%).

Inclusion criteria:


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.


Group 1: pregabalin 150 mg orally 1 h before surgery (n = 27).

Group 2: placebo 1 h before orally surgery (n = 29).


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



(Review)


Agarwal 2008 (Continued)


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.


(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”


bias)

All outcomes

Low risk Quote: “Outcomes were assessed by an independent anaes-

thesia registrar blinded to group allocation”


All outcomes

High risk Comment: There were post-randomisation drop-outs.



Akaraviputh 2009


Participants Country: Thailand.


Post-randomisation drop-outs: not stated.


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.


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.



(Review)


Akaraviputh 2009 (Continued)

Risk of bias



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.


(performance bias)

All outcomes

Unclear risk Comment: Further details were not available.


bias)

All outcomes

Low risk Quote: “The degree of postoperative pain was assessed…by

nursing staff who were unaware of the perioperative inter-

vention”


All outcomes



For-profit bias Low risk Comment: Supported by Faculty of Medicine Siriraj Hos-

pital Research Project Grant

Akarsu 2012


Participants Country: Turkey.




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.


(Review)


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.



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)


Allocation concealment (selection bias) Unclear risk Comment: This information was not available.


(performance bias)

All outcomes

High risk Quote: “Single-blind study, subjects do not know the

methodology applied. The investigator knows” (author

replies)


bias)

All outcomes

Low risk Quote: “The outcome assessors were blinded” (author

replies)


All outcomes


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






Mean age: 45 years.

Females: 27 (65.9%).

Inclusion criteria:

1. ASA status I or II.


(Review)


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.


Group 1: tramadol 100 mg IV (n = 21).

Group 2: placebo (n = 20).

Outcomes No outcomes of interest for this review were reported.


Risk of bias



bias)

Low risk Quote: “Computerised allocation schedule used”.



(performance bias)

All outcomes

Unclear risk Quote: “Coded syringes used”.



bias)

All outcomes



All outcomes




Balaban 2012







(Review)


Balaban 2012 (Continued)

Mean age: 53 years.

Females: 69 (76.7%).

Inclusion criteria:



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.


8. Duration of surgery in excess of 60 min.




Group 3: placebo orally (n = 30).



Risk of bias



bias)

Unclear risk Comment: This information was not available

Allocation concealment (selection bias) Unclear risk Quote: “Randomisation achieved sealed envelope assign-

ment”.



(performance bias)

All outcomes



bias)

All outcomes



All outcomes




(Review)


Balaban 2012 (Continued)


Belzarena 1998


Participants Country: Portugal.




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.


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).



Risk of bias



bias)

Low risk Quote: “Computer-generated table”.



(performance bias)

All outcomes

Unclear risk Quote: “Venipuncture was performed by a nurse who was

unaware of the nature of the study”.



bias)

All outcomes



(Review)


Belzarena 1998 (Continued)


All outcomes




Cheng 2004


Participants Country: China.




Mean age: 50 years.

Females: 37 (62.7%).

Inclusion criteria:

1. ASA I or II.


3. Elective laparoscopic cholecystectomy.

Exclusion criteria:

1. Chronic pain other than gallstones.


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.


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)


Risk of bias



(Review)


Cheng 2004 (Continued)


bias)


Allocation concealment (selection bias) Unclear risk Quote: “Patients were randomized into two groups by sealed

envelopes”.



(performance bias)

All outcomes



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”.



All outcomes

Low risk Comment: There was a post-randomisation drop-out but

this was unlikely to be related to the intervention



Chung 2004


Participants Country: Canada.




Mean age: 48 years.

Females: not stated.

Inclusion criteria:


2. Scheduled to undergo laparoscopic cholecystectomy.


Group 1: paracetamol (acetaminophen) 300 mg orally every 6 h for 48 h (n = 33).


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


(Review)


Chung 2004 (Continued)

report)

Attempts were made to contact the authors. Replies were received from authors in August

2013

Risk of bias



bias)

Low risk Quote: “Computer generated sequence (author replies)”.



(performance bias)

All outcomes

Low risk Quote: “Double-dummy technique, with matching

placebo used”.


bias)

All outcomes

Low risk Quote: “Outcome blinded” (author replies).


All outcomes


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


Participants Country: not stated.




Mean age: 48 years.


Inclusion criteria:



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.


(Review)


Dong 2003 (Continued)


Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes




Fanelli 2008


Participants Country: Italy.




Mean age: 57 years.


Inclusion criteria:

1. People scheduled for elective laparoscopic cholecystectomy.


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.


(Review)


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.


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)



Risk of bias



bias)

Low risk Quote: “Computer-generated random number table used”.



(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”


bias)

All outcomes

Low risk Quote: “The patient was first asked by a blind observer to

express his/her pain”


All outcomes



For-profit bias Low risk Quote: “Sources of financial support for the work: Univer-

sity of Parma”

Forse 1996







(Review)


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.


Group 1: ketorolac IM before surgery (n = 17).

Group 2: indomethacin rectally before surgery (n= 17).


Outcomes Operative complications.

Notes Reasons for post-randomisation drop-outs: not stated.


Risk of bias



bias)


Allocation concealment (selection bias) Unclear risk Quote: “Sealed numbered envelopes”.



(performance bias)

All outcomes



bias)

All outcomes



All outcomes





(Review)


Gilron 2009






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.


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)

Low risk Quote: “A concealed, computer-generated random treat-

ment allocation schedule, which randomized... three treat-


(Review)


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)”


(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”


bias)

All outcomes



All outcomes



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


Participants Country: Mexico.




Mean age: 30 years.

Females: not stated

Inclusion criteria:


2. Weight 55 to 100 kg.

3. Diagnosis of cholecystitis to be operated on electively.


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.


(Review)


Gomez-Vazquez 2012 (Continued)


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)



Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes




Horattas 2004


Participants Country: USA.




Mean age: 49 years.

Females: 85 (73.3%).

Inclusion criteria:


Exclusion criteria:

1. Allergy to rofecoxib or any other NSAIDs.

2. Acute cholecystitis or pancreatitis.

3. History of hepatic or renal disease.


(Review)


Horattas 2004 (Continued)

4. History of pain management problems.

5. Chemical substance abuse.

6. Emergency or non-elective surgery.


8. Pregnancy.

9. Analgesic usage 6 h prior to scheduled surgery time.


Group 1: rofecoxib 50 mg orally preoperatively (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)


Risk of bias



bias)




(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”


bias)

All outcomes



All outcomes





(Review)


Ji 2010






Mean age: 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.


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.


Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes



(Review)


Ji 2010 (Continued)

Selective reporting (reporting bias) High risk Comment: Some important outcomes which will generally

be assessed were not reported


Joshi 2004






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.


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)

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


(Review)


Joshi 2004 (Continued)

collection prepared the IV study drugs (2 mL solution iden-

tical in appearance) and provided them to the investigator”


(performance bias)

All outcomes

Low risk Quote: “The hospital pharmacist who was not involved





bias)

All outcomes

Low risk Quote: “The hospital pharmacist who was not involved





All outcomes



For-profit bias High risk Quote: “Supported, in part, by Pharmacia Corporation and

Pfizer Inc”

Karakoc 2011









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



Risk of bias



(Review)


Karakoc 2011 (Continued)


bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes





Lane 1996






Mean age: 44.

Females: 107.

Inclusion criteria:



Exclusion criteria:

1. Mentally and physically unable to fill out a simple form.

2. Hypersensitivity to study medication.

3. Receiving monoamine oxidase inhibitors.


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.


(Review)


Lane 1996 (Continued)


Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes




Liu 1993






Mean age: 46 years.

Females: 15 (25%).

Inclusion criteria:



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.


(Review)


Liu 1993 (Continued)


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.



Risk of bias



bias)




(performance bias)

All outcomes

Unclear risk Quote: “Medication was prepared in a 2-mL numbered

(unlabeled) syringe by the pharmacy”.



bias)

All outcomes

Low risk Quote: “Recorded by a blinded nurse observer”.


All outcomes




Mebazaa 2008






Mean age: 46 years.

Females: not stated

Inclusion criteria:



3. ASA class I or II.

Exclusion criteria:


(Review)


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.


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.


Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes




Munro 1998


Participants Country: not stated.




Mean age: 51 years.


(Review)


Munro 1998 (Continued)

Females: 30 (81.1%).

Inclusion criteria:



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.


Group 1: tenoxicam 40 mg IV on skin closure (n = 19).

Group 2: placebo on skin closure (n = 18).




Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes





(Review)


Muñoz 2002


Participants Country: Chile.




Mean age: 42 years.

Females: 80 (66.7%).

Inclusion criteria:



Exclusion criteria:

1. Chronic or acute (within last 48 h) intake of sedatives or analgesic drugs.

2. Adverse reaction to study drugs.


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).




Risk of bias



bias)

Low risk Quote: “Computer-generated list”.



(performance bias)

All outcomes



bias)

All outcomes



All outcomes





(Review)


Nesek-Adam 2012


Participants Country: Croatia.




Mean age: 51 years.

Females: 58 (72.5%).

Inclusion criteria:




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.


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.


Risk of bias



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”



(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”



(Review)


Nesek-Adam 2012 (Continued)


bias)

All outcomes



All outcomes




Pandey 2004


Participants Country: India.




Mean age: 42 years.

Females: 308 (67.1%).

Inclusion criteria:

1. ASA I or II.



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.


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.


Risk of bias


(Review)


Pandey 2004 (Continued)



bias)

Low risk Quote: “Computer generated table of random numbers

used”.



(performance bias)

All outcomes



bias)

All outcomes

Unclear risk Quote: “A senior resident, who was not part of the anesthe-

sia team recorded the pain score”.



All outcomes




Peng 2010






Mean age: 45 years.

Females: 95 (77.2%).

Inclusion criteria:


2. ASA physical status I to III.

3. Laparoscopic cholecystectomy.

Exclusion criteria:

1. Urgent or emergent cholecystectomy.

2. Analgesics in 24 h before surgery.


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.


(Review)


Peng 2010 (Continued)


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)

Low risk Quote: “According to a computer-generated randomization

list”



(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”


bias)

All outcomes



All outcomes


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


Participants Country: Finland.





(Review)


Puura 2006 (Continued)

Mean age: 46 years.

Females: not stated

Inclusion criteria:


2. ASA physiological status I to III.


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.



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)


Risk of bias



bias)

Low risk Quote: “Using a random number table”.



(performance bias)

All outcomes

Unclear risk Quote: “Drug-containing bags used”.



bias)

All outcomes



(Review)


Puura 2006 (Continued)


All outcomes



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






Mean age: 42 years.

Females: 31 (77.5%).

Inclusion criteria:


Exclusion criteria:

1. Chronic analgesic or alcohol intake.

2. Hypersensitivity to the drugs used in the study.


4. Diminished liver and kidney functions.


Group 1: paracetamol (acetaminophen) 1 g IV after intubation (n = 20).

Group 2: saline IV after intubation (n = 20).

Outcomes Serious adverse events.


Risk of bias



bias)

Low risk Quote: “Random number generator”.



(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”


(Review)


Salihoglu 2009 (Continued)


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”



All outcomes




Sandhu 2011


Participants Country: Thailand.




Mean age: 53 years.

Females: 78 (65.5%).

Inclusion criteria:

1. ASA I or II.



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.


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.



Risk of bias



(Review)


Sandhu 2011 (Continued)


bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes

High risk Comment: There was one post-randomisation drop-out.


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


Participants Country: Greece.




Mean age: 54 years.

Females: 24 (60%).

Inclusion criteria:


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.


Group 1: pregabalin 600 mg orally divided in 2 doses, the night before surgery and 1 h

preoperatively (n = 20).


(Review)


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)


Risk of bias



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”.



(performance bias)

All outcomes

Low risk Quote: “All medications were provided by the hospital

pharmacy, and they were identical in shape and colour”


bias)

All outcomes



All outcomes




Schuster 2005








Inclusion criteria:


2. Aged ≥ 18.

Exclusion criteria:


(Review)


Schuster 2005 (Continued)



3. Renal insufficiency or failure.

4. History of gastrointestinal bleeding.

5. Allergy to NSAIDs or cyclo-oxygenase-2 inhibitors.


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)


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)

Unclear risk Quote: “Random card pull design method”.




(performance bias)

All outcomes

Unclear risk Quote: “The patient, surgeon and researcher were all

blinded to the patient’s treatment group”.



bias)

All outcomes

Unclear risk Quote: “The patient, surgeon and researcher were all

blinded to the patient’s treatment group”.



All outcomes





(Review)


Sen 2010






Mean age: 54 years.

Females: 81 (68.6%).

Inclusion criteria:


2. Elective laparoscopic cholecystectomy under general anaesthesia.

Exclusion criteria:


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.


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)


Risk of bias



bias)

Low risk Quote: “Computer-generated, blinded randomisation list”.



(performance bias)

All outcomes



bias)

All outcomes



All outcomes



(Review)


Sen 2010 (Continued)



Wilson 1994


Participants Country: England.




Mean age: 48 years.

Females: 40 (81.6%).

Inclusion criteria:


Exclusion criteria:


2. Hepatic or renal insufficiency.

3. History of haemorrhagic diathesis.

4. Hypersensitivity to diclofenac.


Group 1: diclofenac 75 mg IM (n = 26).


Outcomes Pain.

Notes Reasons for post-randomisation drop-outs: incomplete data extraction (n = 3), conver-

sion to open (n = 3)


Risk of bias



bias)

Low risk Quote: “Computer random number generation”.



(performance bias)

All outcomes

Low risk Quote: “Pharmacy provided identical pre-packed syringes”.


bias)

All outcomes



(Review)


Wilson 1994 (Continued)


All outcomes




Yeh 2004


Participants Country: Taiwan.




Mean age: 49 years.

Females: 27 (62.8%).

Inclusion criteria:



Exclusion criteria:

1. NSAIDs contraindicated.

2. Received opioids or NSAIDs less than 1 week before the study.


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)


Risk of bias



bias)




(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”


(Review)


Yeh 2004 (Continued)


bias)

All outcomes



All outcomes




Zajaczkowska 2004


Participants Country: Poland.




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:


2. Significant cardiac, respiratory, hepatic, renal, or neurological disease.

3. Local anaesthetic and morphine allergies.

4. Analgesics for non-biliary complaints.


Group 1: morphine SC (n = 30).

Group 2: no intervention (n = 30).

Outcomes Pain.


Risk of bias



bias)

Low risk Quote: “Computer-generated random-number table”.

Allocation concealment (selection bias) Unclear risk Quote: “Sealed envelope method used”.



(Review)


Zajaczkowska 2004 (Continued)


(performance bias)

All outcomes



bias)

All outcomes



All outcomes




Zhu 2011






Mean age: 44 years.

Females: 25 (42.4%).

Inclusion criteria:




Exclusion criteria:

1. History of chronic pain or daily intake of analgesics.

2. Uncontrolled medical disease.

3. Inability to operated patient-controlled analgesia.


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.



Risk of bias



(Review)


Zhu 2011 (Continued)


bias)

Low risk Quote: “Computer-generated table used”.



(performance bias)

All outcomes



bias)

All outcomes



All outcomes





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


(Review)


(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]


(Review)


Gan 2003

Methods

Participants

Interventions

Outcomes

Notes Full text unavailable.


(Review)


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]


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]


8 Pain (4 to 8 hours) sensitivity

analysis

4 433 Mean Difference (IV, Fixed, 95% CI) -0.91 [-1.10, -0.71]


analysis


10 Pain (4 to 8 hours) stratified by

drug


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


11.1 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


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]


(Review)


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


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


studies

No. of




3 Pain (4 to 8 hours) (sensitivity

analysis)


4 Pain (9 to 24 hours) (sensitivity

analysis)


Comparison 3. Anticonvulsant analgesic versus control


studies

No. of


1 Morbidity 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected



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]


4.3 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]


analysis



analysis



(Review)


Comparison 4. Anticonvulsant analgesic versus NSAID


studies

No. of


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


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


studies

No. of





(Review)


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.



Outcome: 2 Proportion discharged as day-surgery

Study or subgroup NSAID Control Risk Ratio Risk Ratio


Horattas 2004 35/58 35/58 1.00 [ 0.74, 1.34 ]

0.5 0.7 1 1.5 2

Favours control Favours NSAID


(Review)


Analysis 1.3. Comparison 1 NSAID versus control, Outcome 3 Length of hospital stay.



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


Analysis 1.4. Comparison 1 NSAID versus control, Outcome 4 Pain (4 to 8 hours).



Outcome: 4 Pain (4 to 8 hours)


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


(Continued . . . )


(Review)


(. . . Continued)



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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)


-4 -2 0 2 4



(Review)


Analysis 1.5. Comparison 1 NSAID versus control, Outcome 5 Pain (9 to 24 hours).






Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-4 -2 0 2 4



(Review)


Analysis 1.6. Comparison 1 NSAID versus control, Outcome 6 Morbidity (sensitivity analysis).



Outcome: 6 Morbidity (sensitivity analysis)

Study or subgroup NSAID Control Risk Ratio Weight Risk Ratio


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 ]



Subtotal (95% CI) 283 284 17.9 % 0.75 [ 0.36, 1.53 ]




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 ]


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 ]


Heterogeneity: Chi2 = 1.24, df = 3 (P = 0.74); I2 =0.0%


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 ]



Subtotal (95% CI) 283 284 17.9 % 1.46 [ 0.79, 2.67 ]




0.02 0.1 1 10 50


(Continued . . . )


(Review)


(. . . Continued)Study or subgroup NSAID Control Risk Ratio Weight Risk Ratio


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 ]


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 (95% CI) 1132 1136 100.0 % 0.80 [ 0.59, 1.07 ]




Test for subgroup differences: Chi2 = 7.42, df = 3 (P = 0.06), I2 =60%

0.02 0.1 1 10 50



(Review)


Analysis 1.7. Comparison 1 NSAID versus control, Outcome 7 Proportion discharged as day-surgery

(sensitivity analysis).



Outcome: 7 Proportion discharged as day-surgery (sensitivity analysis)

Study or subgroup NSAID Control Risk Ratio Risk Ratio


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


(Review)


Analysis 1.8. Comparison 1 NSAID versus control, Outcome 8 Pain (4 to 8 hours) sensitivity analysis.



Outcome: 8 Pain (4 to 8 hours) sensitivity analysis



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-4 -2 0 2 4



(Review)


Analysis 1.9. Comparison 1 NSAID versus control, Outcome 9 Pain (9 to 24 hours) sensitivity analysis.






Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-4 -2 0 2 4



(Review)


Analysis 1.10. Comparison 1 NSAID versus control, Outcome 10 Pain (4 to 8 hours) stratified by drug.



Outcome: 10 Pain (4 to 8 hours) stratified by drug



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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


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 ]



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 ]



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 ]



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 ]



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 ]



7 Paracetamol

-4 -2 0 2 4


(Continued . . . )


(Review)


(. . . Continued)



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]



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 ]



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 ]



Total (95% CI) 586 413 100.0 % -0.88 [ -1.07, -0.70 ]




-4 -2 0 2 4



(Review)


Analysis 1.11. Comparison 1 NSAID versus control, Outcome 11 Pain (4 to 8 hours) stratified by time.



Outcome: 11 Pain (4 to 8 hours) stratified by time



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]



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 ]



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 ]



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


(Continued . . . )


(Review)


(. . . Continued)



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]



Total (95% CI) 586 413 100.0 % -0.88 [ -1.07, -0.70 ]




-4 -2 0 2 4


Analysis 1.12. Comparison 1 NSAID versus control, Outcome 12 Pain (9 to 24 hours) stratified by drug.



Outcome: 12 Pain (9 to 24 hours) stratified by drug



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]



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 ]



3 Etofenomate

-4 -2 0 2 4


(Continued . . . )


(Review)


(. . . Continued)



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]



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 ]



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 ]



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 ]



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 ]



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 ]



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 ]


-4 -2 0 2 4


(Continued . . . )


(Review)


(. . . Continued)



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm



Total (95% CI) 434 273 100.0 % -0.50 [ -0.67, -0.33 ]




-4 -2 0 2 4


Analysis 1.13. Comparison 1 NSAID versus control, Outcome 13 Pain (9 to 24 hours) stratified by time.



Outcome: 13 Pain (9 to 24 hours) stratified by time



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]



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


(Continued . . . )


(Review)


(. . . Continued)



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


Subtotal (95% CI) 100 50 22.7 % -2.07 [ -2.42, -1.72 ]



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 ]



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 ]



Total (95% CI) 434 273 100.0 % -0.50 [ -0.67, -0.33 ]




-4 -2 0 2 4



(Review)


Analysis 2.1. Comparison 2 Opioid versus control, Outcome 1 Pain (4 to 8 hours).


Comparison: 2 Opioid versus control


Study or subgroup Opioid ControlMean


Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-4 -2 0 2 4

Favours opioid Favours control


(Review)


Analysis 2.2. Comparison 2 Opioid versus control, Outcome 2 Pain (9 to 24 hours).






Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-4 -2 0 2 4


Analysis 2.3. Comparison 2 Opioid versus control, Outcome 3 Pain (4 to 8 hours) (sensitivity analysis).



Outcome: 3 Pain (4 to 8 hours) (sensitivity analysis)



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-2 -1 0 1 2



(Review)


Analysis 2.4. Comparison 2 Opioid versus control, Outcome 4 Pain (9 to 24 hours) (sensitivity analysis).



Outcome: 4 Pain (9 to 24 hours) (sensitivity analysis)



Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-0.5 -0.25 0 0.25 0.5


Analysis 3.1. Comparison 3 Anticonvulsant analgesic versus control, Outcome 1 Morbidity.


Comparison: 3 Anticonvulsant analgesic versus control


Study or subgroup Anticonvulsant Control Risk Ratio Risk Ratio


Gilron 2009 3/25 1/25 3.00 [ 0.33, 26.92 ]

0.05 0.2 1 5 20

Favours anticonvulsant Favours control


(Review)


Analysis 3.2. Comparison 3 Anticonvulsant analgesic versus control, Outcome 2 Pain (4 to 8 hours).




Study or subgroup Anticonvulsant ControlMean


Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-10 -5 0 5 10



(Review)


Analysis 3.3. Comparison 3 Anticonvulsant analgesic versus control, Outcome 3 Pain (9 to 24 hours).






Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-10 -5 0 5 10



(Review)


Analysis 3.4. Comparison 3 Anticonvulsant analgesic versus control, Outcome 4 Morbidity (sensitivity

analysis).






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


Analysis 3.5. Comparison 3 Anticonvulsant analgesic versus control, Outcome 5 Pain (4 to 8 hours)

sensitivity analysis.






Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-4 -2 0 2 4



(Review)


Analysis 3.6. Comparison 3 Anticonvulsant analgesic versus control, Outcome 6 Pain (9 to 24 hours)

sensitivity analysis.






Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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 ]




-4 -2 0 2 4


Analysis 4.1. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 1 Morbidity.


Comparison: 4 Anticonvulsant analgesic versus NSAID




Gilron 2009 2/25 1/27 2.16 [ 0.21, 22.38 ]

0.05 0.2 1 5 20



(Review)


Analysis 4.2. 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


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).





analgesic NSAIDMean

DifferenceMean

Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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



(Review)


Analysis 4.4. Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 4 Morbidity (sensitivity

analysis).





analgesic NSAID Risk Ratio Weight Risk Ratio


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)



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 ]




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 ]




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 (95% CI) 120 120 100.0 % 1.00 [ 0.50, 2.01 ]





0.02 0.1 1 10 50



(Review)


Analysis 5.1. Comparison 5 Anticonvulsant analgesic versus opioid, Outcome 1 Pain (4 to 8 hours).


Comparison: 5 Anticonvulsant analgesic versus opioid



analgesic NSAIDMean

DifferenceMean

Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


Pandey 2004 153 2.65 (3) 153 2.97 (2.35) -0.32 [ -0.92, 0.28 ]

-1 -0.5 0 0.5 1


Analysis 5.2. Comparison 5 Anticonvulsant analgesic versus opioid, Outcome 2 Pain (9 to 24 hours).


Comparison: 5 Anticonvulsant analgesic versus opioid



analgesic NSAIDMean

DifferenceMean

Difference

NMean(SD)[cm

VAS] NMean(SD)[cm


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



(Review)


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


(Review)


(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.


(Review)


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


(Review)


MeSH check words

Humans


(Review)


gaba colecistectomia cochrane 2014

Health & Medicine