Background
Non-steroid anti-inflammatory drugs (NSAIDs) such as diclofenac, ketorolac, tenoxicam, flurbiprofen, etc. are commonly used to relieve biliary colic pain.
Study characteristics
We searched for randomised clinical trials recruiting participants presenting with biliary colic and comparing NSAIDs versus no intervention, placebo, or other drugs.
Key results
We included 12 randomised clinical trials with 828 participants, of whom 416 received NSAIDs and 412 received placebo, spasmolytic drugs, or opioids, in the review. Considering the common occurrence of biliary colic, these numbers of trials and participants are insufficient. Elderly participants and participants with co-morbidities were poorly represented in the trials. Twenty-four per cent of the participants were males. The age of participants ranged from 18 to 86 years. All people were admitted to emergency department for acute biliary pain. There was no mortality. None of the included trials reported quality of life. We found that NSAIDs significantly reduced biliary pain when compared with placebo and spasmolytic drugs. NSAIDs also significantly reduced cholelithiasis-related complications (e.g. acute cholecystitis, acute pancreatitis, jaundice, cholangitis) as compared to placebo and spasmolytic drugs. One trial comparing NSAIDs versus opioids reported results on complications, finding no significant difference between treatments.
None of the trials reported major adverse events. Seven out of 12 trials reported minor adverse events; in two out of the eight trials adverse events were not observed, and minor events were reported in the remaining five trials.
We found one ongoing randomised clinical trial aimed at assessing the analgesic effectiveness of intravenous ibuprofen in biliary colic.
Funding
The trials appeared to be free of industry sponsorship or other type of for-profit support that may manipulate the trial design, conductance, results, or conclusions of the trial.
Quality of evidence
The quality of evidence according to GRADE criteria (a system developed to grade evidence and recommendations in health care) was moderate for the comparison NSAIDs versus placebo for the outcome lack of pain relief and low or very low for the other outcomes and comparisons.
Only one of 12 trials was at low risk of bias following predefined 'Risk of bias' domains.
The results of the present systematic review with meta-analysis suggest that NSAIDs can be used for pain relief, but further randomised clinical trials are warranted, and NSAIDs should be used with care in certain patient groups, such as the elderly and people with co-morbidities.
NSAIDs have been assessed in relatively few trials including a limited number of participants for biliary colic, considering its common occurrence. We found only one trial to be at low risk of bias. There was no mortality. None of the included trials reported quality of life. The generalisability of the review is low as most of the RCTs included neither elderly people nor participants with comorbidities, who are more prone to complications as compared to others with biliary colic.
The beneficial effect of NSAIDs compared with placebo on pain relief was confirmed when we applied Trial Sequential Analysis.
The quality of evidence according to GRADE criteria was moderate for the comparison of NSAIDs versus placebo regarding the outcome lack of pain relief and low or very low for the other outcomes and comparisons.
We found only one trial at low risk of bias, following the predefined 'Risk of bias' domains. We found the risk of selection bias to be unclear in nine studies due to poor reporting, leading to uncertainty in the pooled effect estimates.
Cholelithiasis refers to the presence of gallstones, which are concretions that form in the biliary tract, usually in the gallbladder. Cholelithiasis is one of the most common surgical problems worldwide and is particularly prevalent in most Western countries.
Biliary colic is the term used for gallbladder pain experienced by a person with gallstones and without overt infection around the gallbladder. It is the most common manifestation of cholelithiasis, observed in over one-third of people with gallstones over the course of 10 or more years. Non-steroid anti-inflammatory drugs (NSAIDs) have been widely used to relieve biliary colic pain, but their role needs further elucidation. They may decrease the frequency of short-term complications, such as mild form of acute cholecystitis, jaundice, cholangitis, and acute pancreatitis, but they may also increase the occurrence of more severe and possibly life-threatening adverse events such as gastrointestinal bleeding, renal function impairment, cardiovascular events, or milder events such as abdominal pain, drowsiness, headache, dizziness, or cutaneous manifestations.
To assess the benefits and harms of NSAIDs in people with biliary colic.
We searched the Cochrane Hepato-Biliary Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE (Ovid SP), Embase (Ovid SP), Science Citation Index Expanded (Web of Science), and ClinicalTrials.gov until July 2016. We applied no language limitation.
Randomised clinical trials recruiting participants presenting with biliary colic and comparing NSAIDs versus no intervention, placebo, or other drugs.
Two review authors (MF and AC) independently identified trials for inclusion. We used risk ratios (RR) to express intervention effect estimates, and we analysed the data with both fixed-effect and random-effects model meta-analyses, depending on the amount of heterogeneity. We controlled random errors with Trial Sequential Analysis. We assessed the methodological quality of the evidence using GRADE criteria.
Twelve randomised clinical trials (RCTs) met our predefined review protocol criteria for analysis. We found only one trial to be at low risk of bias, considering the remaining trials to be at high risk of bias. The risk of selection bias in nine studies was unclear due to poor reporting, leading to uncertainty in the pooled effect estimates. Five trials compared NSAIDs versus placebo, four trials compared NSAID versus opioids, and four trials compared NSAID versus spasmolytic drugs (one of the 12 trials was a three-arm study comparing NSAIDs versus both opioids and spasmolytic drugs). There were 828 randomised participants (minimum 30 and maximum 324 per trial), of whom 416 received NSAIDs and 412 received placebo, spasmolytic drugs, or opioids. Twenty-four per cent of the participants were males. The age of the participants in the trials ranged from 18 to 86 years. All people were admitted to emergency departments for acute biliary pain. There was no mortality. When compared with placebo, NSAIDs obtained a significantly lower proportion of participants without complete pain relief (RR 0.27, 95% confidence interval (CI) 0.19 to 0.40; I2 = 0%; 5 trials; moderate-quality evidence), which was confirmed by Trial Sequential Analysis, but not regarding participants with complications (RR 0.66, 95% CI 0.38 to 1.15; I2 = 26%; 3 trials; very low-quality evidence). NSAIDs showed more pain control than spasmolytic drugs (RR 0.51, 95% CI 0.37 to 0.71; I2 = 0%; 4 trials; low-quality evidence), which was not confirmed by Trial Sequential Analysis, and a significantly lower proportion of participants with complications (RR 0.27, 95% CI 0.12 to 0.57; I2 = 0%; 2 trials; low-quality evidence), which was also not confirmed by Trial Sequential Analysis. We found no difference in the proportions of participants without complete pain relief when comparing NSAIDs versus opioids (RR 0.98, 95% CI 0.47 to 2.07; I2 = 52%), suggesting moderate heterogeneity among trials (4 trials; very low-quality evidence). Only one trial comparing NSAIDs versus opioids reported results on complications, finding no significant difference between treatments. None of the included trials reported severe adverse events. Seven out of the 12 trials assessed non-severe adverse events: in two out of the seven trials, adverse events were not observed, and minor events were reported in the remaining five trials.
In addition, we found one ongoing RCT assessing the analgesic efficacy of intravenous ibuprofen in biliary colic.