Systematic review of the relative efficacy of non-steroidal anti-inflammatory drugs and opioids in the treatment of acute renal colic
http://www.100md.com
《英国医生杂志》
1 Department of Emergency Medicine, St George Hospital, Gray St, Kogarah, NSW 2217, Australia
Correspondence to: A Holdgate holdgatean@sesahs.nsw.gov.au
Abstract
Of 74 potentially relevant studies, we excluded 49 on review of the abstract (fig 1). Twenty five articles were retrieved for more detailed evaluation, of which five were excluded for failure to meet our inclusion criteria, leaving 20 trials for review.4 11 12 17-33
Fig 1 Flow of studies through trial
Study characteristics
The 20 trials were conducted in nine countries, included 1613 participants, and were published between 1982 and 1999 (table 1). Most studies included only those participants with renal calculi confirmed on subsequent testing using a variety of techniques, specifically excluding patients without such a confirmation. Overall, the trials used five different NSAIDs and seven different opioids, although each trial used only one type of each drug. All but two trials used fixed doses of drugs, regardless of the patient's weight.22 32 Drugs were given by the parenteral route (intravenous or intramuscular) in all but three trials. In these three trials, NSAIDs were given orally or rectally and opioids were given parenterally.18 20 31
Table 1 Characteristics of included studies of efficacy of non-steroidal anti-inflammatory drugs compared with opioids for pain relief in acute renal colic
Many of the included trials did not report variance data or outcomes in a form suitable for meta-analysis, and we were unable to gain any further information from the authors. Six studies had treatment arms in addition to NSAIDs and opioids12 17 20 23 25 28; we analysed only data for the opioid and NSAID groups for these trials. Two studies used a crossover design, when the comparator drug was given if inadequate analgesia was achieved with the first drug. We included only data from the precrossover phase of these trials.18 21 One study included a third treatment arm with combined opioids and NSAIDs.11 Data from this treatment arm were not included.
No trial reported time to pain relief, although several reported the proportion of patients with complete pain relief within a fixed time. We therefore used this proportion as an alternative outcome measure. No trials reported rates of pain recurrence or specifically reported serious adverse events such as renal dysfunction or gastrointestinal bleeding.
Overall, no single study met all the quality criteria (table 2). For most studies, quality criteria were not met owing to lack of information rather than explicit reporting of methods that did not conform to the quality criteria.
Table 2 Assessment of quality criteria for trial of efficacy of non-steroidal anti-inflammatory drugs and opioids for pain relief in acute renal colic
As the results from random and fixed effects models did not differ, we report only results from the random effects model.
Patient rated pain scores
Fifteen trials measured pain scores at enrolment and at a fixed time after the study drug had been given. In two trials this outcome was measured but not reported.19 20 Four trials reported data that were not suitable for pooled analysis.29-32 All but one of these four trials showed a greater reduction in pain scores in the NSAID group than in the opioid group.30 Nine trials reported pain on a 100 mm visual analogue scale; six recorded scores at 30 minutes,4 11 17 25 27 33 two at 20 minutes,21 22 and one at 60 minutes.26 Seven of the nine trials favoured treatment with NSAIDs,11 17 21 25-27 33 one showed no difference,4 and one showed lower pain scores in patients treated with opioids.22 Subgroup analysis by type of NSAID showed heterogeneity for studies using ketorolac but homogeneity among all other trials using any other type of NSAID. Combined analysis of the six trials not using ketorolac showed the visual analogue scale was on average 4.6 mm (95% confidence interval 1.7 mm to 7.5 mm) lower in patients receiving NSAIDs than in those receiving opioids (fig 2). Subgroup analysis by type and route of opioid did not explain heterogeneity. Addition of the three trials using ketorolac to the pooled analysis showed a similar effect. We could find no obvious biological or clinical explanation for this heterogeneity.
Fig 2 Patient rated scores on visual analogue scale for pain due to renal colic according to type of non-steroidal anti-inflammatory drug, excluding trials using ketorolac
Of the 13 trials with reported results, 10 found lower pain scores in patients treated with NSAIDs, two showed no difference, and only one found lower pain scores in patients treated with opioids.
Failure to achieve complete pain relief
Nine trials (647 participants) reported the proportion of patients who failed to achieve complete pain relief at 30 or 60 minutes after receiving the study drug.12 23 25-31 33 No study found a significant difference in the proportion of patients with complete pain relief, and there was no significant heterogeneity between studies. Combined analysis of these studies showed a trend towards a higher rate of complete pain relief in patients treated with NSAIDs, but this finding was not significant (relative risk 0.87, 0.74 to 1.03; fig 3). Subgroup analysis by NSAID or opioid type did not show significant benefit for any one drug.
Fig 3 Number of patients failing to achieve complete pain relief from renal colic after receiving anti-inflammatory drugs (NSAIDs) or opioids
Need for rescue analgesia
Ten trials (854 participants) reported the need for rescue analgesia within four hours of giving the study drug.4 11 12 17 19 22 23 31-33 The decision to use rescue analgesia was generally determined by clinician's preference in all trials, and the decision to give further analgesia had no objective criteria in eight of the studies. In four trials, pethidine was given if further analgesia was needed 30 minutes after the study drug had been given.4 11 12 17 In the remaining trials the drug used for rescue analgesia was either not specified, was a second dose of the study drug, or was the alternate study drug. The pooled analysis showed no statistical heterogeneity, and patients receiving NSAIDs were significantly less likely to require rescue analgesia than those receiving narcotics (0.75, 0.61 to 0.93; fig 4). Subgroup analysis of only those trials with blinding of investigators and participants continued to show in favour of NSAIDs. All but one of the pooled trials used pethidine as the opiate (dose range 50-150 mg).33 Based on this analysis, approximately 16 patients would require treatment with a NSAID rather than with an opioid for one additional patient to avoid the need for rescue analgesia.
Fig 4 Number of patients requiring rescue analgesia after treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or opioids for acute renal colic
Adverse events
The definition of adverse effects varied between trials, and many trials included any complaint recorded on general questioning after the study drug had been given. No trial specifically defined or reported serious adverse events such as gastrointestinal bleeding or renal impairment. Most trials had a short period of follow up (maximum 24 hours).29 All studies included reporting of adverse events, and all but four trials11 17 28 31 reported the total number of patients mentioning any adverse event, rather than total number of adverse events. Most of these 16 trials showed a higher incidence of adverse events in patients who were treated with opioids, but there was significant heterogeneity between studies. Subgroup analysis by type of opioid, route of opioid administration, and type of NSAID did not explain this heterogeneity. This heterogeneity may be explained by the ad hoc nature of reporting adverse events in most trials.
Vomiting was reported as a specific adverse event in 10 trials (826 participants), with no evidence of heterogeneity. The pooled analysis showed significantly less vomiting in patients treated with NSAIDs than in those treated with opioids (0.35, 0.23 to 0.53; fig 5): overall rate 5.8% in patients treated with NSAIDs and 19.5% in patients receiving opioids. Thus for every seven patients treated with NSAIDs rather than with opioids, one less patient will experience vomiting. Subgroup analysis by type of narcotic showed that the risk of vomiting was particularly dominant in patients receiving pethidine (0.30, 0.18 to 0.49). Adverse event rates did not vary according to dosage of opioid.
Fig 5 Incidence of vomiting as adverse event in patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) or opioids for acute renal colic
Other subgroup analysis and publication bias
Data were insufficient for subgroup analysis by participants' age and sex, size and site of stone, or drug dose for all outcomes. As all opioids and all but three NSAIDs were given parenterally it was not possible to analyse the effect of different routes of administration other than intravenous and intramuscular. Insufficient trials were available to perform funnel plot analysis.
Discussion
Our systematic review shows that non-steroidal anti-inflammatory drugs (NSAIDs) have better efficacy than opioids for relieving the pain of acute renal colic. Results favoured NSAIDs for the three outcomes of pain scores at a specified time after the study drug had been given, proportion of patients who achieved complete pain relief within a fixed time, and the need for rescue analgesia, although the differences reached significance for only two of the three outcomes.
Both opioids and NSAIDs showed a clinically important analgesic effect in patients with acute renal colic, with a noticeable reduction in pain scores over time. Significant heterogeneity between studies did not allow pooled analysis of pain scores for all studies, but qualitatively most studies showed lower pain scores for patients receiving NSAIDs rather than opioids, although the differences were small. In the subgroup of patients receiving NSAIDs other than ketorolac, there was a statistically significant reduction in pain scores of 4.6 mm. This difference is unlikely to be clinically important, however, as previous studies have shown the minimum clinically important difference in visual analogue scales to be around 9-13 mm.34 35
No significant difference was found between NSAIDs and opioids in the proportion of patients who achieved complete pain relief in the short term. Our findings are consistent with the review by Labrecque et al, which also found a non-significant increase in the proportion of patients achieving complete pain relief when treated with NSAIDs rather than with other analgesics.8 In our review the results varied widely between studies, with some showing almost all patients and others showing less than half of the patients achieving complete pain relief. This may reflect the wide range of agents, doses, and routes of administration for the study drugs.
Although both NSAIDs and opioids led to clinically important analgesia, a greater number of patients who received opioids required rescue analgesia within an hour of receiving the study drug. As nine of 10 trials pooled for this analysis used pethidine, this finding may not be generalisable to all opioids. The lack of clear objective guidelines for giving a rescue drug may also limit interpretation of this finding.
Adverse events were generally more common in patients receiving opioids than NSAIDs, but the ad hoc nature of reporting these events makes interpretation of this finding difficult. The specific adverse event of vomiting showed a clear association with opioids, particularly pethidine. Although no studies reported serious adverse events, the short follow up period and failure to specifically record renal dysfunction and gastrointestinal bleeding necessitates cautious interpretation of these results.
The comparative efficacy NSAIDs and opioids has been examined in several clinical settings. Several studies have shown that NSAIDs and opioids provide at least equivalent levels of postoperative analgesia, with higher rates of nausea, vomiting, and dizziness in patients treated with opioids.36-40 Similar results have been found in patients with acute biliary colic and isolated limb injuries and after lithotripsy.41-44 Our findings that NSAIDs provided slightly better analgesia with fewer side effects than opioids are in keeping with these studies, although the finding of improved analgesia in patients with renal colic may relate to the local synthesis and release of prostaglandins specific to this condition.
Limitations
We aimed to assess the effect of treatment in patients with a clinical diagnosis of renal colic because in practice most patients will be treated initially on the basis of a presumptive diagnosis. The applicability of our findings may be limited because most of the studies reviewed only included patients who had renal calculi confirmed on subsequent testing.
Pain scores were reported in all studies as means with variance, although it is well recognised that data from visual analogue scales are often skewed and therefore may be more accurately analysed as medians. We were unable to access individual patient data to assess whether comparison of medians rather than means may have altered our findings. In general, however, analysis of means rather than medians is unlikely to introduce bias unless the distribution of scores is severely skewed.45
All the included trials used fixed doses of opioids, rather than titration of opioids to an appropriate level of pain relief. The standard practice in most emergency departments is to titrate opioids to effect rather than to give single large boluses, and this limits the applicability of our findings to everyday practice.9 The wide variety of drug types and doses used in the studies make it difficult to identify appropriate dosing regimens for clinical practice.
Conclusion
Single bolus doses of NSAIDs and opioids provide pain relief for patients with acute renal colic. Patients receiving NSAIDs, however, achieve greater reduction in pain scores and are less likely to require further analgesia in the short term. Opioids, particularly pethidine, are associated with a higher rate of vomiting than NSAIDs. We therefore recommend a NSAID rather than an opioid. If opioids are to be used either because of contraindications to NSAIDs or ease of titratability, we recommend that pethidine be avoided.
What is already known on this topic
Both non-steroidal anti-inflammatory drugs (NSAIDs) and opioids provide analgesia in acute renal colic
NSAIDs have well recognised side effects
What this study adds
NSAIDs achieve slightly greater reductions in pain scores than opioids in patients with renal colic
Patients with renal colic are less likely to need rescue analgesia if treated with NSAIDs
Opioids, particularly pethidine, are associated with a higher rate of vomiting and other adverse effects
This review was conducted with substantial support and advice from the Cochrane Renal Group, Sydney, Australia.
Contributors: AH and TP were involved in all stages of study design, data collection, data analysis, and manuscript preparation. AH will act as guarantor for the paper.
Competing interests: None declared.
Ethical approval: Not required.
References
Stewart C. Nephrolithiasis. Emerg Med Clin North Am 1988;6: 617-30.
Drach GW. Urinary lithiasis: etiology, diagnosis, and medical management. In: Walsh PC, Refik AB, Stamey TA, Vaughan ED, eds. Campbell's urology. 6th ed. Philadelphia, WB Saunders, 1992: 2085-156.
Holdgate A, Hardcastle J. Renal colic: a diagnostic and therapeutic review. Emerg Med 1999;11: 9-16.
Curry C, Kelly AM. Intravenous tenoxicam for the treatment of renal colic. NZ Med J 1995;108: 229-30.
Smally AJ. Analgesia in renal colic. Ann Emerg Med 1997;29: 296.
Reich JD, Hanno PM. Factitious renal colic. Urology 1997;50: 858-62.
Tramer MR, Williams JE, Carroll D, Wiffen PG, Moore RA, McQuay HJ. Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs given by different routes in acute and chronic pain: a qualitative systematic review. Acta Anaesthesiol Scand 1998;42: 71-9.
Labrecque M, Dostaler L-P, Rouselle R, Nguyen T, Poirier S. Efficacy of non-steroidal anti-inflammatory drugs in the treatment of acute renal colic. Arch Intern Med 1994;154: 1381-7.
Nicholson F. Renal colic. In: Cameron P, Jelinek G, Kelly AM, Murray L, Heyworth L, eds, Textbook of adult emergency medicine. Edinburgh: Churchill Livingstone, 2000: 372-4.
Moll J, Peacock WF. Urologic stone disease. In: Tintinalli JE, Kelen GD, Stapczynski JS, eds. Emergency medicine: a comprehensive study guide. 5th ed. New York: McGraw-Hill, 1999: 640-5.
Cordell WH, Wright SW, Wolfson AB, Timerding BL, Maneatis TJ, Lewis RH, et al. Comparison of intravenous ketorolac, meperidine, and both (balanced analgesia) for renal colic. Ann Emerg Med 1996;28: 151-8.
al-Sahlawi KS, Tawfik OM. Comparative study of the efficacy of lysine acetylsalicylate, indomethacin and pethidine in acute renal colic. Eur J Emerg Med 1996;3: 183-6.
Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs versus opioids for acute renal colic. Cochrane Database Syst Rev 2004;(1): CD004137.
Edwards JE, Meseguer F, Faura C, Moore RA, McQuay HJ. Single dose dipyrone for acute renal colic. Cochrane Database Syst Rev 2003;(4): CD003867.
Willis NS, Mitchell R, Craig JC. Renal Group. In: Cochrane library, Issue 4. Chichester: Wiley, 2003.
Egger M, Davey-Smith G, Scneider M, Minder C. Bias in meta-analysis detected by a simple graphical test. BMJ 1997;315: 629-34.
Arnau JM, Cami J, Garcia-Alonso F, Laporte JR, Palop R. Comparative study of the efficacy of dipyrone, diclofenac sodium and pethidine in acute renal colic. Eur J Clin Pharmacol 1991;40: 543-6.
Cordell WH, Larson TA, Lingeman JE, Nelson DR, Woods JR, Burns LB, et al. Indomethacin suppositories versus intravenously titrated morphine for the treatment of ureteral colic. Ann Emerg Med 1994;23: 262-9.
Hetherington JW, Philp NH. Diclofenac sodium versus pethidine in acute renal colic. BMJ 1986;292: 237-8.
Indudhara R, Vaidyanathan S, Sankaranarayanan A. Oral diclofenac sodium in the treatment of acute renal colic. A prospective randomized study. Clin Trials J 1990;27: 295-300.
Jonsson PE, Olsson AM, Petersson BA, Johansson K. Intravenous indomethacin and oxycone-papaverine in the treatment of acute renal colic. A double-blind study. BJU Int 1987;59: 396-400.
Larkin GL, Peacock WF, Pearl SM, Blair GA, D'Amico F. Efficacy of ketorolac tromethamine versus meperidine in the ED treatment of acute renal colic. Am J Emerg Med 1999;17: 6-10.
Lehtonen T, Kellokumpu I, Permi J, Sarsila O. Intravenous indomethacin in the treatment of ureteric colic. A clinical multicentre study with pethidine and metamizol as the control preparations. Ann Clin Res 1983;15: 197-9.
Lundstam SOA, Leissner K-H, Wahlander LA, Kral JG. Prostaglandin-synthetase inhibition with diclofenac sodium in treatment of renal colic: comparison with use of a narcotic analgesic. Lancet 1982;i: 1096-7.
Marthak KV, Gokarn AM, Rao AV, Sane SP, Mahanata RK, Sheth RD, et al. A multi-centre comparative study of diclofenac sodium and a dipyrone/spasmolytic combination, and a single-centre comparative study of diclofenac sodium and pethidine in renal colic patients in India. Curr Med Res Opin 1991;12: 366-73.
Oosterlinck W, Philp NH, Charig C, Gillies G, Hetherington JW, Lloyd J. A double-blind single dose comparison of intramuscular ketorolac tromethamine and pethidine in the treatment of renal colic. J Clin Pharm 1990;30: 336-41.
Persson NH, Bergqvist D, Melander A, Zederfelt B. Comparison of a narcotic (oxicone) and a non-narcotic anti-inflammatory analgesic (indoprofen) in the treatment of renal colic. Acta Chir Scand 1985;151: 105-8.
Quilez C, Perez-Mateo M, Hernandez P, Rubio I. Usefulness of a non-steroid anti-inflammatory, sodium diclofenac, in the treatment of renal colic. Comparative study with a spasmolytic and an opiate analgesic. Med Clin (Barc) 1984;82: 754-5.
Sandhu DP, Lacovou JW, Fletcher MS, Kaisary AV, Philip NH, Arkell DG. A comparison of intramuscular ketorolac and pethidine in the alleviation of renal colic. BJU Int 1994;74: 690-3.
Sommer P, Kromann-Andersen B, Lendorf A, Lyngdorf P, Moller P. Analgesic effect and tolerance of Voltaren and Ketogan in acute renal or ureteric colic. BJU Int 1989;63: 4-6.
Thompson JF, Pike JM, Chumas PD, Rundle JS. Rectal diclofenac compared with pethidine injection in acute renal colic. BMJ 1989;299: 1140-1.
Nicolas Torralba JA, Rigabert Montiel M, Banon Perez V, Valdelvira Nadal P, Perez Albacete M. Ketorolaco intramuscular frente a Tramadol subcutaneo en el tratemiento inicial de urgencia del colico renal. Arch Esp Urol 1999;52: 435-7.
Uden P, Rentzhog L, Berger T. A comparative study of the analgesic effects of indomethacin and hydromorphine-chloride-atropine in acute, ureteral-stone pain. Acta Chir Scand 1983;149: 497-9.
Todd KH, Funk KG, Funk JP. Clinical significance of reported changes in pain severity. Ann Emerg Med 1996;27: 485-9.
Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med 2001;38: 633-8.
Smith LA, Carroll D, Edwards JE, Moore RA, McQuay HJ. Single-dose ketorolac and pethidine in acute postoperative pain: systematic review with meta-analysis. Br J Anaesth 2000;84: 48-58.
McEvoy A, Livingstone JI, Cahill CJ. Comparison of diclofenac sodium and morphine sulphate for postoperative analgesia after day case inguinal hernia surgery. Ann R Coll Surg Engl 1996;78: 363-6.
Zackova M, Taddei S, Calo P, Bellochchio A, Zanello M. Ketorolac vs tramadol in the treatment of postoperative pain during maxillofacial surgery. Minerva Anestesiol 2001;67: 641-6.
DeAndrade JR, Maslanka M, Reines HD, Howe, D, Rasmussen GL, Cardea J, et al. Ketorolac versus meperidine for pain relief after orthopaedic surgery. Clin Orthop 1996;1: 302-12.
Shende D, Das K. Comparative effects of intravenous ketorolac and pethidine on peri-operative analgesia and postoperative nausea and vomiting (PONV) for paediatric strabismus surgery. Acta Anaesthesiol Scand 1999;43: 265-9.
Dula DJ, Anderson R, Wood GC. A prospective study comparing i.m. ketorolac with i.m. meperidine in the treatment of acute biliary colic. J Emerg Med 2001;20: 121-4.
Henderson SO, Swadron S, Newton E. Comparison of intravenous ketorolac and meperidine in the treatment of biliary colic. J Emerg Med 2002;23: 237-41.
Rainer TH, Jacobs P, Ng YC, Cheung NK, Tam M, Lam PK, et al. Cost effectiveness analysis of intravenous ketorolac and morphine for treating pain after limb injury: double blind randomised controlled trial. BMJ 2000;321: 1247-51.
Chia YY, Liu K. Prospective randomized trial of intravenous tenoxicam versus fentanyl and tramadol for analgesia in outpatient extracorporeal lithotripsy. Acta Anaesthesiol Sin 1998;36: 17-22.
Streiner DL, Norman GR. Health measurement scales—a practical guide to their development and use, 2nd ed. Oxford: Oxford University Press, 1995.(Anna Holdgate, deputy dir)
Correspondence to: A Holdgate holdgatean@sesahs.nsw.gov.au
Abstract
Of 74 potentially relevant studies, we excluded 49 on review of the abstract (fig 1). Twenty five articles were retrieved for more detailed evaluation, of which five were excluded for failure to meet our inclusion criteria, leaving 20 trials for review.4 11 12 17-33
Fig 1 Flow of studies through trial
Study characteristics
The 20 trials were conducted in nine countries, included 1613 participants, and were published between 1982 and 1999 (table 1). Most studies included only those participants with renal calculi confirmed on subsequent testing using a variety of techniques, specifically excluding patients without such a confirmation. Overall, the trials used five different NSAIDs and seven different opioids, although each trial used only one type of each drug. All but two trials used fixed doses of drugs, regardless of the patient's weight.22 32 Drugs were given by the parenteral route (intravenous or intramuscular) in all but three trials. In these three trials, NSAIDs were given orally or rectally and opioids were given parenterally.18 20 31
Table 1 Characteristics of included studies of efficacy of non-steroidal anti-inflammatory drugs compared with opioids for pain relief in acute renal colic
Many of the included trials did not report variance data or outcomes in a form suitable for meta-analysis, and we were unable to gain any further information from the authors. Six studies had treatment arms in addition to NSAIDs and opioids12 17 20 23 25 28; we analysed only data for the opioid and NSAID groups for these trials. Two studies used a crossover design, when the comparator drug was given if inadequate analgesia was achieved with the first drug. We included only data from the precrossover phase of these trials.18 21 One study included a third treatment arm with combined opioids and NSAIDs.11 Data from this treatment arm were not included.
No trial reported time to pain relief, although several reported the proportion of patients with complete pain relief within a fixed time. We therefore used this proportion as an alternative outcome measure. No trials reported rates of pain recurrence or specifically reported serious adverse events such as renal dysfunction or gastrointestinal bleeding.
Overall, no single study met all the quality criteria (table 2). For most studies, quality criteria were not met owing to lack of information rather than explicit reporting of methods that did not conform to the quality criteria.
Table 2 Assessment of quality criteria for trial of efficacy of non-steroidal anti-inflammatory drugs and opioids for pain relief in acute renal colic
As the results from random and fixed effects models did not differ, we report only results from the random effects model.
Patient rated pain scores
Fifteen trials measured pain scores at enrolment and at a fixed time after the study drug had been given. In two trials this outcome was measured but not reported.19 20 Four trials reported data that were not suitable for pooled analysis.29-32 All but one of these four trials showed a greater reduction in pain scores in the NSAID group than in the opioid group.30 Nine trials reported pain on a 100 mm visual analogue scale; six recorded scores at 30 minutes,4 11 17 25 27 33 two at 20 minutes,21 22 and one at 60 minutes.26 Seven of the nine trials favoured treatment with NSAIDs,11 17 21 25-27 33 one showed no difference,4 and one showed lower pain scores in patients treated with opioids.22 Subgroup analysis by type of NSAID showed heterogeneity for studies using ketorolac but homogeneity among all other trials using any other type of NSAID. Combined analysis of the six trials not using ketorolac showed the visual analogue scale was on average 4.6 mm (95% confidence interval 1.7 mm to 7.5 mm) lower in patients receiving NSAIDs than in those receiving opioids (fig 2). Subgroup analysis by type and route of opioid did not explain heterogeneity. Addition of the three trials using ketorolac to the pooled analysis showed a similar effect. We could find no obvious biological or clinical explanation for this heterogeneity.
Fig 2 Patient rated scores on visual analogue scale for pain due to renal colic according to type of non-steroidal anti-inflammatory drug, excluding trials using ketorolac
Of the 13 trials with reported results, 10 found lower pain scores in patients treated with NSAIDs, two showed no difference, and only one found lower pain scores in patients treated with opioids.
Failure to achieve complete pain relief
Nine trials (647 participants) reported the proportion of patients who failed to achieve complete pain relief at 30 or 60 minutes after receiving the study drug.12 23 25-31 33 No study found a significant difference in the proportion of patients with complete pain relief, and there was no significant heterogeneity between studies. Combined analysis of these studies showed a trend towards a higher rate of complete pain relief in patients treated with NSAIDs, but this finding was not significant (relative risk 0.87, 0.74 to 1.03; fig 3). Subgroup analysis by NSAID or opioid type did not show significant benefit for any one drug.
Fig 3 Number of patients failing to achieve complete pain relief from renal colic after receiving anti-inflammatory drugs (NSAIDs) or opioids
Need for rescue analgesia
Ten trials (854 participants) reported the need for rescue analgesia within four hours of giving the study drug.4 11 12 17 19 22 23 31-33 The decision to use rescue analgesia was generally determined by clinician's preference in all trials, and the decision to give further analgesia had no objective criteria in eight of the studies. In four trials, pethidine was given if further analgesia was needed 30 minutes after the study drug had been given.4 11 12 17 In the remaining trials the drug used for rescue analgesia was either not specified, was a second dose of the study drug, or was the alternate study drug. The pooled analysis showed no statistical heterogeneity, and patients receiving NSAIDs were significantly less likely to require rescue analgesia than those receiving narcotics (0.75, 0.61 to 0.93; fig 4). Subgroup analysis of only those trials with blinding of investigators and participants continued to show in favour of NSAIDs. All but one of the pooled trials used pethidine as the opiate (dose range 50-150 mg).33 Based on this analysis, approximately 16 patients would require treatment with a NSAID rather than with an opioid for one additional patient to avoid the need for rescue analgesia.
Fig 4 Number of patients requiring rescue analgesia after treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or opioids for acute renal colic
Adverse events
The definition of adverse effects varied between trials, and many trials included any complaint recorded on general questioning after the study drug had been given. No trial specifically defined or reported serious adverse events such as gastrointestinal bleeding or renal impairment. Most trials had a short period of follow up (maximum 24 hours).29 All studies included reporting of adverse events, and all but four trials11 17 28 31 reported the total number of patients mentioning any adverse event, rather than total number of adverse events. Most of these 16 trials showed a higher incidence of adverse events in patients who were treated with opioids, but there was significant heterogeneity between studies. Subgroup analysis by type of opioid, route of opioid administration, and type of NSAID did not explain this heterogeneity. This heterogeneity may be explained by the ad hoc nature of reporting adverse events in most trials.
Vomiting was reported as a specific adverse event in 10 trials (826 participants), with no evidence of heterogeneity. The pooled analysis showed significantly less vomiting in patients treated with NSAIDs than in those treated with opioids (0.35, 0.23 to 0.53; fig 5): overall rate 5.8% in patients treated with NSAIDs and 19.5% in patients receiving opioids. Thus for every seven patients treated with NSAIDs rather than with opioids, one less patient will experience vomiting. Subgroup analysis by type of narcotic showed that the risk of vomiting was particularly dominant in patients receiving pethidine (0.30, 0.18 to 0.49). Adverse event rates did not vary according to dosage of opioid.
Fig 5 Incidence of vomiting as adverse event in patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) or opioids for acute renal colic
Other subgroup analysis and publication bias
Data were insufficient for subgroup analysis by participants' age and sex, size and site of stone, or drug dose for all outcomes. As all opioids and all but three NSAIDs were given parenterally it was not possible to analyse the effect of different routes of administration other than intravenous and intramuscular. Insufficient trials were available to perform funnel plot analysis.
Discussion
Our systematic review shows that non-steroidal anti-inflammatory drugs (NSAIDs) have better efficacy than opioids for relieving the pain of acute renal colic. Results favoured NSAIDs for the three outcomes of pain scores at a specified time after the study drug had been given, proportion of patients who achieved complete pain relief within a fixed time, and the need for rescue analgesia, although the differences reached significance for only two of the three outcomes.
Both opioids and NSAIDs showed a clinically important analgesic effect in patients with acute renal colic, with a noticeable reduction in pain scores over time. Significant heterogeneity between studies did not allow pooled analysis of pain scores for all studies, but qualitatively most studies showed lower pain scores for patients receiving NSAIDs rather than opioids, although the differences were small. In the subgroup of patients receiving NSAIDs other than ketorolac, there was a statistically significant reduction in pain scores of 4.6 mm. This difference is unlikely to be clinically important, however, as previous studies have shown the minimum clinically important difference in visual analogue scales to be around 9-13 mm.34 35
No significant difference was found between NSAIDs and opioids in the proportion of patients who achieved complete pain relief in the short term. Our findings are consistent with the review by Labrecque et al, which also found a non-significant increase in the proportion of patients achieving complete pain relief when treated with NSAIDs rather than with other analgesics.8 In our review the results varied widely between studies, with some showing almost all patients and others showing less than half of the patients achieving complete pain relief. This may reflect the wide range of agents, doses, and routes of administration for the study drugs.
Although both NSAIDs and opioids led to clinically important analgesia, a greater number of patients who received opioids required rescue analgesia within an hour of receiving the study drug. As nine of 10 trials pooled for this analysis used pethidine, this finding may not be generalisable to all opioids. The lack of clear objective guidelines for giving a rescue drug may also limit interpretation of this finding.
Adverse events were generally more common in patients receiving opioids than NSAIDs, but the ad hoc nature of reporting these events makes interpretation of this finding difficult. The specific adverse event of vomiting showed a clear association with opioids, particularly pethidine. Although no studies reported serious adverse events, the short follow up period and failure to specifically record renal dysfunction and gastrointestinal bleeding necessitates cautious interpretation of these results.
The comparative efficacy NSAIDs and opioids has been examined in several clinical settings. Several studies have shown that NSAIDs and opioids provide at least equivalent levels of postoperative analgesia, with higher rates of nausea, vomiting, and dizziness in patients treated with opioids.36-40 Similar results have been found in patients with acute biliary colic and isolated limb injuries and after lithotripsy.41-44 Our findings that NSAIDs provided slightly better analgesia with fewer side effects than opioids are in keeping with these studies, although the finding of improved analgesia in patients with renal colic may relate to the local synthesis and release of prostaglandins specific to this condition.
Limitations
We aimed to assess the effect of treatment in patients with a clinical diagnosis of renal colic because in practice most patients will be treated initially on the basis of a presumptive diagnosis. The applicability of our findings may be limited because most of the studies reviewed only included patients who had renal calculi confirmed on subsequent testing.
Pain scores were reported in all studies as means with variance, although it is well recognised that data from visual analogue scales are often skewed and therefore may be more accurately analysed as medians. We were unable to access individual patient data to assess whether comparison of medians rather than means may have altered our findings. In general, however, analysis of means rather than medians is unlikely to introduce bias unless the distribution of scores is severely skewed.45
All the included trials used fixed doses of opioids, rather than titration of opioids to an appropriate level of pain relief. The standard practice in most emergency departments is to titrate opioids to effect rather than to give single large boluses, and this limits the applicability of our findings to everyday practice.9 The wide variety of drug types and doses used in the studies make it difficult to identify appropriate dosing regimens for clinical practice.
Conclusion
Single bolus doses of NSAIDs and opioids provide pain relief for patients with acute renal colic. Patients receiving NSAIDs, however, achieve greater reduction in pain scores and are less likely to require further analgesia in the short term. Opioids, particularly pethidine, are associated with a higher rate of vomiting than NSAIDs. We therefore recommend a NSAID rather than an opioid. If opioids are to be used either because of contraindications to NSAIDs or ease of titratability, we recommend that pethidine be avoided.
What is already known on this topic
Both non-steroidal anti-inflammatory drugs (NSAIDs) and opioids provide analgesia in acute renal colic
NSAIDs have well recognised side effects
What this study adds
NSAIDs achieve slightly greater reductions in pain scores than opioids in patients with renal colic
Patients with renal colic are less likely to need rescue analgesia if treated with NSAIDs
Opioids, particularly pethidine, are associated with a higher rate of vomiting and other adverse effects
This review was conducted with substantial support and advice from the Cochrane Renal Group, Sydney, Australia.
Contributors: AH and TP were involved in all stages of study design, data collection, data analysis, and manuscript preparation. AH will act as guarantor for the paper.
Competing interests: None declared.
Ethical approval: Not required.
References
Stewart C. Nephrolithiasis. Emerg Med Clin North Am 1988;6: 617-30.
Drach GW. Urinary lithiasis: etiology, diagnosis, and medical management. In: Walsh PC, Refik AB, Stamey TA, Vaughan ED, eds. Campbell's urology. 6th ed. Philadelphia, WB Saunders, 1992: 2085-156.
Holdgate A, Hardcastle J. Renal colic: a diagnostic and therapeutic review. Emerg Med 1999;11: 9-16.
Curry C, Kelly AM. Intravenous tenoxicam for the treatment of renal colic. NZ Med J 1995;108: 229-30.
Smally AJ. Analgesia in renal colic. Ann Emerg Med 1997;29: 296.
Reich JD, Hanno PM. Factitious renal colic. Urology 1997;50: 858-62.
Tramer MR, Williams JE, Carroll D, Wiffen PG, Moore RA, McQuay HJ. Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs given by different routes in acute and chronic pain: a qualitative systematic review. Acta Anaesthesiol Scand 1998;42: 71-9.
Labrecque M, Dostaler L-P, Rouselle R, Nguyen T, Poirier S. Efficacy of non-steroidal anti-inflammatory drugs in the treatment of acute renal colic. Arch Intern Med 1994;154: 1381-7.
Nicholson F. Renal colic. In: Cameron P, Jelinek G, Kelly AM, Murray L, Heyworth L, eds, Textbook of adult emergency medicine. Edinburgh: Churchill Livingstone, 2000: 372-4.
Moll J, Peacock WF. Urologic stone disease. In: Tintinalli JE, Kelen GD, Stapczynski JS, eds. Emergency medicine: a comprehensive study guide. 5th ed. New York: McGraw-Hill, 1999: 640-5.
Cordell WH, Wright SW, Wolfson AB, Timerding BL, Maneatis TJ, Lewis RH, et al. Comparison of intravenous ketorolac, meperidine, and both (balanced analgesia) for renal colic. Ann Emerg Med 1996;28: 151-8.
al-Sahlawi KS, Tawfik OM. Comparative study of the efficacy of lysine acetylsalicylate, indomethacin and pethidine in acute renal colic. Eur J Emerg Med 1996;3: 183-6.
Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs versus opioids for acute renal colic. Cochrane Database Syst Rev 2004;(1): CD004137.
Edwards JE, Meseguer F, Faura C, Moore RA, McQuay HJ. Single dose dipyrone for acute renal colic. Cochrane Database Syst Rev 2003;(4): CD003867.
Willis NS, Mitchell R, Craig JC. Renal Group. In: Cochrane library, Issue 4. Chichester: Wiley, 2003.
Egger M, Davey-Smith G, Scneider M, Minder C. Bias in meta-analysis detected by a simple graphical test. BMJ 1997;315: 629-34.
Arnau JM, Cami J, Garcia-Alonso F, Laporte JR, Palop R. Comparative study of the efficacy of dipyrone, diclofenac sodium and pethidine in acute renal colic. Eur J Clin Pharmacol 1991;40: 543-6.
Cordell WH, Larson TA, Lingeman JE, Nelson DR, Woods JR, Burns LB, et al. Indomethacin suppositories versus intravenously titrated morphine for the treatment of ureteral colic. Ann Emerg Med 1994;23: 262-9.
Hetherington JW, Philp NH. Diclofenac sodium versus pethidine in acute renal colic. BMJ 1986;292: 237-8.
Indudhara R, Vaidyanathan S, Sankaranarayanan A. Oral diclofenac sodium in the treatment of acute renal colic. A prospective randomized study. Clin Trials J 1990;27: 295-300.
Jonsson PE, Olsson AM, Petersson BA, Johansson K. Intravenous indomethacin and oxycone-papaverine in the treatment of acute renal colic. A double-blind study. BJU Int 1987;59: 396-400.
Larkin GL, Peacock WF, Pearl SM, Blair GA, D'Amico F. Efficacy of ketorolac tromethamine versus meperidine in the ED treatment of acute renal colic. Am J Emerg Med 1999;17: 6-10.
Lehtonen T, Kellokumpu I, Permi J, Sarsila O. Intravenous indomethacin in the treatment of ureteric colic. A clinical multicentre study with pethidine and metamizol as the control preparations. Ann Clin Res 1983;15: 197-9.
Lundstam SOA, Leissner K-H, Wahlander LA, Kral JG. Prostaglandin-synthetase inhibition with diclofenac sodium in treatment of renal colic: comparison with use of a narcotic analgesic. Lancet 1982;i: 1096-7.
Marthak KV, Gokarn AM, Rao AV, Sane SP, Mahanata RK, Sheth RD, et al. A multi-centre comparative study of diclofenac sodium and a dipyrone/spasmolytic combination, and a single-centre comparative study of diclofenac sodium and pethidine in renal colic patients in India. Curr Med Res Opin 1991;12: 366-73.
Oosterlinck W, Philp NH, Charig C, Gillies G, Hetherington JW, Lloyd J. A double-blind single dose comparison of intramuscular ketorolac tromethamine and pethidine in the treatment of renal colic. J Clin Pharm 1990;30: 336-41.
Persson NH, Bergqvist D, Melander A, Zederfelt B. Comparison of a narcotic (oxicone) and a non-narcotic anti-inflammatory analgesic (indoprofen) in the treatment of renal colic. Acta Chir Scand 1985;151: 105-8.
Quilez C, Perez-Mateo M, Hernandez P, Rubio I. Usefulness of a non-steroid anti-inflammatory, sodium diclofenac, in the treatment of renal colic. Comparative study with a spasmolytic and an opiate analgesic. Med Clin (Barc) 1984;82: 754-5.
Sandhu DP, Lacovou JW, Fletcher MS, Kaisary AV, Philip NH, Arkell DG. A comparison of intramuscular ketorolac and pethidine in the alleviation of renal colic. BJU Int 1994;74: 690-3.
Sommer P, Kromann-Andersen B, Lendorf A, Lyngdorf P, Moller P. Analgesic effect and tolerance of Voltaren and Ketogan in acute renal or ureteric colic. BJU Int 1989;63: 4-6.
Thompson JF, Pike JM, Chumas PD, Rundle JS. Rectal diclofenac compared with pethidine injection in acute renal colic. BMJ 1989;299: 1140-1.
Nicolas Torralba JA, Rigabert Montiel M, Banon Perez V, Valdelvira Nadal P, Perez Albacete M. Ketorolaco intramuscular frente a Tramadol subcutaneo en el tratemiento inicial de urgencia del colico renal. Arch Esp Urol 1999;52: 435-7.
Uden P, Rentzhog L, Berger T. A comparative study of the analgesic effects of indomethacin and hydromorphine-chloride-atropine in acute, ureteral-stone pain. Acta Chir Scand 1983;149: 497-9.
Todd KH, Funk KG, Funk JP. Clinical significance of reported changes in pain severity. Ann Emerg Med 1996;27: 485-9.
Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med 2001;38: 633-8.
Smith LA, Carroll D, Edwards JE, Moore RA, McQuay HJ. Single-dose ketorolac and pethidine in acute postoperative pain: systematic review with meta-analysis. Br J Anaesth 2000;84: 48-58.
McEvoy A, Livingstone JI, Cahill CJ. Comparison of diclofenac sodium and morphine sulphate for postoperative analgesia after day case inguinal hernia surgery. Ann R Coll Surg Engl 1996;78: 363-6.
Zackova M, Taddei S, Calo P, Bellochchio A, Zanello M. Ketorolac vs tramadol in the treatment of postoperative pain during maxillofacial surgery. Minerva Anestesiol 2001;67: 641-6.
DeAndrade JR, Maslanka M, Reines HD, Howe, D, Rasmussen GL, Cardea J, et al. Ketorolac versus meperidine for pain relief after orthopaedic surgery. Clin Orthop 1996;1: 302-12.
Shende D, Das K. Comparative effects of intravenous ketorolac and pethidine on peri-operative analgesia and postoperative nausea and vomiting (PONV) for paediatric strabismus surgery. Acta Anaesthesiol Scand 1999;43: 265-9.
Dula DJ, Anderson R, Wood GC. A prospective study comparing i.m. ketorolac with i.m. meperidine in the treatment of acute biliary colic. J Emerg Med 2001;20: 121-4.
Henderson SO, Swadron S, Newton E. Comparison of intravenous ketorolac and meperidine in the treatment of biliary colic. J Emerg Med 2002;23: 237-41.
Rainer TH, Jacobs P, Ng YC, Cheung NK, Tam M, Lam PK, et al. Cost effectiveness analysis of intravenous ketorolac and morphine for treating pain after limb injury: double blind randomised controlled trial. BMJ 2000;321: 1247-51.
Chia YY, Liu K. Prospective randomized trial of intravenous tenoxicam versus fentanyl and tramadol for analgesia in outpatient extracorporeal lithotripsy. Acta Anaesthesiol Sin 1998;36: 17-22.
Streiner DL, Norman GR. Health measurement scales—a practical guide to their development and use, 2nd ed. Oxford: Oxford University Press, 1995.(Anna Holdgate, deputy dir)