Comparison of Ketorolac versus Diclofenac as Treatment for Acute Renal Colic : A Systematic Review and A Network Meta-Analysis

Acute renal colic is one of the most frequent urologic visits in Emergency Department (ED), and early management should focus on early relief of pain. Non-steroidal anti-inflammatory drugs (NSAIDs), opiates, or combination of both are often used to treat this condition. Diclofenac is stated in European Association of Urology (EAU) guideline as first line treatment. Interestingly, it is ketorolac that currently the most common analgesics used in most EDs. A meta-analysis study was designed to investigate whether ketorolac or diclofenac is a better NSAID for early pain relief in acute renal colic patients. Relevant studies were obtained from PubMed, Science Direct, Cochrane, EBSCO, and Proquest. Based on current studies, both ketorolac and diclofenac are found superior than pethidine, while both providing a comparable pain relief with diclofenac regarded as a safer option. Further prospective data is needed in Indonesian clinical settings for its assurance in efficacy and safety


INTROdUCTION
Acute renal colic is one of the most frequent urologic visits in Emergency Department (ED). 1,2It is usually described as sudden onset of flank pain that sometimes radiate to groin.Upon patients' arrival at ED, early clinical examination and radiology investigations is mandatory because many other life threatening conditions could be misdiagnosed as renal colic pain. 1,2nal colic is acute pain due to obstruction caused by urinary stones.As most stones will eventually pass without any interventions, early management in emergency should focus on early relief of pain.Non-steroidal anti-inflammatory drugs (NSAIDs), opiates, or combination of both are often used to treat this condition.Diclofenac is stated in European Association of Urology (EAU) guideline as first line treatment. 2,3Interestingly, it is ketorolac that currently the most common analgesics used in most EDs.Its low cost and vast availability stood as the main consideration. 4 meta-analysis study was designed to investigate whether ketorolac or diclofenac is a better NSAID for early pain relief in acute renal colic patients.

METHOdS
Relevant studies were obtained from PubMed, Science Direct, Cochrane, EBSCO, and Proquest.We used "(ketorolac OR diclofenac) AND (pethidine) AND (acute renal colic OR kidney stone OR urolithiasis OR nephrolithiasis)" as keywords.All keywords were searched for their respective MeSH thesaurus.Our search strategy was not limited by date or publication status.Trials included were RCTs, comparing either ketorolac or diclofenac with pethidine, adults sample diagnosed with acute renal colic, and measured pain free as outcome.Our PICO and search strategy can be seen in table 1 and diagram 1.

RESULTS
Our search found limited studies directly compared ketorolac and diclofenac.We also faced drawbacks as some studies did not use pain-free criteria as its main output but the visual analog scale (VAS) pain reduction.However, there were several studies comparing NSAIDs with opioids.As seen in diagram 1, we managed to collect a total of 662 studies from 5 search engines using the same keywords, included only Englishwritten RCTs.We focused on 13 studies, with 5 duplicated studies among them.Full text reading was done to screen for studies that matched our PICO.one hour after dosing also provided by the author. 5Other study done by Sandhu, et al, also showed a similar result.In their study, 30 mg of ketorolac and 100 mg of pethidine were used with VRS as its outcome.We noted the number of patients who did not need any rescue drugs in the first 24 hours.This study reported an OR of 0.46 [95% CI 0.23;0.89]. 6ese two studies were homogenous (P=0,33; I 2 =0%) with only one study (Sandhu, et   8 Hetherington, et al, also showed that diclofenac was superior to pethidine to achieve satisfactory relief of pain with OR 0.13 (0.03; 0.66). 9 These three studies had moderate heterogenicity (P=0,06; I 2 =64%) with only one study (Hetherington, et al) found significant difference (CI of the OR less than 1).Combined analysis of these studies showed a significant higher rate of complete pain relief in patient with diclofenac compared to pethidine with OR 0,52 [95% CI 0,29;0,92].This result is still consistent with previous analysis between NSAIDs and all pethidine.
A study by Cohen, et al, compared directly ketorolac and diclofenac.In this study, 27 samples used 30 mg ketorolac and 30 others used diclofenac.The outcome measured in this study was the need of rescue medicine in the first one hour (60 minutes after recieving either ketorolac or diclofenac).This study showed a trend towards a higher rate of complete pain relief in patients treated with diclofenac, but this finding was not significant (p=0,14) with OR 2,74 [95% CI 0,72-10,43]. 10 used a Bucher Model of indirect comparison using Mantel-Haenszel analysis for subgroups differences. 11Thus, we are able to calculate and decided that all studies in both groups are homogenous (p = 0.17; I 2 = 37%).Therefore, we could use random effect analysis models using RevMan 5.3, as described by Borrenstein, et al, to measure the differences in both subgroups. 12,13The test reveals that there is no significant difference between ketorolac and diclofenac (p = 0.48).Total events 67 85

Total events
Odds Ratio Total Heterogenei ty:Tau 2 = 0.15, Chi 2 = 6.40, df = 4 (P =0.17); l 2 = 37% Z = 2.30 (P= 0.02) Test for overal l effect: Test for subgroup di fferences:Chi 2 = 0.48, df = 1 (P =0.49); l 2  In a specific urologic point of view, ketorolac has a higher risk of acute kidney problems compared with other NSAID.A cohort study in Philadelphia by Feldman, et al, documented the event of acute renal failure in patients receiving ketorolac is 3.8 per 1000 courses.This study also stated that the overall incidents of acute renal failure was 1.1% after receiving either ketorolac or opioid as therapy. 17A more recent study by Ingrasciotta, et al, in 2015 reported risks of chronic kidney disease in patients receiving NSAID.Ketorolac group held the highest risk with adjusted OR of 2.54 compared with diclofenac of only 0.86. 18SCUSSION ANd ANALySIS Pathophysiology of Colic Pain The pain in renal colic is due to obstruction in urinary flow resulting in a combination of responses within the urinary system.At first, there will be an increased stimulation for ureteric peristalsis as natural effort to expel the stone.However, if the stone persist, the surrounding smooth ureteric muscle spasm will occur.Hence, increasing pressure proximally of the stone.This increase in pressure leads to the main mechanism of colic pain: distension of renal capsule and increased in prostaglandin synthesis.Distended renal capsule itself will stimulate pain sensation directly.This pain will then be relayed to central nerves system through renal nerves. 2,4,19rthermore, the release on prostaglandin will initiate a series of cascade that worsened the condition.First, it causes local inflammation and edema that further increase prostaglandins production.Then more muscle spasm induced causing further increased in wall tension, which apparently will also increase prostaglandins.Finally, it will affect renal blood flow causing vasodilatation resulting in a diuresis and lattermost, cycling back for an increased in intrarenal pressure.The mechanism of colic pain is described in diagram 2. 2,4,19 Therapeutic Strategy Our findings in this study suggest that NSAID have a better pain relief rate than opioid.As seen in table 4, we analyzed five studies comparing NSAID (either ketorolac or diclofenac) with opioid (pethidine).The combined analyses significantly favoring NSAID over pethidine for difference in pain relief.Moreover, further analyses comparing ketorolac or diclofenac with pethidine separately, also resulting in significant favor of both ketorolac and diclofenac over pethidine (seen in table 5 and table 6).This result could be well explained by the mechanism of actions of both NSAID and opioid.
Both NSAID and opioid provide pain relief for acute renal colic patients in their own distinct  pathways (as seen in diagram 2).The usage of narcotic agent, such as pethidine, has long been known to effectively reduced pain.It exerts its analgesic effect by acting agonist at the µ opioid receptor at the central nerves system, thereby reducing pain sensation.However, there is no data supporting the ability of opioid to reduce muscle spasm.
They also have minimum effect on the core problems in colic pain; the synthesis of prostaglandins.Based on the other five studies, we performed an indirect analysis which gave similar results.Even though ketorolac was regarded as the most potent pain reliever among NSAIDs for various other pain condition, in accordance with our results, we might assume that, in managing acute renal colic pain, there is no difference between ketorolac and diclofenac.
However, it is well noted that ketorolac has a much higher risk of adverse events as stated before.These differences in side effect (GI and kidney problems) might be explained with further particularizing on both drugs' pharmacokinetics and pharmacodynamics (Table 9).Problems in GI system are caused by the abundance of COX-1 receptor in GI mucosal lining.[16] On the other hand, the receptors exist in urinary system are also COX-1, making GI issues unavoidable.We could minimize it however, as studies reported a much lower incidence of GI problems in diclofenac compared to ketorolac.[16] Yet a more important topic arises, as ketorolac also associated with serious kidney problems.Studies reported that ketorolac has a higher risk of inducing AKI or CKD after its treatment, especially for those with previously diagnosed kidney disease.This might be affected due to ketorolac is mainly excreted through kidney (90%), compared with diclofenac that is excreted through liver and kidney (40% liver, 60% kidney).A complete review can be seen in table 9. 17,18 CONCLUSION For patients with acute renal colic in emergency department, we recommend an expedient usage of analgesics.Based on current studies, both ketorolac and diclofenac are found superior than pethidine, while both providing a comparable pain relief with diclofenac regarded as a safer option.Consideration left is applicability issue, of which is yet to be decided as further prospective data is needed in Indonesian clinical settings for its assurance in efficacy and safety. disclaimer 94, Chi 2 = 5.49, df = 2 (P =0.06); l 2 = 64% Total (95%Cl )

table 6
).Finally, a direct and indirect comparison of ketorolac and diclofenac was done (table7 and table 8).The opioid used for renal colic treatment in these studies is pethidine.Five studies (752 participants) reported the proportion of patients who failed to achieve complete pain relief at 60 minutes after

Table 2 .
Summary of search results

Table 3 .
Critical appraisal according to Oxford CEBM worksheet for therapy

Table 5 .
Comparison of ketorolac and pethidine

Table 6 .
Comparison of diclofenac and pethidine

Table 7 .
Direct comparison of ketorolac and diclofenac

Table 9 .
Pharmacokinetics and pharmacodynamics