Comparison of Intravenous Ketorolac, Meperidine, and Both (Balanced Analgesia) for Renal Colic

GENERAL C L I N I C A L I N V E S T I G A T I O N / O R I G I N A L

CONTRIBUTION

/.-,

k_.omparison of Intravenous Ketorolac,

Meperidine, and Both (Balanced Analgesia) for Renal Colic From the Emergency Medicine and Trauma Center* and the Department of Medical Research~, Methodist Hospital of Indiana; the Department of Emergency Medicine, Vanderbilt University, Nashville, Tennessee'; the Department of Medicine, Division of Emergency Medicine, University of Pittsburgh School of Medicine, PittsburghJi;the Department of Emergency Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina~; and Roche Laboratories, Nutley, New Jersey.#

William H Cordell, MD*

Study objective: To compare the analgesic efficacy and safety

Seth W Wright, MD §

of IV ketorolac, the only nonsteroidal antiinflammatory drug indicated for parenteral use in acute pain in the United States, with IV meperidine and with a combination of the two agents in renal colic.

Allan B Wolfson, MD" Beverly L Timerding, MD I Thomas J Maneatis, MO # Ronald H Lewis, MD # Lincoln Bynum, MD # David R Nelson, MS*

Receivedfor publication November 13, 1995. Revision receivedMarch 14, 1996. Accepted for publication March 20, 1996. Presented at the Societyfor Academic Emergency Medicine Annual Meeting, San Antonio, May 1995. Supported by Roche Laboratories. Copyright © by the American College of Emergency Physicians.

Methods: We carried out a double-blind, randomized, multicenter clinical trial in the emergency departments of four urban tertiary care teaching hospitals. Our study subjects were 154 patients with suspected renal colic. Each subject received an initial IV dose of ketorolac 60 mg, meperidine 50 mg, or both supplemented as needed beyond 30 minutes with additional doses of meperidine.

Results: The main outcome measures were changes in painintensity and pain-relief scores, amount of supplemental meperidine required, end-of-study drug tolerability, and adverse events. Analyses of 106 subjects with confirmed renal colic indicated that ketorolac and the combination were significantly better than meperidine alone by all efficacy measures, including pain relief and time elapsed before the need for supplemental meperidine. By 30 minutes, 75% of the ketorotac group and 74% of the combination group had a 50% reduction in pain scores, compared with 23% of the meperidine group (P<.001).The ketorolac and combination groups did not differ significantly in any of the efficacy measures. Conclusion: IV ketorolac, alone or in combination with meperidine, was superior to IV meperidine alone in moderate and severe renal colic. Becausemany subjects in all three treatment groups received supplemental meperidine and because response to ketorolac alone cannot be predicted, clinicians may choose to initiate treatment with a ketorolac-meperidine combination. [Cordell WH, Wright SW, Wolfson AB, Timerding BL, Maneatis TJ, Lewis RH, Bynum L, Nelson DR: Comparison of intravenous ketorotac, meperidine, and both (balanced analgesia) for renal colic. Ann EmergMedAugust 1996;28:151-158.]

AUGUST 1996 28:2 ANNALS OF EMERGENCYMEDICINE

! 5I

KETOROLAC VERSUS MEPERIDINE Cordell et al

INTRODUCTION

Renal colic, typically caused by acute obstruction of the ureter by a calculus, is among the most excruciating types of pain a human being can experience. One of the goals of emergency management is to control the severe pain until the obstruction is relieved by spontaneous passage or surgical manipulation. In the United States, opioids are the primary means of controlling pain in patients with renal colic. Since the late 1970s, however, nonsteroidal antiinflammatory drugs (NSAIDs) have been widely used outside the United States to treat renal colic, and many studies have confirmed their efficacy.>19 Ketorolac tromethamine is the only NSAID labeled for IM or IV administration for acute pain in the United States. No one has compared IV ketorolac with an IV opioid in renal colic using a randomized, double-blind design with objective criteria for stone confirmation. Our purpose in this study was to compare the analgesic efficacy and safety of IV ketorolac tromethamine 60 mg, IV meperidine 50 mg, or a combination of the two drugs supplemented as needed beyond 30 minutes with additional ("rescue") doses of meperidine in subjects with renal colic. The rationale for the combination regimen ("balanced analgesia") was to test whether the use of two different classes of pharmacologic agents, in this case an NSAID plus an opioid, produced greater and more rapid renal colic pain relief with a concomitant reduction of side effects. MATERIALS AND METHODS

ED patients 18 years or older with a history and physical examination findings compatible with renal colic and with pain of moderate to severe intensity on a categorical scale were eligible for participation. This study was approved by the institutional review board at each study site. Written informed consent was obtained from each subject before study enrollment. Exclusion criteria included known allergy or contraindication to any opioid or nonopioid analgesic, history of active peptic ulcer m the preceding 6 months, history of bleeding problems, anticoagulation therapy in the preceding 4 weeks, pregnancy, history of renal insufficiency, and suspicion of drug-seeking behavior. Subjects who had received any analgesic in the preceding 3 hours were also excluded. The diagnosis of renal colic was confirmed with IV pyelography (IVP) or ultrasonography or on the basis of stone passage or stone recovery during surgery. The study was conducted m the EDs of the Bowman Gray School of Medicine, Winston-Salem, North Carolina; Methodist Hospital, Indianapolis, Indiana; the University of

I 52

Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Vanderbih University, Nashville, Tennessee. All four study sites are urban, tertiary care teaching hospitals. We studied three treatment groups in a double-blind, randomized fashion. At time 0, one group was given IV ketorolac 60 mg and placebo (normal saline solution), a second group was given IV meperidme 50 mg and placebo, and the third group was given IV ketorolac 60 mg plus IV meperidine 50 mg. The subjects were stratified according to initial baseline pain into "moderate" and "severe" groups. Randomization was carried out in blocks of three, and a study number was assigned to each patient at each site in accordance with a computer.generated randomization schedule. The study drugs were identical in appearance. All study personnel at the enrolling institutions remained blinded to treatment group assignment until data analysis had been completed. Subjects were observed for up to 6 hours after the initial dose. Subjects with inadequate pain relief at 30 minutes were allowed supplemental IV doses of meperidine as needed, with the dose and interval determined by the attending physician. In the protocol it was recommended that fluids be administered only to keep the IV line patent and not to increase urine output to "flush out" a suspected urinary stone. Subjects were permitted one 200-rag rectal dose of trimethobenzamide hydrochloride one time during the study period for nausea or vomiting. Subjects rated pain intensity on both a visual analog scale (VAS) and a categorical scale at baseline and 15 and 30 minutes and 1, 2, 3, 4, 5, and 6 hours after receiving the study drugs. The VAS was a 100-ram, unnumbered, horizontal scale bounded by the descriptors "no pain" and "worst possible pain". The categorical pain-intensity scale consisted of four rankings (none, mild, moderate, severe). The subjects were also asked to rank how much pain relief from the starting pain they had experienced on a categorical scale (none, a little, some, a lot, complete). End-of-study overall drug tolerability was rated by the subject using a five-point scale (poor, fair, good, very good, excellent). Functional impairment was rated by the observer at baseline and end-of-study using a four-point scale (no impairment, mildly impaired, moderately impaired, severely impaired). Subjects were asked after 2 hours and at the end of the study whether they had experienced any symptoms other than pain since receiving the study medication. Such symptoms were recorded as adverse events. Measurements of blood pressure and pulse, both supine and upright, were recorded at baseline and 30 minutes after administration of study medication. We performed data analyses with the SAS program (SAS Institute, Incorporated). All statistical analyses in-

ANNALS OF EMERGENCY MEDICLNE 28:2

AUGUST 1996

KETOROLAC VERSUS MEPERIDINE Cordell et al

volved two-tailed tests. Demographic and baseline clinical variables were analyzed with the Z 2 test for categorical values and the Kruskal-Wallis test for continuous variables. VAS pain intensity, categorical pain intensity, and categorical pain-relief scores were compared among groups with the use of the Kruskal-Wallis test. When a P value indicated significant treatment effects (P<.05), the three pairwise treatment comparisons were evaluated. We also used Z~ square tests to analyze categories defined by pain scores, such as subjects with and without 50% reduction in VAS pain. To determine whether site and the treatment-site interaction were significant, we used two-way ANOVA with interaction to test all efficacy variables. The time-to-event variables were evaluated with the Kaplan-Meier product-limit method, and the log-rank test was used to compare the treatment groups. Subjects given supplemental meperidine and those in whom complete relief was not achieved were censored in the analysis of time elapsed before complete relief. We derived the following parameters from the measured VAS and categorical scales: pain-intensity difference (PID), summed pain-intensity difference (SPtD), and total pain relief (TOTPAR). Such calculations, frequently used in paincontrol research, help account for differences in base pain intensity among study subjects 2°, as well as variations of pain intensity over time. PID was defined as the difference between baseline pain intensity and the pain intensity recorded at each time point; SPID as the weighted sums of PIDs at 2, 3, and 6 hours; and TOTPAR as the weighted sums of pain-relief scores at 2, 3, and 6 hours. The weight assigned to each PID score or PRS was equal to the elapsed time (in hours) since the preceding evaluation.

Sample-size calculations were based on prior studies comparing IM ketorolac with meperidine, which demonstrated an effect size between .5 and .65 (ie, standardized difference between treatment groups relative to their SDs) with respect to SPID, TOTPAR, and amount of supplemental opioid. A sample size of 40 patients per treatment group was estimated to provide 80% power to detect an effect size of .65 in pairwise comparisons of treatment groups at the 5% significance level. We tabulated adverse events by linking verbatim terms on the case-report forms to preferred terms and related body systems using the COSTART3 mapping system. 21 These preferred terms and related body systems were then used in the tabulations. The likelihood ratio Z2 or two-tailed Fisher exact test was used to compare the treatment groups with regard to the proportion of subjects reporting adverse events in each treatment group when at least 5% of the subjects in any one treatment group reported an adverse event. Summary statistics were reported as mean!SE. The study was designed by two of the investigators at the enrolling institutions (WHC, ABW) in coUaboration with the sponsoring company. All investigators agreed before the start of data collection that the study would be submitted for publication regardless which of the treatments showed the greatest efficacy. Data were analyzed by biostatisticians at the sponsoring company, as well as at one of the study hospitals. None of the investigators at the enrolling hospitals had or has a financial interest in the sponsoring company. RESULTS

During the 21-month study period (December 1, 1992, [o September 2, 1994), 154 nonconsecutive subjects

Table 1.

Baseline characteristics of the three treatment groups (subjects valid for efficacy analysis). Characteristics

Meperidine (N=35)

Ketorelac {N=36)

Combination {N=35)

Total (N=106)

Age (years) Mean_+SE Range

42.0+1.9 19.4-66.0

38,8_+1.7 23.4-62.8

36.1_+1.7 20.7-55.4

39,0_+1.0 19.4-65.0

28 (80) 7 (20)

30 (83) 6 (t7)

25 (71) 10 (29)

83 (78) 23 (22)

29 (83) 5(14) 1(3) 87.5_+3.0 10 (29)

32 (89) 3(8) 1(3) 86.9_+2.7

30 (86) 4(11) 1(3) 80.6_+2.8

91 (86) 12(11) 3 (2) 85.0_+1.6

7 (19)

9 (26)

26 (25)

Sex

.46

No, male (%) No. female (%)

Race

.77

White Black Other

Weight (kg) [mean_+SE] No. hospitalized (%)

AUGUST 1996

P .10

28:2

ANNALS OF EMERGENCY MEDICINE

.28 .66

1 53

KETOROLAC VERSUS MEPERIDINE

Cordell et al

with presentation suggestive of renal colic were enrolled at the four study sites. Of these patients, 51 were assigned to the ketorolac group, 51 to the meperidine group, and 52 to the combination group. Forty-seven subjects without a confirmed diagnosis of renal colic (14 in the ketorolac group, 16 in the meperidine group, and 17 in the combination group) and one subject assigned to receive ketorolac who passed a stone at baseline were excluded from efficacy analysis. The remaining 106 subjects (69%) were included in efficacy analysis, and all 154 subjects were included in the adverse-events analysis. Renal colic was confirmed on the basis of IVP findings alone in 67, by means of both IVP findings and stone passage in 20, by means of both IVP and surgical findings in 14, by means of both IVP findings and ultrasonography in 2, on the basis of stone passage alone in 2, and on the basis of surgical findings alone in 1. No site or treatment-site interaction was significant at a P value less than. 10, so in further analyses we combined sites to evaluate treatment. We detected no significant differences among the three treatment groups for demographic characteristics (Table 1), baseline pain scores (Table 2), or concomitant therapies. No supplemental doses of meperidine were administered during the first 30 minutes of study. At 15 and 30 minutes, VAS intensity scores in both the ketorolac and combination groups were significantly lower than that in the meperidine group (Table 2). We noted no significant

differences between the ketorolac and combination groups at 15 and 30 minutes. By 15 minutes, 25 combination subjects (71%), 19 ketorolac (53%) subjects, and 9 meperidine subjects (26%) had 50% reduction in VAS pain scores (P=.001, %2 test). By 30 minutes, 27 ketorolac subjects (75%), 26 combination subjects (74%), and 8 meperidine subjects (23%) had 50% reduction in VAS pain scores (P<.001, 22). An intent-to-treat efficacy analysis for all 154 subjects likewise demonstrated that both ketorolac and combination treatment were significantly more efficacious than meperidine but not significantly different from each other for both VAS and categorical pain scores at 15 and 30 minutes. Kaplan-Meier curves demonstrated that meperidine yielded significantly less complete relief over the 6-hour study period than did the other two treatments (P<.001, log-rank test) (Figure 1). The percentages of subjects without complete pain relief over the course of the 6hour study period were not significantly different between the ketorolac and combination groups (P=.86, log-rank test). For categorical and VAS SPID and TOTPAR, ketorolac was significantly superior to meperidine at 2, 3, and 6 hours (P<.003) (Table 3). Combination treatment was significantly superior to meperidine (P<.037) for all scores except the 6-hour VAS SPID. We detected no significant differences between ketorolac and combination treatment (P_>.052).

Table 2.

Mean pain-intensity scores and pain-relief scores for first 30 minutes of study. P

Parameters

Meperidine

Meperidine

Versos

Versus

Ketorolac Versus

Meperidine

Ketorolac

Combination

Overall

Ketorolac

Combination

Combination

77.4+3.6 55.0+4.3 56.6+5.2

80.3&3.5 34.8+4.5 242+4.6

73.3+3.3 25.8+4.5 23.5+4.7

,21 <.001 <.001

£2 .003 <.001

30 <.001 <.001

.08 .10 .87

Z7+.1 1.9+.1 2.1+_.1

2.8_+.1 1.4_+.1 1.1_+.1

2.7+,1 1.1_+.1 .9_+.2

.63 <.001 <.001

.40 .02 <.001

.44 .001 <.001

.95 .11 .27

1.6_+.2 1.5-+.2

2.5+_2 2.8-+.2

2.9-+.1 2.6_+,2

<.001 <.001

<001 <.001

<001 <.001

.17 .59

VAS, pain-intensity scare (100-mm scale) 0 Minutes 15 Minutes 30 Minutes

Categorical painseverity score (O, none; 3, severe) 0 Minutes 15 Minutes 30 Minutes

Categorical pain-relief scores (O, none; 5, complete) 15 Minutes 30 Minutes

1 54

ANNALS OF EMERGENCY MEDICINE 28:2 AUGUST 1996

KETOROLAC VERSUS MEPERIDINE Corddl ¢t al

Seventy-seven of the 106 subjects (73%) received supplemental meperidine: 31 in the meperidine group (89%), 23 in the ketorolac group (64%), and 23 in the combination group (66%). The number of meperidine subjects given supplemental meperidine was significantly higher compared with the other two groups (P=.04, Z2). KaplanMeier curves demonstrated that meperidine subjects needed supplemental meperidine significantly earlier than did members of the other two study groups (P=.004, log-rank test) (Figure 2). Total supplemental meperidine doses over the entire study period ranged from 12.5 to 550 mg (median, 75 rag). The mean cumulative dose of meperidine (loading plus supplemental) was significantly higher in the mepeddine group (102.9+14.2 mg) than the ketorolac (56.9+16.9 mg) and combination (65.0+20.6 rag) groups (P<.001). The mean supplemental dose was not significantly different between the ketorolac and combination groups (P=.67). The mean scores for end-of-study overall pain relief (0, none; 5, complete) were 3.6 for ketorolac, 3.3 for combination therapy, and 2.5 for meperidine (P<.003, ketorolac and comparison therapy versus meperidine; P=. 11, ketorolac versus combination therapy). The end-of-study mean improvement in functional impairment (0, none; 4, severe) was 1.8 for ketorolac, 1.5 for combination therapy, and 1.2 for meperi.dine. Only the comparison of meperidine and ketorolac was significant (P=.003). Subject end- ofstudy rating of overall drug tolerability (0, poor; 4, excellent) averaged 3.2 in the ketorolac group, 3.1 in the Figure

1.

combination group, and 2.5 in the meperidine group. Meperidine tolerability was significantly lower than that in the other two groups (P<.003). One hundred twenty-nine subjects (84%) reported 406 adverse events. One ketorolac subject was withdrawn from the study after the development of a severe rash on the head, neck, and chest. Adverse events categorized by the investigator as "probably or possibly related to treatment" were reported by 35 combination subjects (67%), 28 meperidine subjects (55%), and 19 ketorolac subjects (37%). The number of subjects who reported adverse events probably or possibly related to treatment was significantly higher in the combination group than in the ketorolac group (P=.002) but not different between the meperidine and ketorolac groups (P=.073) or between the meperidine and combination groups (P=. 196). The most frequently reported of these adverse events were dizziness and somnolence. Dizziness was reported by 18 meperidine subjects, 16 combination subjects, and 4 ketorolac subjects; somnolence was reported by 16 combination subjects, 6 ketorolac subjects, and 4 meperidine subjects. We noted no statistically significant differences among the groups with regard to changes in supine systolic, standing systolic, and standing diastolic blood pressures (P=.51,. 10, and .28, respectively). Subjects in the ketorolac and combination groups had decreases in supine diastolic blood pressure significantly greater than that in the meperidine group (-12.6+4.3 mm Hg in the ketorolac Figure

Kaplan-Meier curvefor time elapsed before complete relief of pa~nfor the entire study period. Complete Relief (%) ..... q ...... 0 10 ---i 20 i~--30 - - ~ 40 ................ 50 60 70 80 90 100 1.0 2.0

No Supplemental Meperidine (%) 100

90 ' [ ~ \

q ___ Meperidine (N=35) - - Combination (N=35) Keterolac (N=36)

28:2

80

':~

70

tA

60

--- Meperidine (N=35) -Combination (N=35) ..... Keterelac (N=36)

L '-"-"L,

40

!L - ]

30

20

~-,

"-: ..........

! .... _L...........

- I _ _

~-~ '---~--

10 0

3.0

4.0

Time since baseline (hours)

A U G U S T 1996

2.

Kaplan-Meier cuYvefor time elapsedbefore the needfor supplemental meperidinefor the entire study period.

ANNALS OF EMERGENCY MEDICINE

5.0

6.0

110

210

310

410

510

810

Time since baseline (hours)

1 5 5

KETOROLAC VERSUS MEPERIDINE Cordell et al

group, -12.7___4.0 mm Hg in the combination group, and +.5_+3.7 mm Hg in the meperidine group; P=.02). DISCUSSION

NSAIDs are an important advance in the management of renal colic. Their clinical use in renal colic is the result of better understanding of the pathophysiologic consequences of acute ureterat obstruction and the role of prostaglandins in modulating renal blood flow and ureteric smooth muscle contractility. 22-25 Prostaglandin inhibitors offer a potential avenue of therapy for renal colic, different from opioids, by interfering with these underlying pathophysiologic mechanisms rather than by simply suppressing pain. 22 By inhibiting prostaglandin synthesis, NSAIDs diminish renal blood flow, diuresis 26, ureteral smooth muscle activity, and local ureteral inflammation. Since 1978, human studies conducted mostly outside the United States have confirmed the efficacy of NSAIDs-including indomethacin, diclofenac, and aspirin--in relieving the excruciating pain associated with acute ureteral obstruction. Labrecque et al2r, in a metaanalysis of 20 studies, concluded that parenteral NSAIDs are more effective than placebo and as effective as analgesic agents (primarily opioids) in the treatment of renal colic. Although the extent of use of NSAIDs in the United States for patients with renal colic has not been reported, it is probably far less than that in Scandinavian and European countries. This may be attributable to the poor diffusion and adoption of the results of NSAID renal colic studies (conducted primarily in Scandinavian and

European countries) and, until recently, the lack of a parenteral NSAID in the United States for the treatment of acute pain. Furthermore, the use of opioids for severe pain is one of the most entrenched habits in acute pain control. In 1989, ketorolac became the first NSAID in the United States to be labeled for IM use as an analgesic. In December 1994, the US Food and Drug Administration permitted IV administration of doses up to 30 mg. Although the analgesic effect of parenteral ketorolac in several pain states, including postsurgical pain 28-29, has been investigated in randomized double-blind comparative trials, few studies have evaluated its use in renal colic. Oosterlinck et aP ° compared a single dose of IM ketorolac (10 mg or a "supramaximal" dose of 90 mg) with IM meperidine 100 mg, and Sandhu et aP 1 compared IM ketorolac 30 mg with IM meperidine 100 mg in subjects with renal colic. Larsen et aP 2 administered IV ketorolac 30 mg in 25 subjects with renal colic, and Martin Carrasco et aP 3 compared the analgesic efficacy of IV ketorolac 30 mg with dipyrone (another NSAID) 2.5 g combined with a spasmolytic agent in 34 subjects with renal colic. Our study is the first to compare IV ketorolac and IV meperidine in a randomized, double-blind design with objective criteria for stone confirmation. We found that IV ketorolac 60 mg was superior to and more rapid than IV meperidine 50 mg alone in relieving pain in subjects with moderate or severe renal colic by all measures of efficacy. To our knowledge, our study is the first to compare a combination regimen of IV ketorolac plus meperidine with

Table 3.

Analysis of SPID and TOTPAR.

Parameters

Meperidine

I(etorolac

Combination

Overall

Meperidine Versus Ketorolac

Meperidine Versus Combination

Ketorolac Versus Combination

Categorical SPID 2 Hours 3 Hours 6 Hours

2.0+,3 3.3+,4 7.9+_.8

3.7_+.3 6.0+.4 13.0+.7

3.5+.3 5.4+.4 11.0+.9

<.001 <001 <.001

<,001 <.001 <.001

<.001 <.001 .001

.443 .242 ,098

<.001 <.001 <.001

<.001 <.001 <.001

<,001 .008 .124

.113 .050 .009

<.001 <.001 <.001

<.001 <.001 <.001

<.001 <,001 .008

.407 .075 ,034

VAS SPID 2 Hours 3 Hours 6 Hours

65,4+8.6 110.8+12.7 267.8_+26,0

119.2_+.9.5 190.6+13.2 409.1_+242

105,8_+8.1 158.6+15.9 319,3_+26.2

TOTPAR 2 Hours 3 Hours 6 Hours

156

4.1_+.3 6.6+_.4 14.3+-.8

6.1+_.3 9.7_+.4 20.4+_2

5.8_+.3 8.7_+.5 17.7+1,0

ANNALS OF EMERGENCY MEDIOINE 28:2 AUGUST1996

KETOROLAC VERSUS MEPERIDINE Cordell et al

either agent alone in renal colic. Combinations of pharmacologic agents have been used postoperatively to treat or prevent pain, and the term "balanced analgesia" is frequently u s e d Y ,35 The rationale for balanced analgesia is to achieve sufficient analgesia through additive or synergistic effects between different analgesics with concomitant reduction of side effects as a result of lower doses of analgesics and differences in side-effect profiles. 36 Although we noted trends toward greater and more rapid pain relief in the balanced-analgesia group in our study than with ketorolac alone, these differences were not significant. Our study had a power of 86% to detect a difference of 20 mm on a VAS of pain intensity among treatment groups. There were also significantly more adverse events probably or possibly related to treatment in the balanced-analgesia group than in the ketorolac group. The observed differences in adverse events were confined to dizziness, which tended to increase whenever meperidine was used; and somnolence, which was increased in the balanced-analgesia group. Although we could not demonstrate improved analgesic efficacy and side-effect profile with balanced-analgesia over ketorolac alone, our findings do not refute the value of combining an opioid with an NSAID in the treating of renal colic. Nor do they negate the role of opioids in renal colic; nearly three quarters of all subjects received supplemental meperidine at some point during the study period. Although the percentage was highest m the meperidine group (89%), nearly two thirds of both the ketorolac and combination groups also received supplemental meperidine. This underscores the severity and often fluctuating intensity of renal colic. Because response to ketorolac alone cannot be predicted, clinicians may choose to initiate treatment with a ketorolac-meperidine combination regimen in the individual patient with suspected renal colic in anticipation that many will require supplemental meperidine. The first limitation of our study is the loss of 31% of our subjects from efficacy analysis because renal colic could not be objectively confirmed. The exclusion of these subjects, however, did not statistically unbalance the study groups or alter our conclusions regarding efficacy, as evidenced by an intent-to-treat analysis. A second limitation is our use of a 60-mg IV dose of ketorolac. Product labeling for the IV use of ketorolac was not approved until after the data collection of our study had been completed. Although the labeled dose recommendation remains 60 mg for single doses of IM ketorolac, the recommended dose for IV administration is 30 rag. Although we did not study a 30-rag IV dose of ketorolac, the fiat dose-response curve of ketorolac 37-39 and the findings of studies involv-

AUGUST 1996

28:2

ANNALS OF EMERGENCY MEI~ICrNE

ing lower doses of ketorolac in renal colic 30-33 suggest that 30-mg IV doses may be effective in renal colic. Finally, we wish to address our choice of an initial IV meperidine dose of 50 rag. We recognize that the choice of opioid, loading dose, route, and amount and time intervals of supplemental dose administration vary widely in clinical practice. We used a single-dose comparison for the first 30 minutes and a 50-mg initial dose because it is typical of initial doses in clinical practice, as well as of the doses used in previous clinical trials. 6,9 We emphasize that our analysis was not limited to the first 30 minutes and that the initial 50-mg dose was not the only meperidine subjects could or did receive. After 30 minutes, 73% of all subjects received supplemental meperidine in a wide range of doses (12.5 to 550 mg). The effects of supplemental doses of mepeddine were analyzed statistically, including the use of time-to-event analysis. We recommend that if a single agent must be chosen, IV ketorolac should be considered over IV meperidine for patients with moderate or severe renal colic pain who have no contraindications to ketorolac or NSAIDs. However, because many patients can be expected to require supplemental mepefidine and because response to ketorolac alone cannot be predicted, clinicians may choose to initiate treatment with a ketorolac-meperidine combination in the individual patient with renal colic. Our results and the large body of cumulative data from other international studies should challenge the common practice in the United States of treating renal colic with opioids alone. REFERENCES 1. Hoimlund D, Sjodin JG: Treatment of ureteral colic with intravenous indomethacin. J Urol 1978;120:676-677. 2. Lundstam S, Wahlander L, Kral GJ: Treatment of ureteral colic by prostaglandin synthntase inhibition with diclofenac sodium. Curt TherRes ClinExp 1980;28:355-358. 3. Lundstam SO, Leissner KH, Wahlaeder LA, et ai: Prostaglandin-synthetase inhibition with diclofenac sodium in treatment of renal cnlic: Comparison with use of a narcotic analgesic. Lancet1982;1:1096-1097. 4. Sjodin JG, Helmlund D: Indomethacin by intravenous infusion in ureteral colic. ScandJ Urol Nephrol1982;16:221-225. 5. Flannigan GM, Clifford RP, Carver RA, et al: Indomethacin: An alternative to pethidine in ureteric colic. Br J Uro11993;85:6-9. 6. Lehtonen T, Keilokumpu I, Permi J, et at: intravenous indemethacin in the treatment of ureteric colic: A clinical multicentre study with pethidine and metamizol as the control preparations. Ann Clin Res 1983;t 5:197-I 99. 7. Llden P, Rentzhog L, Berger T: A comparative study on the analgesic effects of indomethacin and hydromorphieecNoride-atropine in acute, ureterar-stone pain. Acta ChirScand1983;149:497499. 8. Hetherington JW, Philp NH: Dielofenac sodium versus pethidine in acute renal colic. BMJ 1988;292:237-238. 9. Khalifa MS, Sharkawi MA: Treatment ef pain owing to acute ureteral obstruction with prostaglandie-synthetase inhibitor: A prospective randomized study. J Uro11986;136:393-395.

15 7

KETOROLAC VERSUS M E P E R I D I N E CordeZZ et al

10, Jensson PE, OlssonAM, PeterssonBA, et el: Intravenous indomethacin and oxycone-papaverine in the treatment of acute renal colic: A double blind study. Br J Uro11987;59:396-400.

35. Power I, Bowler GM, Pugh 6C, et al: Ketorolac as a component of balanced analgesia after thoracotomy. BrJAnaesth 1994;72:224-246.

11. Miralles R, Cami J, GutierrezJ, et el: Diclofenac versus dipyrone in acute renal colic: A double-blind controlled trial. EurJClin Pharmaco11987;33:527-528.

36. Kehlet H, DaN JB: The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. AnesthAnalg 1993;77:1048-1056.

12. Nelson CE, Nylander C, OlssonAM, etal: Rectal v. intravenous administration of indomethacin in the treatment of renal colic. Acta ChirScand1988;154:253-255.

37. Sevarino FB, Sinatra RS, Paige D, et el: The efficacy of intramuscular ketorolac in combination with intravenous PCA morphine for postoperative pain relief. J ClinAnesth 1992;4:285-288.

13. Sommer P, Kromann-AndersenB, Lendorf A, etal: Analgesic effect and tolerance of Voltaren and Ketogan in acute renal or uretedc colic. BrJ Uro11989;63:4-6.

38. FrickeJR Jr, Angeleoci D, Fox K, et al: Comparisonof the efficacy and safety of ketorolac and meperidine in the relief of dental pain. J Clin Pharmaco11992;32:376-384.

14. ThompsonJF, Pike JM, Chumas PD, et al: Rectal diclofenac compared with pethidine injection in acute renal colic. BMJ 1989;299:1140-1141.

39. Staquet M J: A double-blind study with placebo control of intramuscular ketorolac tromethamine in the treatment of cancer pain. J Clin Pharmaco11989;29:1031-1036.

15. eI-Shedf AE, Foda R, Norlen LJ, et al: Treatment of renal colic by prostaglandin synthetase inhibitors and avafortan (analgesic antispasmodic). Br J Uro11990;66:602-60& 16. SanahujaJ, Corbera G, Garau J, etal: Intramuscular diclofenac sodium versus intravenous Baralgin in the treatment of renal colic. DICP1990;24:361-364. 17. Collaborative Group of the Spanish Society of Clinical Pharmacology:Comparativestudy of the efficacy of dipyrone, diclofenac sodium and pethidine in acute renal colic. EurJ Clin Pharmacel1991;40:543-546. 18. Marthak I(V, GokarnAM, RoeAV, et el: 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. CurrMedResOpin1991;12:366373. 19. Corde]l WH, LarsonTA, LingemanJE, et al: Indomethacin suppositories versus intravenously titrated morphine for the treatment of ureteral colic. Ann EmergMed 1994;23:262-269.

Statistical analysis was performed by David B Nelson, MS, at Methodist Hospital and Marjorie Cadden, MS, and Steven Chang, PhD, at Roche Laboratories. The investigators thank the emergency physicians, emergency nurses, clinical research nurses, and pharmacists at the four study hospitals for their participation in this study. Also, the following individuals contributed substantially to the completion of this project: Beverly K Giles, RN, and James E Lingeman, MD, at Methodist Hospital; Thomas E Auble, PhD, atthe University of Pittsburgh School of Medicine; Marie H Zeldin, RN, at Vanderbilt University; Karen H Bawlin, RN, and Cynthia M Holland at the Bowman Gray School of Medicine; and Michael Burchmore, PharmD, and John Hoskins, MS, at Roche Laboratories. R e p r i n t no. 47/1/74138

Address for reprints:

20. Max MB, Laska EM: Single-dose analgesic comparisons. In: Max MB, Portenoy RK, LaskaEM (eds):Advancesin PainResearchand Therapy:TheDesignof Analgesic Clinical Trials,vol 18. New York: Raven Press, 1991:63.

William H Cordell, MD

21. US Foodand Drug Administration: COSTART3: CodingSymbolsfor Thesaurusof Adverse Reaction Terms,Publication no. HFN-735,ed 2. Rockville, Maryland: Center of Drugs and Biologics, Division of Drug and Biological Products Experience,1989.

Methodist Hospital of Indiana

22. Welfsen AB, Yealy DM: Oral indomethacin for acute renal colic. Am J EmergMed 1991;9:1619. 23. Van Laecke E, Oosterlinck W: Physiopathologyof renal colic and the therapeutic consequences. Acta UrelBelg 1994;62:15-18.

Emergency Medicine and Trauma Center

1701 North Senate Boulevard Indianapolis, Indiana 46202 317-929-3088 Fax 317-929-2306 E-mail wcordel)@mhi.com

24. Holmlund D: The pathophysiology of ureteral colic. ScandJ Urol NephrolSupp11983;75:2527. 25. Cole RS, Fry CH, Shuttleworth KE: The action of prostaglandins on isolated human ureteric smooth muscle. BrJUre11988;61:19-26. 26. Sjodin JG: Effects of intravenous indomethacin during acute ureteral obstruction: Experimental studies and studies in patients with pain due to ureteral stone obstruction. ScandJ UrolNephrolSuppl1981;66:1-43. 27. LabrecqueM, Dostaler LP, Rousselle R, et el: Efficacy of nonsteroidal anti-inflammatory drugs in the treatment of acute renal colic: A meta-analysis. Arch InternMed1994;154:1381-1387. 28. Nuutinen LS, Laitinen JO, Salomaki TE: A risk-benefit appraisal of injectable NSAIDs in the management of postoperative pain. DrugSaf1993;9:380-393. 29. Wong HY, Carpenter RL, KopaczDJ, et al: A randomized,double-blind evaluation of ketorolac tromethamine for postoperative analgesia in ambulatory surgery patients. Anesthesiology 1993;78:8-14. 30. Oosterlinck W, Philp NH, Charig C, etal: A double-blind single dose comparison of intramuscular ketorolac tromethamine and pethidine in the treatment of renal colic. J Clin Pharmacol 1990;30:336-341. 31. Sandhu DP, lacovou JW, Fletcher MS, et al: A comparison of intramuscular ketorolac and Pethidine in the alleviation of renal colic. BrJ Uro11994;74:690-693. 32. Larsen LS, Miller A, Allegro JR: The use of intravenous ketorolac for the treatment of renal colic in the emergencydepartment. Am J EmergMed 1993;11:197-199. 33. Martin CarrasceC, RodriquezVazquezM, Palacios Garcia R: A double-blind study of the analgesic efficacy in kidney colic of the combination of dipyrone and spasmolytic with keterolac trometamol. Arch Esp Ure11993;46:763-768. 34. CodeW: NSAIDs and balanced analgesia [editorial]. CanJAnaesth 1993;40:401-405.

1 58

ANNALS OF EMERGENCY MEDICINE

28:2

AUGUST 1996