Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy

Abstract

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 Expanded, 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 pharmacological 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).

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 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. 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.

Plain language summary

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 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.

Summary of findings

Summary of findings for the main comparison. Various interventions compared with control for people undergoing laparoscopic cholecystectomy.

Various interventions compared with control for people undergoing laparoscopic cholecystectomy
Patient or population: people undergoing laparoscopic cholecystectomy Settings: secondary or tertiary Intervention: various interventions versus control
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Various interventions
Non‐steroidal anti‐inflammatory drugs (NSAIDs) versus no active intervention
Morbidity	59 per 1000	44 per 1000 (22 to 90)	RR 0.75 (0.37 to 1.53)	543 (5 studies)	⊕⊝⊝⊝ very low1,2
Proportion discharged as day‐surgery	603 per 1000	603 per 1000 (447 to 809)	RR 1 (0.74 to 1.34)	116 (1 study)	⊕⊝⊝⊝ very low1,2
Length of hospital stay	The mean length of hospital stay in the control groups was 1.1 days	The mean length of hospital stay in the intervention group was 0.1 lower (0.72 lower to 0.52 higher)	‐	119 (1 study)	⊕⊝⊝⊝ very low1,3
Pain (4 to 8 hours)	The mean pain (4 to 8 hours) in the control groups was 3.49 cm VAS	The mean pain (4 to 8 hours) in the intervention groups was 0.88 lower (1.07 to 0.7 lower)	‐	999 (11 studies)	⊕⊝⊝⊝ very low1,4
Pain (9 to 24 hours)	The mean pain (9 to 24 hours) in the control groups was 2.2 cm VAS	The mean pain (9 to 24 hours) in the intervention groups was 0.5 lower (0.67 to 0.33 lower)	‐	707 (9 studies)	⊕⊝⊝⊝ very low1,4
Mortality, patient quality of life, and return to normal activity were not reported in any trials. Return to work was not reported adequately in any of the trials.
Opioids versus no active intervention
Pain (4 to 8 hours)	The mean pain (4 to 8 hours) in the control groups was 4.00 cm VAS	The mean pain (4 to 8 hours) in the intervention groups was 2.51 lower (3.02 to 2.01 lower)	‐	425 (3 studies)	⊕⊕⊝⊝ low1
Pain (9 to 24 hours)	The mean pain (9 to 24 hours) in the control groups was 2.76 cm VAS	The mean pain (9 to 24 hours) in the intervention groups was 0.32 lower (0.44 to 0.2 lower)	‐	425 (3 studies)	⊕⊕⊝⊝ low1
Mortality, patient quality of life, hospital stay, and return to normal activity or work were not reported in any trials. Morbidity was reported adequately in any of the trials.
Anticonvulsant analgesics versus no active intervention
Mortality	There was no mortality in either group		Not estimable	123 (1 study)	⊕⊝⊝⊝ very low1,2
Morbidity	40 per 1000	120 per 1000 (13 to 1000)	RR 3 (0.33 to 26.92)	50 (1 study)	⊕⊝⊝⊝ very low1,2
Pain (4 to 8 hours)	The mean pain (4 to 8 hours) in the control groups was 4 cm VAS	The mean pain (4 to 8 hours) in the intervention groups was 2.52 lower (2.95 to 2.09 lower)	‐	402 (3 studies)	⊕⊝⊝⊝ very low1,4
Pain (9 to 24 hours)	The mean pain (9 to 24 hours) in the control groups was 3 cm VAS	The mean pain (9 to 24 hours) in the intervention groups was 0.55 lower (0.68 to 0.42 lower)	‐	402 (3 studies)	⊕⊕⊝⊝ low1
Patient quality of life, hospital stay, and return to normal activity were not reported in any trials. Return to work was not reported adequately in any of the trials.
Opioids versus NSAIDs
Only one trial was included in this comparison. None of the outcomes was reported adequately in this trial.
Anticonvulsant analgesics versus NSAIDs
Mortality	There was no mortality in either group		Not estimable	60 (1 study)	⊕⊝⊝⊝ very low1,2
Morbidity	37 per 1000	80 per 1000 (8 to 829)	RR 2.16 (0.21 to 22.38)	52 (1 study)	⊕⊝⊝⊝ very low1,2
Pain (4 to 8 hours)	The mean pain (4 to 8 hours) in the control groups was 4.3 cm VAS	The mean pain (4 to 8 hours) in the intervention groups was 2.5 lower (2.84 to 2.16 lower)	‐	60 (1 study)	⊕⊝⊝⊝ very low1,3
Pain (9 to 24 hours)	The mean pain (9 to 24 hours) in the control groups was 2.1 cm VAS	The mean pain (9 to 24 hours) in the intervention groups was 0.5 lower (0.84 to 0.16 lower)	‐	60 (1 study)	⊕⊝⊝⊝ very low1,3
Patient quality of life, hospital stay, and return to normal activity were not reported in any trials. Return to work was not reported adequately in any of the trials.
Anticonvulsant analgesics versus opioids
Pain (4 to 8 hours)	The mean pain (4 to 8 hours) in the control groups was 2.97 VAS	The mean pain (4 to 8 hours) in the intervention groups was 0.32 lower (0.92 lower to 0.28 higher)	‐	306 (1 study)	⊕⊝⊝⊝ very low1,3
Pain (9 to 24 hours)	The mean pain (9 to 24 hours) in the control groups was 0.87 VAS	The mean pain (9 to 24 hours) in the intervention groups was 0.22 lower (0.34 to 0.1 lower)	‐	306 (1 study)	⊕⊝⊝⊝ very low1,3
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).

Background

Description of the condition

About 5% to 25% of the adult western population have gallstones (GREPCO 1984; GREPCO 1988; Bates 1992; Halldestam 2004). The annual incidence of gallstones is about 1 in 200 people (NIH 1992). Only 2% to 4% of people with gallstones become 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 symptomatic 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 cholecystectomies 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 cholecystectomy 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 neuropathic pain (Argoff 2013). The analgesics can be administered by different routes including orally, sublingually, intravenously, subcutaneously, 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 ulceration and severe gastrointestinal bleeding may occur (Martindale 2011). The most common adverse events related to opioids used in usual doses include nausea, vomiting, constipation, drowsiness, confusion, difficulty in micturition, dry mouth, dizziness, sweating, facial flushing, headache, vertigo, bradycardia, tachycardia, palpitations, orthostatic hypotension, hypothermia, restlessness, changes of mood, decreased libido or potency, hallucinations, and raised intracranial pressure. Larger doses of opioids produce muscle rigidity, respiratory depression, hypotension with circulatory failure, and deepening coma (Martindale 2011). The most commonly reported adverse events associated with gabapentin are somnolence, dizziness, ataxia, and fatigue although psychiatric effects including confusion, depression, and nervousness can occur in some people (Martindale 2011). Common adverse events related to pregabalin include dizziness, somnolence, blurred vision, diplopia (double vision), dry mouth, constipation, vomiting, flatulence, 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 Specific Postoperative Pain Management (PROSPECT) group recommended routine use of NSAIDs and recommended against routine use of opioid analgesics during or after laparoscopic cholecystectomy (Kehlet 2005). Another systematic review by Bisgaard et al. made similar recommendations as the PROSPECT group and, in addition, recommended against routine use of gabapentin during or after laparoscopic cholecystectomy (Bisgaard 2006). Reduction in pain may improve quality of life and allow earlier return to normal activity and work, which may have financial implications to the people undergoing the operations, their carers, and their employers. Reduction in pain may also improve the proportion of laparoscopic cholecystectomies performed as day‐surgery and decrease the length of hospital stay, which may be important for the people undergoing the procedure in a private‐funded healthcare system and may be important for state‐funded or insurance‐funded healthcare systems. We have been unable to identify any recent systematic reviews or Cochrane reviews assessing the role of different analgesics in people undergoing laparoscopic cholecystectomy.

Objectives

To assess the benefits and harms of different analgesics in people undergoing laparoscopic cholecystectomy.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised clinical trials (irrespective of language, blinding, publication status, or sample size) for inclusion. We excluded quasi‐randomised trials (where the method of allocating participants to a treatment are not strictly random, for example, 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 laparoscopic 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 administered 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 analgesics 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 undergoing laparoscopic cholecystectomy. We excluded trials that involved a combination of two or more classes of drugs against inactive interventions. We excluded trials considering pharmacological agents not primarily meant for analgesia such as intravenous ketamine (used for its sedative property to perform short procedures) (Gottschling 2005), α₂‐adrenoceptor antagonist, such as clonidine (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.

We have reported all the outcomes with at least one trial in the Table 1.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003), and the World Health Organization International 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 clinicaltrials.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 recommendations 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 inclusion independently of each other. We have also listed the excluded 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 arbitration of the third review author (BRD).

Assessment of risk of bias in included studies

We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2014). According 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.

• High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.

Blinding of outcome assessors

• Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.

• Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.

• High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.

Incomplete outcome data

• Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, have been employed to handle missing data.

• Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

• High risk of bias: the results were likely to be biased due to missing data.

Selective outcome reporting

• Low risk of bias: all outcomes were pre‐defined and reported, or all clinically relevant and reasonably expected outcomes were reported. For this purpose, the trial should have been registered either on the www.clinicaltrials.gov website or a similar register with sufficient evidence that the protocol had not been revised during the update, or there should be a protocol, for example, published in a paper journal. In the case when the trial was run and published in the years when trial registration was not required, we carefully scrutinized all publications reporting on the trial to identify the trial objectives and outcomes and determine whether usable data were provided in the publication results section on all outcomes specified in the trial objectives.

• Uncertain risk of bias: it is unclear whether all pre‐defined and clinically relevant (mortality and morbidity) and reasonably expected outcomes were reported.

• High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

For‐profit bias

• Low risk of bias: the trial appeared to be free of industry sponsorship or other type of for‐profit support that may manipulate the trial design, conductance, or results of the trial.

• Uncertain risk of bias: the trial may or may not be free of for‐profit bias as no information on clinical trial support or sponsorship was provided.

• High risk of bias: the trial was sponsored by the industry or had received other type of for‐profit support.

We considered trials that were classified as low risk of bias in all the above domains as trials with low risk of bias and the remaining as trials with high risk of bias.

Measures of treatment effect

For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval (CI). We also calculated the risk difference 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 laparoscopic cholecystectomy and randomised to the intraperitoneal local 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 imputed the standard deviation from P values according to the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and we used the median for the meta‐analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the CI, we planned to impute the standard deviation as the highest standard 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 heterogeneity using the I² statistic (Higgins 2002). We also used overlapping of CIs on the forest plot to determine heterogeneity.

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 Review Manager 5 (RevMan 2012), and following the recommendations 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 discrepancy between the two models, we have reported both results; otherwise, 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 errors 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 inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information 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 continue 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 reporting 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 perform 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 Review Manager 5 (RevMan 2012) to identify the differences between subgroups. We used the random‐effects model for this purpose.

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 Table 1 prepared using GRADEPro 3.6 (ims.cochrane.org/revman/gradepro).

Results

Description of studies

Results of the search

We identified 1238 references through electronic searches of CENTRAL (n = 274), MEDLINE (n = 269), EMBASE (n = 302), and 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 assessment. 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‐randomised studies that reported treatment‐related harms.

1.

Study flow diagram.

Included studies

Of the 36 randomised clinical trials that reported the inclusion criteria, 10 trials did not provide any information for this systematic 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 participants randomised to the intervention and control groups (Schuster 2005). Thus, we included 25 randomised clinical trials including 2505 participants randomised to different interventions and controls 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 before the participants reported pain. Nineteen trials reported that they included only people undergoing elective laparoscopic cholecystectomy (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 remaining six trials stated whether people undergoing emergency laparoscopic cholecystectomy were included (Lane 1996; Munro 1998; Dong 2003; Agarwal 2008; Mebazaa 2008; Ji 2010). Fifteen 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 trials compared opioids versus inactive controls (Lane 1996; Pandey 2004; Zajaczkowska 2004; Zhu 2011). Five trials compared anticonvulsant 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 compared opioid versus NSAID (Lane 1996). Two trials compared anticonvulsant analgesics versus NSAID (Gilron 2009; Akarsu 2012). One trial compared anticonvulsant analgesics versus opioid (Pandey 2004).

Co‐interventions

Intraperitoneal local anaesthetic instillation was used as a co‐intervention 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‐randomisation drop‐outs, intervention and control, comparisons, outcomes, 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).

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Only three trials (3/36 (8.3%)) described random sequence generation 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 participants 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: Table 1

The results are summarised in Table 1.

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 trials 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 accrued was only 4.5% of the diversity‐adjusted required information 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 imputing missing outcomes according to different scenarios resulted in different results (Analysis 1.6).

1.1. Analysis.

Comparison 1 NSAID versus control, Outcome 1 Morbidity.

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.

1.6. Analysis.

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

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 between NSAID and control (RR 1.00; 95% CI 0.74 to 1.34; 116 participants; very low quality evidence) (Analysis 1.2). Trial sequential analysis was not performed because of the presence of only one trial. The results were robust to sensitivity analysis by imputing missing outcomes according to different scenarios (Analysis 1.7).

1.2. Analysis.

Comparison 1 NSAID versus control, Outcome 2 Proportion discharged as day‐surgery.

1.7. Analysis.

Comparison 1 NSAID versus control, Outcome 7 Proportion discharged as day‐surgery (sensitivity analysis).

Length of hospital stay

One trial reported length of hospital stay (Sandhu 2011). There were no significant differences in the length of hospital stay between 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.

1.3. Analysis.

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

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 evidence) (Analysis 1.4). 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 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 imputed. 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 findings were consistent with NSAID decreasing pain between 4 and 8 hours compared with inactive control with a low risk of random errors (Figure 5).

1.4. Analysis.

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

1.8. Analysis.

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

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.

Pain at 9 to 24 hours

Nine trials reported pain at 9 to 24 hours (Wilson 1994; Munro 1998; Dong 2003; Yeh 2004; Mebazaa 2008; Akaraviputh 2009; Ji 2010; Sen 2010; Abdulla 2012). The pain scores as measured by VAS were significantly lower in the NSAID group than the control group (MD ‐0.50 cm VAS; 95% CI ‐0.67 to ‐0.33; 707 participants; very low quality evidence) (Analysis 1.5). On using the random‐effects model, there was no significant difference between 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 imputed. 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 findings were consistent with NSAID decreasing pain between 9 and 24 hours compared with inactive control with a low risk of random errors (Figure 6).

1.5. Analysis.

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

1.9. Analysis.

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

6.

Trial sequential analysis of pain (9 to 24 hours) (non‐steroidal anti‐inflammatory drug (NSAID) versus control) 
 The diversity‐adjusted required information size (DARIS) was 1525 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 2.62, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D²) of 94.56%. The conventional statistical boundaries (dotted red line) are crossed by the cumulative Z curve (blue line) after the third trial. The trial sequential monitoring boundaries (red line) are crossed by cumulative Z curve after the fifth trial. Although the DARIS has not been reached, the findings are consistent with NSAID decreasing pain between 9 and 24 hours compared with inactive control with low risk of random errors.

Return to normal activity

None of the trials reported return to normal activity.

Return to work

One trial (54 participants) reported return to work (Gilron 2009). The trial did not report the standard deviation. The trial reported that there were no significant differences in the time taken to return to work. Trial sequential analysis was not performed because of the presence of only one trial and because of the lack of standard deviation in the trial that reported this outcome (Gilron 2009).

Subgroup analysis

Only pain at 4 to 8 hours and pain at 9 to 24 hours were suitable for various subgroup analyses because of the paucity of data in the other outcomes. We did not perform the following subgroup analyses.

• Trials with low bias risk compared to trials with high bias risk. None of the trials were at low risk of bias.

• Elective compared with emergency laparoscopic cholecystectomy. None of the trials reported data for emergency laparoscopic cholecystectomy separately.

• With and without intraperitoneal local anaesthetic instillation. None of the trials that provided information about intraperitoneal local anaesthetic instillation used local anaesthetic instillation.

• With and without peri‐laparoscopic‐portal infiltration with local anaesthetic. None of the trials that provided information about local anaesthetic wound infiltration used local anaesthetic wound infiltration.

The results of the other two subgroup analyses are as follows.

• Different times of administration (one to two hours before surgery, on induction, or at the end of surgery). The tests for subgroup differences were significant for both pain at 4 to 8 hours and for pain at 9 to 24 hours (P value < 0.00001). At both 4 to 8 hours and 9 to 24 hours, NSAID administration during the surgery appeared to be more effective than administration at other times.

• Different pharmacological agents. The test for subgroup differences were significant for both pain at 4 to 8 hours and for pain at 9 to 24 hours (P value < 0.00001). At 4 to 8 hours, diclofenac, flurbiprofen, and lornoxicam appeared to be more effective than other agents (celecoxib, etofenomate, metamizol, paracetamol, parecoxib, and tenoxicam). At 9 to 24 hours, lornoxicam appeared to be more effective than other agents (celecoxib, diclofenac, etofenomate, fluribiprofen, metamizol, paracetamol, parecoxib, and tenoxicam).

Reporting bias

We explored reporting bias only for pain at 4 to 8 hours and for pain at 9 to 24 hours by funnel plots because of the presence of an adequate number of trials for these two outcomes only. The funnel plots did not reveal any evidence of reporting bias. The Egger's test did not reveal any evidence of reporting bias (pain at 4 to 8 hours: P value = 0.716; pain at 9 to 24 hours: P value = 0.871).

Opioids versus control

Mortality

None of the trials reported mortality.

Morbidity

None of the trials reported overall serious adverse events. Two trials reported drug‐related serious adverse event (Lane 1996; Pandey 2004). There were six serious adverse events (respiratory depression) in the opioid group compared with one serious adverse event (respiratory depression) in the control group in one trial (Pandey 2004). There were no drug‐related serious adverse events in the other trial (Lane 1996).

Patient quality of life

None of the trials reported patient quality of life.

Hospital stay

None of the trials reported the proportion of people discharged as day‐surgery or the length of hospital stay.

Pain

Pain at 4 to 8 hours

Three trials reported pain at 4 to 8 hours (Pandey 2004; Zajaczkowska 2004; Zhu 2011). The pain scores as measured by VAS were significantly lower in the opioid group than the control group (MD ‐2.51 cm VAS; 95% CI ‐3.02 to ‐2.01; 425 participants; low quality evidence) (Analysis 2.1). There were no changes in the interpretation of results by using a random‐effects meta‐analysis. Either the mean or the standard deviation was imputed in two trials (Zajaczkowska 2004; Zhu 2011). Exclusion of these trials did not alter the results (MD ‐2.56 cm VAS; 95% CI ‐3.07 to ‐2.05) (Analysis 2.3). Trial sequential analysis revealed that the trial sequential monitoring boundaries were crossed by cumulative Z curve favouring opioid. The findings were consistent with opioid decreasing pain between 4 and 8 hours compared with inactive control with a low risk of random errors (Figure 7).

2.1. Analysis.

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

2.3. Analysis.

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

7.

Trial sequential analysis of pain (4 to 8 hours) (opioid versus control) 
 The diversity‐adjusted required information size (DARIS) was 445 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 14.16, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D²) of 0%. The conventional statistical boundaries (dotted red line) and the trial sequential monitoring boundaries (red line) are crossed by the cumulative Z curve (blue line) after the first trial. Although the DARIS is not reached, the findings are consistent with opioid decreasing pain between 4 and 8 hours compared with inactive control with low risk of random errors.

Pain at 9 to 24 hours

Three trials reported pain at 9 to 24 hours (Pandey 2004; Zajaczkowska 2004; Zhu 2011). The pain scores as measured by VAS were significantly lower in the opioid group than the control group (MD ‐0.32 cm VAS; 95% CI ‐0.44 to ‐0.20; 425 participants; low quality evidence) (Analysis 2.2). There were no changes in the interpretation of results by using a random‐effects meta‐analysis. Either the mean or the standard deviation was imputed in two trials (Zajaczkowska 2004; Zhu 2011). Exclusion of these trials did not alter the results (MD ‐0.32 cm VAS; 95% CI ‐0.44 to ‐0.20) (Analysis 2.4). Trial sequential analysis revealed that the diversity‐adjusted required information size was 25 participants based on a minimal relevant difference (MIRD) of 1 cm on the VAS, a variance (VAR) of 0.78, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D²) of 0%. As this was crossed by the first trial, the trial sequential boundaries were not drawn. A post hoc analysis with the MIRD revised to 0.25 cm was performed. The conventional statistical boundaries and the trial sequential monitoring 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).

2.2. Analysis.

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

2.4. Analysis.

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

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.

Return to normal activity

None of the trials reported return to normal activity.

Return to work

None of the trials reported return to work.

Subgroup analysis

We did not perform subgroup analysis because of the few trials included in this comparison.

Reporting bias

We did not assess the reporting bias by using funnel plots because of the few trials included in this comparison.

Anticonvulsant analgesics versus control

Mortality

One trial (123 participants) reported mortality (Peng 2010). There was no mortality in either group (0/82 (0%) in anticonvulsant analgesic group versus 0/41 (0%) in control group). Trial sequential 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 significant 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 serious 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 comparison. The results were robust to sensitivity analysis by imputing missing outcomes according to different scenarios (Analysis 3.4).

3.1. Analysis.

Comparison 3 Anticonvulsant analgesic versus control, Outcome 1 Morbidity.

3.4. Analysis.

Comparison 3 Anticonvulsant analgesic versus control, Outcome 4 Morbidity (sensitivity analysis).

Patient quality of life

None of the trials reported patient quality of life.

Hospital stay

Proportion discharged as day‐surgery

None of the trials reported the proportion of people discharged as day surgery or the length of hospital stay.

Pain

Pain at 4 to 8 hours

Three trials reported pain at 4 to 8 hours (Pandey 2004; Agarwal 2008; Sarakatsianou 2013). The pain scores as measured by VAS were significantly lower in the anticonvulsant analgesic group than the control group (MD ‐2.52 cm VAS; 95% CI ‐2.95 to ‐2.09; 402 participants; very low quality evidence) (Analysis 3.2). There were no changes in the interpretation of results by using a 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 ‐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.

3.2. Analysis.

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

3.5. Analysis.

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

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.

Pain at 9 to 24 hours

Three trials reported pain at 9 to 24 hours (Pandey 2004; Agarwal 2008; Sarakatsianou 2013). The pain scores as measured by VAS were significantly lower in the anticonvulsant analgesic group than the control group (MD ‐0.55 cm VAS; 95% CI ‐0.68 to ‐0.42; 402 participants; very low quality evidence) (Analysis 3.3). There were no changes in the interpretation of results by using a random‐effects meta‐analysis. Either the mean or the standard deviation was imputed in two trials (Agarwal 2008; Sarakatsianou 2013). Exclusion of these trials did not alter the results (MD ‐0.54 cm VAS; 95% CI ‐0.67 to ‐0.41) (Analysis 3.6). Trial sequential analysis revealed that the diversity‐adjusted required information size (DARIS) 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 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).

3.3. Analysis.

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

3.6. Analysis.

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

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.

Return to normal activity

None of the trials reported return to normal activity.

Return to work

One trial (50 participants) reported return to work (Gilron 2009). The trial did not report the standard deviation. The trial reported that there were no significant differences in the time taken to return to work. Trial sequential analysis was not performed because of the presence of only one trial and because of the lack of standard deviation in the trial that reported this outcome (Gilron 2009).

Subgroup analysis

We did not perform subgroup analysis because of the few trials included in this comparison.

Reporting bias

We did not assess the reporting bias by using funnel plots because of the few trials included in this comparison.

Opioids versus non‐steroidal anti‐inflammatory drugs

Only one trial compared opioids versus NSAIDs. The only outcome 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 mortality in either group in this trial (0/30 (0%) in anticonvulsant analgesic 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 significant 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 adverse 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 because of the presence of only one trial.

4.1. Analysis.

Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 1 Morbidity.

Patient quality of life

None of the trials reported patient quality of life.

Hospital stay

None of the trials reported the proportion of people discharged as day‐surgery or the length of hospital stay.

Pain

Pain at 4 to 8 hours

One trial reported pain at 4 to 8 hours (Akarsu 2012). The pain scores as measured by VAS were significantly lower in the anticonvulsant 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 deviation was imputed in this trial. Trial sequential analysis was not performed because of the presence of only one trial.

4.2. Analysis.

Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 2 Pain (4 to 8 hours).

Pain at 9 to 24 hours

One trial reported pain at 9 to 24 hours (Akarsu 2012). The pain scores as measured by VAS were significantly lower in the anticonvulsant analgesic group than the NSAID group (MD ‐0.50 cm VAS; 95% CI ‐0.84 to ‐0.16; 60 participants; very low quality evidence) (Analysis 4.3). Neither the mean nor the standard deviation was imputed in this trial. Trial sequential analysis was not performed because of the presence of only one trial.

4.3. Analysis.

Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 3 Pain (9 to 24 hours).

Return to normal activity

None of the trials reported return to normal activity.

Return to work

One trial (52 participants) reported return to work (Gilron 2009). The trial did not report the standard deviation. The trial reported that there were no significant differences in the time taken to return to work. Trial sequential analysis was not performed because of the presence of only one trial and because of the lack of standard deviation in the trial that reported this outcome (Gilron 2009).

Subgroup analysis

We did not perform subgroup analysis because of the few trials included in this comparison.

Reporting bias

We did not assess reporting bias by using funnel plots because of the few trials included in this comparison.

Anticonvulsant analgesics versus opioids

Only one trial could be included under this comparison (Pandey 2004). The outcomes reported by this trial were drug‐related serious adverse events (respiratory depression) (0/153 (0%) in anticonvulsant 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 quality 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.

5.1. Analysis.

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

5.2. Analysis.

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

Discussion

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 mortality 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 unlikely that trials will be powered to measure differences in mortality during laparoscopic cholecystectomy. Major complications during laparoscopic cholecystectomy are also rare. Although respiratory 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 urinary retention (Martindale 2011). Common adverse effects of anticonvulsant 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; agranulocytosis; renal toxicity; central nervous system‐related adverse effects including depression, drowsiness, and insomnia; fluid retention; congestive heart failure; photosensitivity; and hypersensitivity 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 serious adverse events as an important outcome.

None of the trials reported quality of life or return to normal activity. 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 reported return to work. The main purpose of the pharmacological 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 return 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 different sensitivity analyses in most of the comparisons. Trial sequential analysis also confirmed the risk of random errors in concluding 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 estimates, 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 clinically significant (Todd 1996). Thus, it appears that some pharmacological 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 difference 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 trials 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 laparoscopic 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 laparoscopic 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 analgesics can be administered orally on a regular basis for a few days postoperatively. The question is whether such routine administration is more beneficial than administration as required or whether there is any benefit in administering prescription‐only agents compared 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 routinely.

Overall completeness and applicability of evidence

Most of the trials included in this review included people undergoing 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 (Table 1). 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 evidence 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 included 'pain' as one of the domains in this search strategy. Considering 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 authors independently identified trials for inclusion and extracted data, thus minimising errors. However, we imputed the mean and standard deviation when these were not available. We performed a sensitivity analysis excluding such trials but this did not change the results significantly thus demonstrating the minimal impact of missing mean or standard deviation.

Agreements and disagreements with other studies or reviews

A systematic review by Procedure Specific Postoperative Pain Management (PROSPECT) group recommended routine use of NSAIDs and recommended against routine use of opioid analgesics during laparoscopic cholecystectomy (Kehlet 2005). Another systematic review by Bisgaard et al. made similar recommendations as the PROSPECT group and in addition recommended against routine use of gabapentin during laparoscopic cholecystectomy (Bisgaard 2006). We do not recommend routine use of any of these pharmacological agents.

Authors' conclusions

Implications for practice.

There is evidence of very low quality that different pharmacological 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 research.

1. 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).

Notes

Change in review's author team. It is as follows: Kurinchi Selvan Gurusamy, Jessica Vaughan, Clare D Toon, Brian R Davidson.

Appendices

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 peritoneoscop* #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 peritoneoscop*) AND (cholecystectom* OR "cholecystectomy, laparoscopic"[MeSH]) AND (Analgesia OR bupivacain* OR buvacaina OR sensorcaine OR marcain* OR svedocain* OR levobupivacaine 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 epidural analgesia OR opioids analgesia OR preemptive gabapentin OR clonidine OR ketamine OR esmolol AND ("Pain"[Mesh] OR pain OR ache* OR suffering*) AND (((randomized controlled 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:noexp]) 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. 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 morphine 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 peritoneoscop*) #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 Indomethacine OR Paracetamolo OR tenoxicam OR parecoxib OR valecoxib OR intraperitoneal morphine OR intraperitoneal meperidine OR intraperitoneal bupivacaine OR thoracic epidural 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

Data and analyses

Comparison 1. NSAID versus control.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Morbidity	5	543	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.37, 1.53]
2 Proportion discharged as day‐surgery	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Length of hospital stay	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4 Pain (4 to 8 hours)	11	999	Mean Difference (IV, Fixed, 95% CI)	‐0.88 [‐1.07, ‐0.70]
5 Pain (9 to 24 hours)	9	707	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐0.67, ‐0.33]
6 Morbidity (sensitivity analysis)	5	2268	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.59, 1.07]
6.1 Best‐best	5	567	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.36, 1.53]
6.2 Best‐worst	5	567	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.23, 0.82]
6.3 Worst‐best	5	567	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.79, 2.67]
6.4 Worst‐worst	5	567	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.50, 1.36]
7 Proportion discharged as day‐surgery (sensitivity analysis)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.1 Best‐best	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Best‐worst	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 Worst‐best	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.4 Best‐worst	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Pain (4 to 8 hours) sensitivity analysis	4	433	Mean Difference (IV, Fixed, 95% CI)	‐0.91 [‐1.10, ‐0.71]
9 Pain (9 to 24 hours) sensitivity analysis	4	433	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐0.67, ‐0.33]
10 Pain (4 to 8 hours) stratified by drug	11	999	Mean Difference (IV, Fixed, 95% CI)	‐0.88 [‐1.07, ‐0.70]
10.1 Celecoxib	1	38	Mean Difference (IV, Fixed, 95% CI)	‐1.03 [‐7.01, 4.95]
10.2 Diclofenac	1	49	Mean Difference (IV, Fixed, 95% CI)	‐2.50 [‐7.56, 2.56]
10.3 Etofenomate	1	118	Mean Difference (IV, Fixed, 95% CI)	‐0.34 [‐0.60, ‐0.08]
10.4 Flurbiprofen	1	23	Mean Difference (IV, Fixed, 95% CI)	‐2.26 [‐3.26, ‐1.26]
10.5 Lornoxicam	1	150	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐3.13, ‐2.26]
10.6 Metamizol	1	40	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.74, 1.14]
10.7 Paracetamol	3	146	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐1.02, 0.82]
10.8 Parecoxib	4	355	Mean Difference (IV, Fixed, 95% CI)	‐0.76 [‐1.21, ‐0.31]
10.9 Tenoxicam	2	80	Mean Difference (IV, Fixed, 95% CI)	‐0.46 [‐4.42, 3.51]
11 Pain (4 to 8 hours) stratified by time	11	999	Mean Difference (IV, Fixed, 95% CI)	‐0.88 [‐1.07, ‐0.70]
11.1 Before	4	285	Mean Difference (IV, Fixed, 95% CI)	‐0.35 [‐0.60, ‐0.09]
11.2 During	1	150	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐3.13, ‐2.26]
11.3 After	4	271	Mean Difference (IV, Fixed, 95% CI)	‐0.73 [‐1.17, ‐0.29]
11.4 Before and after	2	293	Mean Difference (IV, Fixed, 95% CI)	‐0.69 [‐1.28, ‐0.11]
12 Pain (9 to 24 hours) stratified by drug	9	707	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐0.67, ‐0.33]
12.1 Celecoxib	1	38	Mean Difference (IV, Fixed, 95% CI)	‐0.37 [‐5.52, 4.78]
12.2 Diclofenac	1	49	Mean Difference (IV, Fixed, 95% CI)	0.5 [‐3.94, 4.94]
12.3 Etofenomate	1	118	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.22, 0.24]
12.4 Flurbiprofen	1	23	Mean Difference (IV, Fixed, 95% CI)	‐0.98 [‐2.08, 0.12]
12.5 Lornoxicam	1	150	Mean Difference (IV, Fixed, 95% CI)	‐2.07 [‐2.42, ‐1.72]
12.6 Metamizol	1	40	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐0.35, 1.15]
12.7 Paracetamol	2	77	Mean Difference (IV, Fixed, 95% CI)	0.21 [‐0.48, 0.90]
12.8 Parecoxib	3	132	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐1.08, 0.08]
12.9 Tenoxicam	2	80	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐4.10, 2.89]
13 Pain (9 to 24 hours) stratified by time	9	707	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐0.67, ‐0.33]
13.1 Before	4	285	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.22, 0.24]
13.2 During	1	150	Mean Difference (IV, Fixed, 95% CI)	‐2.07 [‐2.42, ‐1.72]
13.3 After	3	202	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.53, 0.20]
13.4 Before and after	1	70	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐3.62, 3.80]

1.10. Analysis.

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

1.11. Analysis.

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

1.12. Analysis.

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

1.13. Analysis.

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

Comparison 2. Opioid versus control.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain (4 to 8 hours)	3	425	Mean Difference (IV, Fixed, 95% CI)	‐2.51 [‐3.02, ‐2.01]
2 Pain (9 to 24 hours)	3	425	Mean Difference (IV, Fixed, 95% CI)	‐0.32 [‐0.44, ‐0.20]
3 Pain (4 to 8 hours) (sensitivity analysis)	1	306	Mean Difference (IV, Fixed, 95% CI)	‐2.56 [‐3.07, ‐2.05]
4 Pain (9 to 24 hours) (sensitivity analysis)	1	306	Mean Difference (IV, Fixed, 95% CI)	‐0.32 [‐0.44, ‐0.20]

Comparison 3. Anticonvulsant analgesic versus control.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Morbidity	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Pain (4 to 8 hours)	3	402	Mean Difference (IV, Fixed, 95% CI)	‐2.52 [‐2.95, ‐2.09]
3 Pain (9 to 24 hours)	3	402	Mean Difference (IV, Fixed, 95% CI)	‐0.55 [‐0.68, ‐0.42]
4 Morbidity (sensitivity analysis)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.1 Best‐best	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Best‐worst	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Worst‐best	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Worst‐worst	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Pain (4 to 8 hours) sensitivity analysis	1	306	Mean Difference (IV, Fixed, 95% CI)	‐2.88 [‐3.36, ‐2.40]
6 Pain (9 to 24 hours) sensitivity analysis	1	306	Mean Difference (IV, Fixed, 95% CI)	‐0.54 [‐0.67, ‐0.41]

Comparison 4. Anticonvulsant analgesic versus NSAID.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Morbidity	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Pain (4 to 8 hours)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3 Pain (9 to 24 hours)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4 Morbidity (sensitivity analysis)	1	240	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.50, 2.01]
4.1 Best‐best	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 20.90]
4.2 Best‐worst	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.07, 1.52]
4.3 Worst‐best	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.62, 40.28]
4.4 Worst‐worst	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.28, 2.44]

4.4. Analysis.

Comparison 4 Anticonvulsant analgesic versus NSAID, Outcome 4 Morbidity (sensitivity analysis).

Comparison 5. Anticonvulsant analgesic versus opioid.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain (4 to 8 hours)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2 Pain (9 to 24 hours)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Characteristics of studies

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: ASA I to III. Aged 18 to 75 years. Exclusion criteria: Cardiac, pulmonary, hepatic, or renal disease. Morbid obesity. Chronic pain. Drug or alcohol abuse. 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 conclusion of the study".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Group assignment code retained until the conclusion of the study".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Group assignment code retained until the conclusion of the study".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Agarwal 2008.

Methods	Randomised clinical trial.
Participants	Country: India. Number randomised: 60. Post‐randomisation drop‐outs: 4 (6.7%). Revised sample size: 56. Mean age: 46 years. Females: 19 (33.9%). Inclusion criteria: Aged 16 to 60 years. ASA physical status I or II. Undergoing laparoscopic cholecystectomy under general anaesthesia. Written informed consent given. Exclusion criteria: Impaired kidney functions. History of drug or alcohol abuse. History of chronic pain or daily intake of analgesics. Uncontrolled medical disease. History of intake of NSAIDs in 24 h before surgery. Inability to operated patient‐controlled analgesia.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: pregabalin 150 mg orally 1 h before surgery (n = 27). Group 2: placebo 1 h before orally surgery (n = 29).
Outcomes	Drug‐related serious adverse events and pain.
Notes	Reasons for post‐randomisation drop‐outs: conversion to open cholecystectomy (n = 3), re‐exploration on account of postoperative bleeding (n = 1). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated table of random numbers used".
Allocation concealment (selection bias)	Unclear risk	Quote: "Selected using sealed envelopes to be opened by anesthesia resident". Comment: Further details not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "All the medications…were identical, and were administered…by a staff nurse who was not involved in the study".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Outcomes were assessed by an independent anaesthesia registrar blinded to group allocation".
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Akaraviputh 2009.

Methods	Randomised clinical trial.
Participants	Country: Thailand. Number randomised: 70. Post‐randomisation drop‐outs: not stated. Revised sample size: 70. Mean age: 57 years. Females: 41 (58.6%). Inclusion criteria: People undergoing laparoscopic cholecystectomy. Aged > 18 years. Exclusion criteria: Hypersensitivity to NSAIDs. Conversion to open cholecystectomy.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: parecoxib 20 mg infusion 30 min before induction of anaesthesia and at 12 h after the first dose (n = 40). Group 2: saline infusion 30 min before induction of anaesthesia and at 12 h after the first dose (n = 30).
Outcomes	Pain.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Quote: "Sealed envelope technique used". Comment: Further details were not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: Further details were not available.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The degree of postoperative pain was assessed…by nursing staff who were unaware of the perioperative intervention".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Low risk	Comment: Supported by Faculty of Medicine Siriraj Hospital Research Project Grant.

Akarsu 2012.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Number randomised: 60. Post‐randomisation drop‐outs: 0 (0%). Revised sample size: 60. Mean age: 59 years. Females: 24 (40%). Inclusion criteria: ASA physical status I to III. Aged ≥ 18 years. Weighed > 40 kg. Exclusion criteria: Known allergy, sensitivity, or contraindication to pregabalin, diclofenac sodium, and pethidine, or any NSAID. Renal insufficiency. Severe coronary, pulmonary, hepatic disease. History of previous neurological disease or seizure disorder. A history of peptic ulcer. A history of alcohol or substance abuse. Ongoing therapy with sustained‐release opioids. Pregnancy. History of intake of NSAID and antidepressant drugs in 24 h before surgery.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: pregabalin 300 mg orally 1 h before surgery (n = 30). Group 2: diclofenac 75 mg IM 15 to 20 min before completion of surgery (n = 30).
Outcomes	Mortality, drug‐related serious adverse events, and pain.
Notes	Attempts were made to contact authors in August 2013. Authors provided replies.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Single‐blind study, subjects do not know the methodology applied. The investigator knows" (author replies).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The outcome assessors were blinded" (author replies).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Overall morbidity was not reported.
For‐profit bias	Low risk	Quote: "The study was funded by us" (author replies).

Akinci 2008.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Number randomised: 41. Post‐randomisation drop‐outs: not stated. Revised sample size: 41. Mean age: 45 years. Females: 27 (65.9%). Inclusion criteria: ASA status I or II. Exclusion criteria: Acute cholecystitis. History of analgesic or narcotic use. Previous abdominal surgery. Hypersensitivity to study drugs. Needed conversion to open cholecystectomy. Needed postoperative drains.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: tramadol 100 mg IV (n = 21). Group 2: placebo (n = 20).
Outcomes	No outcomes of interest for this review were reported.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computerised allocation schedule used".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Coded syringes used". Comment: Further details were not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Balaban 2012.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Number randomised: 90. Post‐randomisation drop‐outs: 0 (0%). Revised sample size: 90. Mean age: 53 years. Females: 69 (76.7%). Inclusion criteria: ASA physical status I or II. Aged ≥ 18 years. Scheduled for laparoscopic cholecystectomy. Exclusion criteria: Inability to co‐operate. Pregnancy. Emergency surgical intervention. Severe renal or hepatic dysfunction, or both. History of allergy to pregabalin. Limited or insufficient respiratory reserve. Conversion to open cholecystectomy. Duration of surgery in excess of 60 min.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: pregabalin 150 mg orally 1 h before surgery (n = 30). Group 2: pregabalin 300 mg orally 1 h before surgery (n = 30). Group 3: placebo orally (n = 30).
Outcomes	No outcomes of interest for this review were reported.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available
Allocation concealment (selection bias)	Unclear risk	Quote: "Randomisation achieved sealed envelope assignment". Comment: Further details were not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Belzarena 1998.

Methods	Randomised clinical trial.
Participants	Country: Portugal. Number randomised: 90. Post‐randomisation drop‐outs: not stated. Revised sample size: 90. Mean age: 42 years. Females: 65 (72.2%). Inclusion criteria: ASA I or II. Exclusion criteria: History of allergy or intolerance to NSAIDs. Concomitant disease that would allow any patient classification criteria ASA III or IV. Previous use of NSAIDs for any indication or self medication in the last 4 weeks. Liver or kidney disease. Pre‐existing asthma. Coagulation disorders or use of anticoagulants.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: tenoxicam 20 mg in 4‐mL saline IV (n = 30). Group 2: tenoxicam 40 mg in 4‐mL saline IV (n = 30). Group 3: saline IV (n = 30).
Outcomes	No outcomes of interest for this review were reported.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated table".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Venipuncture was performed by a nurse who was unaware of the nature of the study". Comment: Further details were not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Cheng 2004.

Methods	Randomised clinical trial.
Participants	Country: China. Number randomised: 60. Post‐randomisation drop‐outs: 1 (1.7%). Revised sample size: 59. Mean age: 50 years. Females: 37 (62.7%). Inclusion criteria: ASA I or II. Aged 18 to 75 years. Elective laparoscopic cholecystectomy. Exclusion criteria: Chronic pain other than gallstones. Acute cholecystitis. Advanced renal disease. Fluid retention. Heart failure. Pre‐operative NSAIDs or opioids within 24 h of the scheduled operation. Prescribed aspirin and sulphonamides. Known hypersensitivity to NSAIDs. Pregnancy. Unable to use patient‐controlled analgesia. Procedures converted to laparotomies.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: celecoxib 200 mg orally before surgery (n = 30). Group 2: placebo orally before surgery (n = 29).
Outcomes	Pain.
Notes	Reasons for post‐randomisation drop‐outs: non‐standardisation of the anaesthetic drugs (n = 1). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Quote: "Patients were randomized into two groups by sealed envelopes". Comment: Further details were not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "A post‐anaesthetic care unit nurse, who was unaware of the study drug recorded the time of the first dose of PCA morphine and evaluated the post operative pain and intensity". Comment: Further details were not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There was a post‐randomisation drop‐out but this was unlikely to be related to the intervention.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Chung 2004.

Methods	Randomised clinical trial.
Participants	Country: Canada. Number randomised: 84. Post‐randomisation drop‐outs: 15 (17.9%). Revised sample size: 69. Mean age: 48 years. Females: not stated. Inclusion criteria: Aged ≥ 18 years. Scheduled to undergo laparoscopic cholecystectomy.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: paracetamol (acetaminophen) 300 mg orally every 6 h for 48 h (n = 33). Group 2: placebo (n = 36). Co‐intervention: codeine 48 h postoperatively
Outcomes	Serious adverse events and pain.
Notes	Reasons for post‐randomisation drop‐outs: lack of pain (n = 4), loss to follow‐up (n = 3), adverse events (n = 3), inadequate pain control (n = 6) (note that there was discrepancy in the number of post‐randomisation drop‐outs and the reasons for drop‐outs in the report). Attempts were made to contact the authors. Replies were received from authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer generated sequence (author replies)".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Double‐dummy technique, with matching placebo used".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Outcome blinded" (author replies).
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality was not reported.
For‐profit bias	High risk	Quote: "This study was partially supported by a grant from Purdue Pharma (Canada) Inc".

Dong 2003.

Methods	Randomised clinical trial.
Participants	Country: not stated. Number randomised: 150. Post‐randomisation drop‐outs: not stated. Revised sample size: 150. Mean age: 48 years. Females: not stated. Inclusion criteria: People undergoing laparoscopic cholecystectomy.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: lornoxicam 16 mg (8 mg IM and 8 mg IV) (n = 50). Group 2: lornoxicam 24 mg (8 mg IM and 16 mg IV) (n = 50). Group 3: control (n = 50).
Outcomes	Pain.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Fanelli 2008.

Methods	Randomised clinical trial.
Participants	Country: Italy. Number randomised: 50. Post‐randomisation drop‐outs: 0 (0%). Revised sample size: 50. Mean age: 57 years. Females: not stated. Inclusion criteria: People scheduled for elective laparoscopic cholecystectomy. Aged ≥ 18 years. ASA status I, II, or III. Exclusion criteria: Allergy or contraindication to protocol drugs. Documented myocardial infarction in the previous 6 months. Impaired renal function. Uncontrolled hypertension. Body mass index > 30. Clinical history of respiratory pathologies with pharmacological therapy. Psychiatric disorders. Actual or suspected pregnancy. Anaemia. Epilepsy. Family history or previous history of malignant hyperthermia. Chronic treatment with pain medications.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: oxycodone, 10 mg for people with age ≥ 60 years and 20 mg for those aged < 60 years, orally 1 h before surgery and 12 h after the first administration (n = 25). Group 2: placebo 1 h before surgery and 12 h after the first administration (n = 25).
Outcomes	No outcomes of interest for this review were reported.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated random number table used".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Placebo tablets were apparently identical to the active drug tablets and all treatments were given to patients double blindly".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The patient was first asked by a blind observer to express his/her pain".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Low risk	Quote: "Sources of financial support for the work: University of Parma".

Forse 1996.

Methods	Randomised clinical trial.
Participants	Country: Canada. Number randomised: 60. Post‐randomisation drop‐outs: 8 (13.3%). Revised sample size: 52. Mean age: 47 years. Females: 32 (61.5%). Inclusion criteria: ASA I or II. Exclusion criteria: Allergy to study medications. History of prolonged bleeding. Peptic ulcer disease. Cardiac, lung, renal, or liver disease. Use of opiate or NSAIDs within 2 weeks of surgery. Open cholecystectomy.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: ketorolac IM before surgery (n = 17). Group 2: indomethacin rectally before surgery (n= 17). Group 3: placebo (n = 18).
Outcomes	Operative complications.
Notes	Reasons for post‐randomisation drop‐outs: not stated. Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Quote: "Sealed numbered envelopes". Comment: Further details were not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Gilron 2009.

Methods	Randomised clinical trial.
Participants	Country: Canada. Number randomised: 89. Post‐randomisation drop‐outs: 12 (13.5%). Revised sample size: 77. Mean age: 46 years. Females: 64 (83.1%). Inclusion criteria: Aged > 18 years. Body mass index < 36. ASA I or II. Elective cholecystectomy. Exclusion criteria: Hypersensitivity to any drugs to be used in the study. Serious organ disease/dysfunction. Persistent postoperative pain. Daily intake, or intake within 48 h before surgery, of any glucocorticoid drugs, NSAIDs, or other analgesics. Evidence of substance or alcohol abuse. Major psychiatric disorder. Bleeding disorder. Peptic ulcer disease. Moderate‐to‐severe asthma. Seizure disorder requiring treatment with anticonvulsant. Language barrier to communicating with research staff.
Interventions	Participants were randomly assigned to 1 of 3 groups: Group 1: meloxicam 15 mg daily orally, 1 h before until 2 days after surgery (n = 25). Group 2: gabapentin 1200 to 1600 mg daily orally 1 h before until 2 days after surgery (n = 27). Group 3: meloxicam 15 mg and gabapentin 1200 to 1600 mg daily orally 1 h before until 2 days after surgery (n = 25).
Outcomes	Serious adverse events and return to work.
Notes	Reasons for post‐randomisation drop‐outs: surgery cancellation (n = 2), dizziness (n = 3), liver laceration (n = 1), hypoxaemia (n = 1), intra‐operative electrocardiogram changes (n =1), personal reasons (n = 1), protocol withdrawal (n =1), reflux (n = 1), pruritus (n = 1). Attempts were made to contact the authors in August 2013. Replies from authors were received in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A concealed, computer‐generated random treatment allocation schedule, which randomized... three treatments".
Allocation concealment (selection bias)	Low risk	Quote: "The investigational pharmacist and the biostatistician determine the treatment randomization sequence and block size without sharing this information with trial investigators and research personnel (author replies)".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Study medications were encapsulated in identically appearing red (rofecoxib or "rofecoxib" placebo) and gray (gabapentin or "gabapentin" placebo) gelatin capsules".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality was not reported.
For‐profit bias	Low risk	Quote: "Supported by Physicians’ Services Incorporated Foundation Grant no. 03‐30 and by Canadian Institutes of Health Research Grant no. MSH‐55041".

Gomez‐Vazquez 2012.

Methods	Randomised clinical trial.
Participants	Country: Mexico. Number randomised: 40. Post‐randomisation drop‐outs: 0 (0%). Revised sample size: 40. Mean age: 30 years. Females: not stated Inclusion criteria: Aged 20 to 60 years. Weight 55 to 100 kg. Diagnosis of cholecystitis to be operated on electively. ASA status I or II. Exclusion criteria: History of alcohol. Psychotropic substances. Chronic obstructive pulmonary disease, asthma, or bronchospasm. Kidney or liver disease. History of cognitive impairment. Seizures. Peptic ulcer.
Interventions	Participants were randomly assigned to 1 of 2 groups: Group 1: morphine 0.15 mg/kg IV postoperatively for 40 min (n = 20). Group 2: ketorolac 0.7 mg/kg IV postoperatively for 40 min (n = 20).
Outcomes	No outcomes of interest for this review were reported.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Horattas 2004.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 120. Post‐randomisation drop‐outs: 4 (3.3%). Revised sample size: 116. Mean age: 49 years. Females: 85 (73.3%). Inclusion criteria: People undergoing laparoscopic cholecystectomy. Exclusion criteria: Allergy to rofecoxib or any other NSAIDs. Acute cholecystitis or pancreatitis. History of hepatic or renal disease. History of pain management problems. Chemical substance abuse. Emergency or non‐elective surgery. Conversion to open cholecystectomy. Pregnancy. Analgesic usage 6 h prior to scheduled surgery time.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: rofecoxib 50 mg orally preoperatively (n = 58). Group 2: placebo (n = 58).
Outcomes	Proportion discharged as day‐surgery.
Notes	Reasons for post‐randomisation drop‐outs: incomplete data extraction (n = 2), conversion to open cholecystectomy (n = 2). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The hospital pharmacist prepared individual unmarked 30 cc bottles of rofecoxib elixir (50 mg), or an identical amount of indistinguishable strawberry‐flavored placebo elixir. Bottles were randomly identified by number and then sequentially administered to each participating patient in the presurgery unit 1 to 2 hours before their surgery".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Ji 2010.

Methods	Randomised clinical trial.
Participants	Country: China. Number randomised: 30. Post‐randomisation drop‐outs: 0 (0%). Revised sample size: 30. Mean age: not stated. Females: not stated. Inclusion criteria: ASA I or II. Laparoscopic cholecystectomy. Exclusion criteria: History of bleeding liability. Gastrointestinal ulcer. Renal or hepatic dysfunction. Severe cardiovascular disease. Heave hypertension.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: flurbiprofen axetil 1.0 mg/kg parenteral (IV or IM not stated) postoperative (n = 15). Group 2: parecoxib 0.8 mg/kg parenteral (IV or IM not stated) postoperative (n = 15). Group 3: saline 10 mL postoperative (n = 15).
Outcomes	Pain.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Some important outcomes which will generally be assessed were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Joshi 2004.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 276. Post‐randomisation drop‐outs: 13 (4.7%). Revised sample size: 263. Mean age: 44 years. Females: 215 (81.7%). Inclusion criteria: People aged 18 to 75 years requiring elective ambulatory laparoscopic cholecystectomy. Exclusion criteria: Clinically diagnosed acute pancreatitis. Scheduled to undergo any surgical procedure expected to produce more trauma than laparoscopic cholecystectomy alone. Had acute preoperative pain other than biliary colic. Required chronic pain treatment. Had current or recent cancer or any condition that would contraindicate participation in a surgical study of this nature.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: parecoxib 40 mg IV 30 to 45 min before surgery plus oral valdecoxib 40 mg 6 to 12 h after IV parecoxib (n = 134). Group 2: placebo IV 30 to 45 min before surgery and oral placebo 6 to 12 h after IV placebo (n = 129).
Outcomes	Serious adverse events and pain.
Notes	Attempts were made to contact the authors in August 2013. Reasons for post‐randomisation drop‐outs: did not receive medication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Based on the computer generated randomization scheme".
Allocation concealment (selection bias)	Low risk	Quote: "The hospital pharmacist who was not involved with patient care or data collection prepared the IV study drugs (2 mL solution identical in appearance) and provided them to the investigator".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The hospital pharmacist who was not involved with patient care or data collection prepared the IV study drugs (2 mL solution identical in appearance) and provided them to the investigator".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The hospital pharmacist who was not involved with patient care or data collection prepared the IV study drugs (2 mL solution identical in appearance) and provided them to the investigator".
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality was not reported.
For‐profit bias	High risk	Quote: "Supported, in part, by Pharmacia Corporation and Pfizer Inc".

Karakoc 2011.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Number randomised: 80. Post‐randomisation drop‐outs: not stated. Revised sample size: 80. Mean age: not stated. Females: not stated.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: dexketoprofen trometamol 50 mg IV 30 min before the completion of surgery (n = not stated). Group 2: 0.9% normal saline IV 30 min before the completion of surgery (n = not stated). Co‐intervention: morphine at end of surgery in both groups, then delivered by patient‐controlled analgesia.
Outcomes	No outcomes of interest for this review were reported.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Some important outcomes which will generally be assessed were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Lane 1996.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 125. Post‐randomisation drop‐outs: 0 (0%). Revised sample size: 125. Mean age: 44. Females: 107. Inclusion criteria: People undergoing laparoscopic cholecystectomy. ASA status I or II. Exclusion criteria: Mentally and physically unable to fill out a simple form. Hypersensitivity to study medication. Receiving monoamine oxidase inhibitors.
Interventions	Participants were randomly assigned to 1 of 5 groups: Group 1: placebo (n = 23) Group 2: meripedine 100 mg IM intra‐operatively, pre‐procedure (n = 31). Group 3: meripedine 100 mg IM intra‐operatively, post‐procedure (n = 20). Group 4: ketorolac tromethamine 60 mg IM intra‐operatively, pre‐procedure (n = 25). Group 5: ketorolac tromethamine 60 mg IM intra‐operatively, post‐procedure (n = 26).
Outcomes	Drug‐related serious adverse events.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Liu 1993.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 60. Post‐randomisation drop‐outs: not stated. Revised sample size: 60. Mean age: 46 years. Females: 15 (25%). Inclusion criteria: ASA physical status I or II. Aged 18 to 65 years. Scheduled for elective laparoscopic cholecystectomy. Exclusion criteria: Pregnancy. Anyone chronically taking analgesics and psychotropic drugs. History of opioid abuse. Allergic reactions to NSAIDs or opioid analgesics.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: ketorolac 60 mg in 2 mL IM 20 to 40 min before surgery (n = 31). Group 2: saline 2 mL IM 20 to 40 min before surgery (n = 29). Co‐intervention: midazolam 2 mg.
Outcomes	No outcomes of interest for this review were reported.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Medication was prepared in a 2‐mL numbered (unlabeled) syringe by the pharmacy". Comment: Further details were not available.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Recorded by a blinded nurse observer".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Mebazaa 2008.

Methods	Randomised clinical trial.
Participants	Country: Canada. Number randomised: 75. Post‐randomisation drop‐outs: not stated. Revised sample size: 75. Mean age: 46 years. Females: not stated Inclusion criteria: People undergoing laparoscopic cholecystectomy. Aged 18 to 75 years. ASA class I or II. Exclusion criteria: Surgical complications. Surgery > 180 min. Use of intraperitoneal local anaesthetics. Deviation from the anaesthetic protocol. Surgical conversion. Contraindications to paracetamol (acetaminophen) and celecoxib.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: paracetamol (acetaminophen) 1000 mg orally 1 h before induction (n = 24). Group 2: celecoxib 200 mg orally 1 h before induction (n= 25). Group 3: control (n = 26).
Outcomes	Pain.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Munro 1998.

Methods	Randomised clinical trial.
Participants	Country: not stated. Number randomised: 40. Post‐randomisation drop‐outs: 3 (7.5%). Revised sample size: 37. Mean age: 51 years. Females: 30 (81.1%). Inclusion criteria: People undergoing laparoscopic cholecystectomy. Aged 18 to 70 years. Exclusion criteria: Hypersensitivity to NSAIDs. Possibility of pregnancy. Administration of opioid or NSAID 24 h before surgery. Use of diuretics or angiotensin‐converting enzyme inhibitors. Asthma. Peptic ulcers or peptic bleeding. Bleeding disorders. Renal impairment. Hepatic, cardiac, or haemopoietic disease. Inability to operate a patient‐controlled analgesia device.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: tenoxicam 40 mg IV on skin closure (n = 19). Group 2: placebo on skin closure (n = 18).
Outcomes	Drug‐related serious adverse events and pain.
Notes	Reasons for post‐randomisation drop‐outs: conversion to open cholecystectomy (n = 3). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Muñoz 2002.

Methods	Randomised clinical trial.
Participants	Country: Chile. Number randomised: 120. Post‐randomisation drop‐outs: not stated. Revised sample size: 120. Mean age: 42 years. Females: 80 (66.7%). Inclusion criteria: ASA status I or II. Aged 20 to 60 years. Exclusion criteria: Chronic or acute (within last 48 h) intake of sedatives or analgesic drugs. Adverse reaction to study drugs.
Interventions	Participants were randomly assigned to 1 of 4 groups. Group 1: morphine 0.15 mg/kg IV < 20 min before surgery (n = 33). Group 2: morphine 0.15 mg/kg IV 20 to 40 min before surgery (n = 30). Group 3: morphine 0.15 mg/kg IV > 40 min before surgery (n= 27). Group 4: placebo (n = 30).
Outcomes	No outcomes of interest for this review were reported.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated list".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Nesek‐Adam 2012.

Methods	Randomised clinical trial.
Participants	Country: Croatia. Number randomised: 80. Post‐randomisation drop‐outs: not stated. Revised sample size: 80. Mean age: 51 years. Females: 58 (72.5%). Inclusion criteria: Aged 18 to 70 years. Scheduled for laparoscopic cholecystectomy. ASA physical status I or II. Exclusion criteria: Pre‐existing neurological or psychiatric disease. Chronic pain syndrome. History of peptic ulceration, hepatic, and renal insufficiency. Pregnancy. Receiving regular opioids or drugs with any analgesic properties in 24 h before surgery. Operation for acute cholecystitis. Operation converted to an open procedure.
Interventions	Participants were randomly assigned to 1 of 4 groups. Group 1: diclofenac 1 mg/kg IV 20 min before induction (n = 20). Group 2: saline 100 mL IV 20 min before induction (n = 20). Group 3: same as group 1 with ketamine IV as co‐intervention (n = 20). Group 4: same as group 2 with ketamine IV as co‐intervention (n = 20).
Outcomes	Drug‐related serious adverse events.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated table of random numbers".
Allocation concealment (selection bias)	Unclear risk	Quote: "An envelope containing group assignment was prepared, sealed, and numbered for each patient". Comment: Further details were not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "On the morning of surgery, anesthesia technician opened the envelope and prepared completely identical syringes and infusion that were labeled "infusion" and "skin bolus" in equal volume to make the study double blind". Comment: Further details were not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Pandey 2004.

Methods	Randomised clinical trial.
Participants	Country: India. Number randomised: 459. Post‐randomisation drop‐outs: not stated. Revised sample size: 459. Mean age: 42 years. Females: 308 (67.1%). Inclusion criteria: ASA I or II. Aged 18 to 70 years. Elective laparoscopic cholecystectomy. Exclusion criteria: Body weight exceeding 20% of the ideal body weight. Known history of hypersensitivity to any drug. History of drug or alcohol abuse. Uncontrolled concomitant medical diseases. People with history of chronic pain conditions. Impaired kidney or liver function. Cholelithiasis with known common bile duct pathology or indications of cholecystectomy other than cholelithiasis, laparoscopic converted into open cholecystectomy. Administration of analgesics within 48 h of scheduled surgery.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: gabapentin 300 mg orally 2 h before surgery (n = 153). Group 2: tramadol 100 mg orally 2 h before surgery (n = 153). Group 3: placebo 2 h before surgery (n = 153).
Outcomes	Pain.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer generated table of random numbers used".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "A senior resident, who was not part of the anesthesia team recorded the pain score". Comment: Further details were not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Peng 2010.

Methods	Randomised clinical trial.
Participants	Country: Canada. Number randomised: 165. Post‐randomisation drop‐outs: 42 (25.5%). Revised sample size: 123. Mean age: 45 years. Females: 95 (77.2%). Inclusion criteria: Aged 18 to 65 years. ASA physical status I to III. Laparoscopic cholecystectomy. Exclusion criteria: Urgent or emergent cholecystectomy. Analgesics in 24 h before surgery. Body mass index > 40. Clinical diagnosis of acute pancreatitis. Contraindication to gabapentin, pregabalin, NSAIDs, codeine, or paracetamol (acetaminophen). Serious organ disease or dysfunction. Severe psychiatric disease. Drug addiction. Pregnancy. Unable to communicate in English.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: pregabalin 50 mg orally 1 h before surgery and then every 12 h after operation for 3 doses (n = 42). Group 2: pregabalin 75 mg orally 1 h before surgery and then every 12 h after operation for 3 doses. (n = 40). Group 3: placebo 1 h before surgery and then every 12 h after operation for 3 doses (n = 41).
Outcomes	Mortality.
Notes	Reasons for post‐randomisation drop‐outs: protocol violation (n = 23), questionnaire not completed or returned (n = 19). Attempts were made to contact authors in August 2013. Authors provided replies.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "According to a computer‐generated randomization list".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The study medications were prepared in capsules of identical colour and appearance and were packaged by the hospital pharmacy".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Morbidity was not reported.
For‐profit bias	High risk	Quote: "This research was funded by the Pfizer Global Investigator Initiated Grant. The medications in this study were provided by Pfizer Inc".

Puura 2006.

Methods	Randomised clinical trial.
Participants	Country: Finland. Number randomised: 75. Post‐randomisation drop‐outs: 3 (4%). Revised sample size: 72. Mean age: 46 years. Females: not stated Inclusion criteria: Aged 16 to 70 years. ASA physiological status I to III. Elective laparoscopic cholecystectomy. Exclusion criteria: Allergy to NSAIDs. Chronic pain syndrome. Psychiatric disorder. Substance abuse. Gastrointestinal bleeding. Any disease of the liver or the kidneys. Pregnancy. Congestive heart disease. Angina pectoris. Cerebrovascular circulatory symptoms. Body mass index > 40.
Interventions	Participants were randomly assigned to 1 of 3 groups. Group 1: etoricoxib 120 mg plus paracetamol (acetaminophen) 1 g orally 1.5 h before surgery (n = 25). Group 2: etoricoxib 120 mg orally 1.5 h before surgery (n = 24). Group 3: placebo 1.5 h before surgery (n = 23).
Outcomes	No outcomes of interest were reported.
Notes	Reasons for post‐randomisation drop‐outs: cirrhosis (n = 1), needed open cholecystectomy (n = 2). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Using a random number table".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Drug‐containing bags used". Comment: Further details were not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Low risk	Quote: "This study was supported by a grant from the Medical Research Fund of Tampere University Hospital".

Salihoglu 2009.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Number randomised: 40. Post‐randomisation drop‐outs: 0 (0%). Revised sample size: 40. Mean age: 42 years. Females: 31 (77.5%). Inclusion criteria: ASA status I or II. Exclusion criteria: Chronic analgesic or alcohol intake. Hypersensitivity to the drugs used in the study. Body mass index > 35. Diminished liver and kidney functions.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: paracetamol (acetaminophen) 1 g IV after intubation (n = 20). Group 2: saline IV after intubation (n = 20).
Outcomes	Serious adverse events.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Random number generator".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The anaesthetist who intubated and followed the patient during surgery, and the surgical team were also unaware about which patient received paracetamol or not".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The researchers were unaware about the patients or the anaesthetists, who were taken into the study while the study was going on". Comment: Further details not available.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality was not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Sandhu 2011.

Methods	Randomised clinical trial.
Participants	Country: Thailand. Number randomised: 120. Post‐randomisation drop‐outs: 1 (0.8%). Revised sample size: 119. Mean age: 53 years. Females: 78 (65.5%). Inclusion criteria: ASA I or II. Aged 18 to 75 years. Elective laparoscopic cholecystectomy. Exclusion criteria: Acute pre‐operative pain other than biliary colic. Chronic pain treatment. Advanced renal disease, heart failure, or fluid retention. Use of pre‐operative NSAIDs or opioids within 24 h of the scheduled operation. Known hypersensitivity to NSAIDs. Pregnancy.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: etoricoxib 120 mg (route not stated) 1 h before surgery (n = 60). Group 2: placebo 1 h (route not stated) before surgery (n = 59).
Outcomes	Length of hospital stay.
Notes	Reasons for post‐randomisation drop‐outs: conversion to open cholecystectomy (n = 1). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There was one post‐randomisation drop‐out.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Low risk	Quote: "This study was supported by the Prasert Prasarttong‐Osoth Research Fund, Medical Association of Thailand".

Sarakatsianou 2013.

Methods	Randomised clinical trial.
Participants	Country: Greece. Number randomised: 50. Post‐randomisation drop‐outs: 10 (20%). Revised sample size: 40. Mean age: 54 years. Females: 24 (60%). Inclusion criteria: ASA physical status I or II. Elective laparoscopic cholecystectomy under general anaesthesia. Exclusion criteria: History of chronic pain or daily use of analgesics. Renal or hepatic insufficiency. Uncontrolled medical diseases. Psychiatric disorders. History of alcohol or drug abuse. Inability of person to use patient‐controlled analgesia pump. Administration of NSAIDs within 24 h before surgery. Use of drainage at the end of the procedure.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: pregabalin 600 mg orally divided in 2 doses, the night before surgery and 1 h preoperatively (n = 20). Group 2: placebo divided in 2 doses, the night before surgery and 1 h preoperatively (n = 20).
Outcomes	Pain.
Notes	Reasons for post‐randomisation drop‐outs: converted to open cholecystectomy (n = 4), use of drain (n = 6). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated table of random numbers with sex stratification".
Allocation concealment (selection bias)	Unclear risk	Quote: "Patients were randomised by a computer‐generated, blinded randomisation list". Comment: Further details were not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "All medications were provided by the hospital pharmacy, and they were identical in shape and colour".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Schuster 2005.

Methods	Randomised clinical trial.
Participants	Country: USA. Number randomised: 80. Post‐randomisation drop‐outs: 8 (10%). Revised sample size: 72. Mean age: not stated. Females: not stated. Inclusion criteria: People undergoing laparoscopic cholecystectomy. Aged ≥ 18. Exclusion criteria: Acute cholecystitis. Conversion to open cholecystectomy. Renal insufficiency or failure. History of gastrointestinal bleeding. Allergy to NSAIDs or cyclo‐oxygenase‐2 inhibitors.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: rofecoxib 25 mg orally presurgically (n = not stated). Group 2: placebo (n = not stated).
Outcomes	Serious adverse events, hospital stay, and pain.
Notes	Reasons for post‐randomisation drop‐outs: converted to open cholecystectomy (n = 2), refused (n = 2), acute cholecystitis (n = 3), postoperative NSAID use (n = 1). Attempts were made to contact authors in August 2013. There were no serious adverse events in either group. There was no significant difference in the length of hospital stay and pain in either group.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Random card pull design method". Comment: Further details were not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "The patient, surgeon and researcher were all blinded to the patient's treatment group". Comment: Further details were not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The patient, surgeon and researcher were all blinded to the patient's treatment group". Comment: Further details were not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Sen 2010.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Number randomised: 120. Post‐randomisation drop‐outs: 2 (1.7%). Revised sample size: 118. Mean age: 54 years. Females: 81 (68.6%). Inclusion criteria: ASA physical status I or II. Elective laparoscopic cholecystectomy under general anaesthesia. Exclusion criteria: Acute cholecystitis. Acute pancreatitis. Known history of hypersensitivity to any drug. Uncontrolled concomitant medical diseases. Chronic opioid therapy. Cholelithiasis with known bile duct pathology. Administration of analgesics within 48 h of the day before surgery.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: etofenomate 1 g (2 mL) IM 1 h before surgery (n = 59). Group 2: saline IM 1 h before surgery (n = 59).
Outcomes	Pain.
Notes	Reasons for post‐randomisation drop‐outs: protocol violation (n = 2). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated, blinded randomisation list".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Wilson 1994.

Methods	Randomised clinical trial.
Participants	Country: England. Number randomised: 55. Post‐randomisation drop‐outs: 6 (10.9%). Revised sample size: 49. Mean age: 48 years. Females: 40 (81.6%). Inclusion criteria: People undergoing laparoscopic cholecystectomy. Exclusion criteria: Peptic ulcer disease. Hepatic or renal insufficiency. History of haemorrhagic diathesis. Hypersensitivity to diclofenac.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: diclofenac 75 mg IM (n = 26). Group 2: placebo (n = 23).
Outcomes	Pain.
Notes	Reasons for post‐randomisation drop‐outs: incomplete data extraction (n = 3), conversion to open (n = 3). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer random number generation".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Pharmacy provided identical pre‐packed syringes".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Yeh 2004.

Methods	Randomised clinical trial.
Participants	Country: Taiwan. Number randomised: 44. Post‐randomisation drop‐outs: 1 (2.3%). Revised sample size: 43. Mean age: 49 years. Females: 27 (62.8%). Inclusion criteria: ASA physical status I or II. Elective laparoscopic cholecystectomy. Exclusion criteria: NSAIDs contraindicated. Received opioids or NSAIDs less than 1 week before the study.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: tenoxicam 40 mg IV 30 min before incision (n = 21). Group 2: saline 30 min before incision (n = 22).
Outcomes	Pain.
Notes	Reasons for post‐randomisation drop‐outs: ineligibility for laparoscopic cholecystectomy (n = 1). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The study drugs were prepared by the hospital pharmacy in identical, consecutively numbered containers marked with the name of the project, the investigator’s name and route of administration".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There was one post‐randomisation drop‐out.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Zajaczkowska 2004.

Methods	Randomised clinical trial.
Participants	Country: Poland. Number randomised: 60. Post‐randomisation drop‐outs: not stated. Revised sample size: 60. Mean age: 51 years. Females: 44 (73.3%). Inclusion criteria: Symptomatic gallstone disease. ASA I or II. Age > 18 years. Exclusion criteria: Acute cholecystitis. Significant cardiac, respiratory, hepatic, renal, or neurological disease. Local anaesthetic and morphine allergies. Analgesics for non‐biliary complaints.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: morphine SC (n = 30). Group 2: no intervention (n = 30).
Outcomes	Pain.
Notes	Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated random‐number table".
Allocation concealment (selection bias)	Unclear risk	Quote: "Sealed envelope method used". Comment: Further details not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Zhu 2011.

Methods	Randomised clinical trial.
Participants	Country: China. Number randomised: 60. Post‐randomisation drop‐outs: 1 (1.7%). Revised sample size: 59. Mean age: 44 years. Females: 25 (42.4%). Inclusion criteria: ASA physical status I or II. Scheduled for laparoscopic cholecystectomy. Aged 33 to 65 years. Exclusion criteria: History of chronic pain or daily intake of analgesics. Uncontrolled medical disease. Inability to operated patient‐controlled analgesia.
Interventions	Participants were randomly assigned to 1 of 2 groups. Group 1: dezocine 0.1 mg/kg IM 10 min before induction (n = 30). Group 2: saline IM 10 min before induction (n = 29).
Outcomes	Pain.
Notes	Reasons for post‐randomisation drop‐outs: conversion to open cholecystectomy (n = 1). Attempts were made to contact authors in August 2013.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated table used".
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This information was not available.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There was one post‐randomisation drop‐out.
Selective reporting (reporting bias)	High risk	Comment: Some important outcomes which will generally be assessed were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

ASA: American Society of Anesthesiologists; h: hour; IM: intramuscular; IV: intravenous; min: minute; NSAID: non‐steroidal anti‐inflammatory drug; SC: subcutaneous.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Aftab 2008	Quasi‐randomisation used.
Akca 2004	Separate data for laparoscopic cholecystectomy not available.
Bajaj 2004	Separate data for laparoscopic cholecystectomy not available.
Boccara 2005	Compares different NSAIDs.
Collard 2007	Compares different opioids.
Elhakim 2000	Compares different routes of administration of NSAIDs.
Gan 2004	Combination of ≥ 2 classes of drug used.
Hernandez‐Palazon 2003	Trial features intraperitoneal installation of local anaesthetics.
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]

Gan 2003.

Methods
Participants
Interventions
Outcomes
Notes	Full text unavailable.

Differences between protocol and review

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.

Contributions of authors

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.

Sources of support

Internal sources

• None, Other.

External sources

• None, Other.

Declarations of interest

None known.

New