ANALGESIC/ANTI-INFLAMMATORY/I
MM U NOSU PPRESSIVES
A Double-Blind Single Dose Comparison Intramuscular Ketorolac Tromethamine and Pethidine in the Treatment of Renal Colic W. G.
Gillies,
OosterlinCk, MD,
ChB,
MD, FFA,
N. H. Philp, MB, ChB, RCS, J. W. Hetherington,
FRCS, MB,
C.
ChB,
Charig,
FRCS,
MB,
and
BS,
of
FRCS,
J. Lloyd,
BSc,
MSc
dose of intramuscular ketorolac 10 mg or 90 mg was compared in a randomized double-blind study in 121 patients reporting at moderate pain due to renal colic. Pain was assessed before drug administration, and then at 1 hour and 12 hours after the dose. Sedation was also assessed at these times, and additionally at the 12 hour assessment the time of the next analgesic dose was recorded. At 1 hour after dosing, pain scores had decreased in all groups; the largest decrease was seen in the ketorolac 90 mg group. The difference in the decrease was significant between the two ketorolac groups, but the differences between ketorolac and pethidine were not significant. Fewer patients in the ketorolac 90 mg group (17%) required a further dose of analgesic within 10 hours than in either the ketorolac 10mg group (39%) or the pethidine 100 mg group (47%). The difference between ketorolac 90 mg and pethidine 100 mg was statistically significant. At both assessment times the proportion of patients with no sedation was higher in the two ketorolac groups than in the pet hidine group. The overall incidence of adverse events was low with all drugs, notably so for the occurrence of vomiting after ketorolac. The results of the study show that intramuscular ketorolac is The with least
efficacy pethidine
efficacious
of a single 100 mg
in
the treatment
of renal
colic.
K etorolac
tromethamine (ketorolac) is a new nonnarcotic analgesic whose major mode of action is via the inhibition of prostaglandin synthesis. Ketorolac has been shown to be effective in relieving postoperative pain when administered as single doses of 10 mg and 30 mg.1’2 This high potency means that ketorolac may be formulated into an acceptable solution for injection. It was, therefore, proposed to investigate the efficacy of ketorolac, when administered intramuscularly, in the treatment of the pain of renal colic.
From the Department of Urology, University Hospital, Ghent, Belgium (Dr. Oosterlinck), Department of Urology, New Cross Hospital, Wolverhampton, UK (N. H. Philp), Institute of Urology, London, UK (C. Charig), Royal VictoriaHospital, Glasgow, UK (G. Gillies), Senior Registrar St. Mary’s Hospital, London, UK (J. W. Hetherington) and Syntex Research, Thames House, Maidenhead, Berkshire, UK (J.Lloyd). Address for reprints: J. Lloyd, Syntex Research, Thames House, 1 Bell Street, Maidenhead, Berkshire, 5L6 1BU, United Kingdom.
336
5
J ClIn Pharmacol
1990;30:336.-341
In the doses with
study
reported
of ketorolac 10 mg 100 mg of pethidine.
here and
two
intramuscular
90 mg, were compared 100 mg of pethidine was
chosen as an accepted standard in the treatment of renal colic. A 10 mg dose of ketorolac was chosen as being comparably efficacious to 10 mg of morphine in postoperative pain of moderate to severe intensity.1’2 Single doses of 90 mg of ketorolac have also been used in both volunteers (3) and patients (2) and this dose was used to show the maximal potential of the drug. METHODS Study
Design
This was a single-dose parallel design. Patients
one of the three 90 mg ketorolac
treatment or 100
study, were
with a double-blind randomly assigned
groups, 10 mg ketorolac, mg pethidine, given intra-
to
INTRAMUSCULAR
muscularly. hours
after
Patient The
Patients
were
assessed
administration
of the
TROMETHAMINE
KETOROLAC
at 1 hour single
and
study
Patients
was
set
and
up
as
dose.
a multicenter
a target
who
were
study
of a minimum
eligible
for
with
of 100
entry
were
pa-
those
who were suffering pain due to renal colic, and who described that pain as at least moderate according to a 4-point verbal rating scale. The diagnosis of renal colic required radiological evidence of a renal stone or acute renal obstruction. Patients were to be aged between 18 and 75 years and have a weight between 45 kg and 100 kg. The study protocol allowed entry of fit, healthy patients, including women with adequate contraceptive protection and excluding patients with a known history of allergy or previous adverse reaction to salicylates or nonsteroidal antiinflammatory drugs; patients known to abuse alcohol, narcotics or other drugs; and patients with a temperature above 37.5#{176}C. Study
Medications
The doses administered in the study were single intramuscular doses of 10 mg (1 ml of 1% solution) or 90 mg (3 ml of 3% solution) of ketorolac, or 100 mg (2 ml of 5% solution) of pethidine. To maintain the double-blind
technique
nature
was
of the
used;
the
study,
test
a double
dose
was
observer
administered
by a person who was not involved in the assessment of the patient, and the nature of the given medication was not disclosed to the observer. If insufficient analgesia was reported following the test medication, the clinician was allowed to prescribe his usual standard analgesic, and the time of administration was recorded.
Schedule
of Assessments
When a patient presented with pain typical of renal colic, he/she was asked to assess the severity of the pain according to a 4-point verbal rating scale (none, mild, (VAS).
moderate, The VAS
severe), was 100
and
a visual
analogue
scale
vertical line marked at the bottom with ‘no pain’ and at the top with ‘the worst pain imaginable.’ Patients who assessed their pain as moderate or severe on the verbal rating scale (VRS),
were
entered
into
test medication as an the gluteus maximus.
ANALGESIC/ANTI-IN
PETHIDINE
12
Population
five centers tients.
AND
One hour after administration of the test medication, the severity of pain was assessed by the investigator. Pain severity was assessed using the VRS and VAS as before. The patient was next assessed by the investigator approximately twelve hours after administration of the test medication, when time to next analgesia was recorded. Volunteered adverse events were recorded at each assessment. Sedation was separately assessed using a 3-point scale (no sedation, mild sedation/ drowsiness, asleep), at 1 hour and 12 hours after the
test dose. At 12 hours the nursing staff were asked to assess the overall degree of sedation over the study period, using the same assessment scale. Vital signs were measured and recorded at baseline and at the 1 hour assessment.
Statistical
Analysis
The primary efficacy variables were the pain intensity difference from the VAS, and the pain severity (VRS). The time between the test drug and the next analgesic dose was also analyzed. For each of these variables, a linear additive model, including treatment center and their interaction, was fitted in order to test the difference between treatments and the consistency of this difference across centers. Pain intensity differences derived from the VAS scores were analyzed using a 2-way analysis of variance. The 95% confidence intervals for the differences between each pair of treatments are quoted. Pain severity (VRS) was analyzed by fitting a proportional odds model,4 each pair of treatments being analyzed separately. For time from test dose to the next analgesic, results for each treatment group were summarised using the Kaplan-Meier estimator.5 Analysis was carried out using the Cox proportional hazards model.5 For sedation scores at 1 hour, two of the three categories (mild sedation/drowsiness and asleep), were combined because of the low frequencies in the asleep category and analysis was carried out using All
logistic statistical
regression.5 tests were
two
tailed
with
a 5%
level
of significance. RESULTS
mm
the
study
intramuscular
FLAMMATORY/IMMU
and
received
injection
the
into
NOSUPPRESSIVES
Patient
Population
125 patients included in
were the
entered safety
into analysis
were excluded from all the ses. One patient’s pretrial
the but
study. four
All were patients
primary efficacy analypain was described as
337
OOSTERLINCK
ET AL
any TABLE Summary
I
of Patients
Female
of Demography
Pain
Ketorolac 10mg
Ketorolac
Pethldine
90mg
100mg
45
37
32 (7 1%)
29 (78%)
39 29 (74%)
13 (29%)
8 (22%)
10 (26%)
40 21-71
41 21-69
39 18-70
70 45.5-90 1
Height (cm) Median
172.5
Range Missing
152-187 1
between
Intensity
73.2 47.7-100 0 172
155-196 0
73 54-95.5 0
The mean baseline pain scores from the VAS were high for all groups being 80 mm, 82 mm and 80 mm for ketorolac 10 mg, ketorolac 90 mg and pethidine 100 mg respectively. A marked decrease in VAS pain scores was seen in all three groups, and the mean VAS pain intensity differences at 1 hour after dosing were 54 mm, 65 mm and 57 mm for ketorolac 10 mg, ketorolac 90 mg and pethidine 100 mg respectively. Paired comparisons showed no difference between ketorolac 10 mg and pethidine 100 mg (P = .4), for which the estimated difference between treatments was 5 mm in favor of pethidine with a 95% confidence interval of -7 mm to 17 mm. However, there was evidence of a difference between ketorolac 90
175
152-190 0
Assessment mild, thereby making him ineligible. One patient was found not to have renal colic, and for two patients, pain assessments were not completed. Thus 121 patients were included in the efficacy analysis; 45 in the ketorolac 10 mg group, 37 in the ketorolac 90 mg group and 39 in the pethidine 100 mg group. All 121 patients were included in the analysis of the time to the next analgesic. Several were excluded from the analyses at either I or 12 hours. At 1 hour, nine patients were excluded (6 from ketorolac 10 mg, one from ketorolac 90 mg and 2 from pethidine 100 mg). In five cases this was because the assessment time was different from the scheduled 1 hour (a time of 45 minutes to 90 minutes postdosing was permitted), in two cases because the assessment time was not given, and in two cases because rescue analgesia had been given after only 30 minutes. At 12 hours, patients were included in the analysis whether or not rescue analgesia had already been given. However, of the total 121 patients 18 patients (7 ketorolac 10 mg, 6 ketorolac 90 mg, 5 pethidine 100 mg), were excluded. In one case this was because the patient discharged himself before the assessment time, for one the assessment time was unknown and for the other 16 the assessment was carried out outside 10-14 hours. Details of the patient population are summarized in Table I for all patients. Ninety (74%) were men with ages ranging from 18 to 71 years. Weights ranged from 45.5 to 100 kg. There was no evidence of
5
J Clin Pharmacol
1990;30:336-341
groups
centers.
TABLE
338
treatment
Group
Age
Median Range Weight (kg) Median Range Missing
differences
or between
Treatment
Number Sex Male
marked
II
of Pain IntensIty
Visual Analogue
Scale
BaselIne Scores: Treatment Ketorolac 10mg
Ketorolac
Pethldine
90mg
100mg
80
82
80
Mean
SD Range N
20 11-100 39
VAS Pain intensity
Group
Differences
11 57-100 35 from BaselIne Treatment
Ketorolac 10mg
Mean SD N Not recorded Comparison
54 26 39 0
13 52-100 37 at 1 hour Group
Ketorolac
Pethldine
90mg
100mg
65 18 35 1
57 26 37 0
of Treatments:
95% Estimated
SIgnificance K90-K10 P100-Kb K90-P100
P= P= P=
Dlfference*
Confidence
Interval
.02
14
2,26
.4 .12
5 10
-7, 17 -2,22
SD Standard deviation; K10 ketorolac 10 mg; K90 = ketorolac 90mg: P100 = pethidine 100 mg; * A positive value indicates a greater decrease in pain for the first treatment mentioned.
INTRAMUSCULAR
KETOROLAC
mg and each of the other two treatments, in both cases favouring ketorolac 90 mg. The difference from ketorolac 10 mg was statistically significant (P = .02), the estimated difference being 14 mm in favor of ketorolac 90 mg with a 95% confidence interval of 2 mm to 26 mm. The difference from pethidine 100 mg was less marked and was not statistically significant (P = .12). The estimated difference was 10 mm in favor of ketorolac with a 95% confidence interval of -2 mm to 22 mm. Table II summarizes the results of the VAS assessment of pain intensity. Table III summarizes the results of the assessment of pain intensity using the verbal rating scale. On entry the proportion of patients with severe pain was highest in the ketorolac 90 mg group (72%) and lowest in the ketorolac 10 mg group (59%). At 1 hour after dosing about one third of the patients had no pain (41%, 33% and 30% in the ketorolac 10 mg, ketorolac 90 mg and pethidine 100 mg groups respectively), and few still had moderate or severe pain. The comparison of each pair of treatments showed no differences between them (P> .4). Comparison of the assessment of pain relief at one hour
TROMETHAMINE
Assessment Baseline
of Pain
III
Intens ity Verbal
Analysis
Pethidine
90mg
100mg
16 (41%) 23 (59%)
10 (28%) 26 (72%)
13 (35%) 24 (65%)
Pain SeverIty Treatment Ketorolac 10mg
None Mild Moderate/Severe
16 (41%) 16 (41%) 6/1 (18%)
Group
Ketorolac
Pethidine
90mg
100mg
12 (33%) 19 (53%) 4/1 (14%)
11(30%) 20 (54%) 3/3 (16%)
Comparison of Treatments: Significance
K90-K10 P100-Kb K90-P100 =
from Study Drug Admin istration to Next Analgesic Treatment
Time to Next Analgesic 10 hours Unknown Estimated
27 1*
Group
Ketorolac 90 mg 6 (17%)
30 it
Pethidine 100 mg 18 (47%)
20 b
time
(mins) by which 25% had received rescue anaIgesic Comparison
355
670
300
of Treatments”: Significance
K90-K10 P100-Kb
P=0.08 P> 0.5
K90-P100
P=0.015
Study
completed
at 9 hours
50 minutes.
t Study completed at 9 hours 40 minutes. No times given; excluded from the analysis. § Kap!an-Meier estimate without adjustment for differences between I By Cox regression adjusting for differences between centers. K10 = Ketorolac 10mg; K90 = Ketorolac 90mg; P100 Pethidine
also
Ketorolac
Severe
at One Hour:
Group
Ketorolac 10mg
Moderate
KI 0
of Time
IV
centers. 100mg.
Assessment:
Treatment
Scores
Rati ng Scale
PETHIDINE
TABLE
*
TABLE
AND
P>.5 P= .4 P>.5 ketorolac
10 mg; K90
=
ketorolac 90 mg; P100
ANALGESIC/ANTI-INFLAMMATORY/IMMUNOSU
=
pethidine
100 mg.
PPRESSIVES
revealed
no
significant
differences
between
treatments In order ministration tients who the study summary requiring edly lower either the idine 100
to compare the time from study drug adto next analgesic, the number of parequired an analgesic within 10 hours of drug administration has been used as a measurement (Table IV). The percentage an analgesic within this time was markin the ketorolac 90 mg group (17%), than ketorolac 10 mg group (39%), or the pethmg group (47%). The figure shows graphi-
cally
estimated
the
(P>
.2).
proportion
of patients
who
had
not the
yet received rescue analgesia against time from administration of the study drug. Each pair of treatments was compared and there was no evidence of any difference between ketorolac 10 mg and pethidine 100 mg (P .5), but there was a statistically significant difference between ketorolac 90 mg and pethidine 100 mg (P = .015), and a difference approaching statistical significance between the two doses of ketorolac (P = .08). In each case, the difference favored ketorolac 90 mg. The proportion of patients with no sedation at 1 hour was higher in the two ketorolac groups (54%,
339
OOSTERLINCK
ET
AL
100
90
-
L#{149}:
80
70
60
%
50
KETOROLAC
90mg
40 30 20
PETHIDINE
10
100mg
KETOROLAC
0.
10mg
I 0
5
10
15
20
25
TIME SINCE STUDY DRUG (hours) Figure.
Estimated
percentage
of patients
who
have
not yet received
for 10 mg and 90 mg respectively), than the pethidine 100 mg group (35%). None of the comparisons of the treatment groups were statistically significant (P> .1). Sedation during the study period was recorded at 12 hours. Results are summarized in Table V for patients who had not yet received rescue analgesia. For ketorolac 90 mg, the proportion with no sedation was higher (81%) than either of the other two groups, which were similar to each other (61% for 10 mg ketorolac and 59% for 100 mg pethidine). No clinically important changes occurred in the vital signs. Adverse effects were recorded in 32 of the patients, eight in the ketorolac 10 mg group, 10 in the ketorolac 90 mg group and 14 in the pethidine group. 47%
These
are
summarized
in Table
The standard treatment for renal colic is usually parenteral administration of a narcotic. This has inherent problems due to the adverse event profile; nausea and vomiting are particular problems in patients who are likely to be predisposed to these symptoms. The use of a narcotic in this emergency situation
#{149} .1 CiIn Pharmacol
1990;30:336-341
analgesia.
may
also
be
open
to abuse,
both
by
the
attendants
and malingering patients. The active control group chosen in this study was 100 mg pethidine, an accepted standard in the treatment of renal colic. Two doses of ketorolac, 10 mg and 90 mg were studied in order to identify firstly whether ketorolac shows efficacy in this indication and secondly whether there is any dose-effect rela-
TABLE Summary
of Degree
V
of Sedation
During
Assessed by the Nursing Staff (Recorded Treatment
VI.
DISCUSSION
340
rescue
Not yet received analgesia No sedation Mild sedation/ drowsiness Asleep
Group
Ketorolac 10mg
Ketorolac
Pethidine
90mg
100mg
14 (61%)
17 (81%)
10 (59%)
8 (35%) 1(4%)
3 (14%) 1(5%)
5 (29%) 2 (12%)
0
2
1
Missing Patients
the Study as at 12 Hours)
whose assess ments
were outsi de 10-14
hours
were excluded.
KETOROLAC
INTRAMUSCULAR
TABLE Summary
of Adverse
Events Group
less
Ketorolac 10mg
Ketorolac 90mg
Pethidine
46
38
41
10 (26%)
14 (34%)
8 (17%)
5 2 2 1 1
5 (11%) 2 (4%) 1 (2%) 0 0
A previous
relationship
study
has
100mg
7 (17%) 7 (17%) 0 0 0
(13%) (5%) (5%) (3%) (3%)
shown
a dose-effect
postoperatively.1
In this study, I hour after drugs had displayed efficacy
their administration in relieving pain.
all Of the
two scales used to assess pain intensity, only the visual analogue scale revealed a significant difference between any treatments, and that was between the two ketorolac groups, in favor of 90 mg. Comparison of the assessment of pain intensity using the verbal rating scale showed that by 1 hour few patients
in
any
severe
pain.
The tance
time in the
group
were
still
suffering
moderate
or
to next analgesia is of practical emergency situation, as it has
imporimplicaFor 100 mg
tions concerning patient management. pethidine it was estimated that 25% of the patients required further analgesia within 5 hours of dosing. The time for 10 mg ketorolac was 6 hours, and for 90 mg ketorolac was 11 hours. This result combined with the overall assessment for 90 mg where the mean percentage of time that pain relief was good or complete was 82% indicates that 90 mg ketorolac was a better overall treatment than 100 mg pethidine, despite an initial lack of difference at 1 hour. A similar conclusion was reached in postoperative pain with morphine as a comparator.2 Statistical significance was seen in the difference between 90 mg ketorolac and 100 mg pethidine for both the overall pain relief assessment and the time to next analgesic. The differences between 10 mg and cally
90 mg of ketorolac significant and
ketorolac
were
similar
were pethidine
in this
large, 100
but mg
respect.
ANALGESIC/ANTI-INFLAMMATORY/IMMUNOSUPPRESSIVES
PETHIDINE
not statistiand 10 mg
frequent
with
of adverse events was low. were the most frequently overall and were noted for (especially vomiting), were
ketorolac.
These
references
to
somnolence were spontaneous reports. This feature was also particularly investigated with a sedation scale. At I hour after dosing there was no difference between the groups. At the 12-hour visit, sedation over the whole study period was assessed by the nursing staff. Among patients who had not received a rescue analgesia, 81% of the ketorolac 90 mg group showed no sedation compared to approximately 60% in both of the other two groups. CONCLUSIONS The
tionship.
AND
The overall incidence Somnolence and vomiting reported adverse events all groups. These effects
VI
Treatment
Number of patients Number (%) with Adverse Events Adverse Events Somnolence Vomiting Injection site pain Taste perversion Nausea
TROMETHAMINE
results
of
the
study
show
that
intramuscular
ketorolac is efficacious in the treatment of renal colic. A dose of 10 mg ketorolac is equivalent in efficacy to 100 mg pethidine, a standard treatment in this indication. Although not recommended for repeat dosing a supra-maximal single dose of 90 mg ketorolac showed better pain relief at one hour after dosing. Of greater clinical significance was the significantly longer period of pain relief for this dose. The overall incidence of adverse events was low with all drugs, notably so for the occurrence of vomiting after ketorolac. Acknowledgments are due to the following: Mr. C. McArdle (Consultant Surgeon, The Royal Infirmary, Glasgow); Mr. Scott (Consultant Urologist, Glasgow Royal Infirmary); Mr. P. Freeman (Accident and Emergency Consultant, New Cross Hospital, Wolverhampton); Dr. Moore (Accident and Emergency Consultant, University College Hospital, London); Mr. B. Birch (London Stone Clinic) and Mr. J. Parry (Whittington Hospital, London).
REFERENCES 1. O’Hara DA. Fragen RI, Kinzer M, Pemberton D: Ketorolac methamine as compared with morphine sulphate for treatment post-operative pain. Clin Pharmacol Ther 1987;41:556-561.
troof
2. Yee JP, Koshiver JE, AlIbon C, Brown CR: Comparison of intramuscular ketorolac tromethamine and morphine sulphate for analgesia of pain after major surgery. Pharmacotherapy 1986;6: 25 3-261. 3. Brandon-Bravo LJC, Mattie H, Spierdijk J, Bovill JG, Burm AGL: The effects on ventilation of ketorolac in comparison with morphine. Eur J Gun Pharmacol 1988;35:491-494. 4. Agresti A: Analysis Wiley, 1984.
of Ordinal
5. Cox DR, Oakes D: Analysis and Hall, 1984. 6. Cox DR: Analysis of Binary
Categorical
of Survival Data.
Data.
London,
Data. London, Chapman
New
York.
Chapman and
Hall.
1974.
341
MM U NOSU PPRESSIVES
A Double-Blind Single Dose Comparison Intramuscular Ketorolac Tromethamine and Pethidine in the Treatment of Renal Colic W. G.
Gillies,
OosterlinCk, MD,
ChB,
MD, FFA,
N. H. Philp, MB, ChB, RCS, J. W. Hetherington,
FRCS, MB,
C.
ChB,
Charig,
FRCS,
MB,
and
BS,
of
FRCS,
J. Lloyd,
BSc,
MSc
dose of intramuscular ketorolac 10 mg or 90 mg was compared in a randomized double-blind study in 121 patients reporting at moderate pain due to renal colic. Pain was assessed before drug administration, and then at 1 hour and 12 hours after the dose. Sedation was also assessed at these times, and additionally at the 12 hour assessment the time of the next analgesic dose was recorded. At 1 hour after dosing, pain scores had decreased in all groups; the largest decrease was seen in the ketorolac 90 mg group. The difference in the decrease was significant between the two ketorolac groups, but the differences between ketorolac and pethidine were not significant. Fewer patients in the ketorolac 90 mg group (17%) required a further dose of analgesic within 10 hours than in either the ketorolac 10mg group (39%) or the pethidine 100 mg group (47%). The difference between ketorolac 90 mg and pethidine 100 mg was statistically significant. At both assessment times the proportion of patients with no sedation was higher in the two ketorolac groups than in the pet hidine group. The overall incidence of adverse events was low with all drugs, notably so for the occurrence of vomiting after ketorolac. The results of the study show that intramuscular ketorolac is The with least
efficacy pethidine
efficacious
of a single 100 mg
in
the treatment
of renal
colic.
K etorolac
tromethamine (ketorolac) is a new nonnarcotic analgesic whose major mode of action is via the inhibition of prostaglandin synthesis. Ketorolac has been shown to be effective in relieving postoperative pain when administered as single doses of 10 mg and 30 mg.1’2 This high potency means that ketorolac may be formulated into an acceptable solution for injection. It was, therefore, proposed to investigate the efficacy of ketorolac, when administered intramuscularly, in the treatment of the pain of renal colic.
From the Department of Urology, University Hospital, Ghent, Belgium (Dr. Oosterlinck), Department of Urology, New Cross Hospital, Wolverhampton, UK (N. H. Philp), Institute of Urology, London, UK (C. Charig), Royal VictoriaHospital, Glasgow, UK (G. Gillies), Senior Registrar St. Mary’s Hospital, London, UK (J. W. Hetherington) and Syntex Research, Thames House, Maidenhead, Berkshire, UK (J.Lloyd). Address for reprints: J. Lloyd, Syntex Research, Thames House, 1 Bell Street, Maidenhead, Berkshire, 5L6 1BU, United Kingdom.
336
5
J ClIn Pharmacol
1990;30:336.-341
In the doses with
study
reported
of ketorolac 10 mg 100 mg of pethidine.
here and
two
intramuscular
90 mg, were compared 100 mg of pethidine was
chosen as an accepted standard in the treatment of renal colic. A 10 mg dose of ketorolac was chosen as being comparably efficacious to 10 mg of morphine in postoperative pain of moderate to severe intensity.1’2 Single doses of 90 mg of ketorolac have also been used in both volunteers (3) and patients (2) and this dose was used to show the maximal potential of the drug. METHODS Study
Design
This was a single-dose parallel design. Patients
one of the three 90 mg ketorolac
treatment or 100
study, were
with a double-blind randomly assigned
groups, 10 mg ketorolac, mg pethidine, given intra-
to
INTRAMUSCULAR
muscularly. hours
after
Patient The
Patients
were
assessed
administration
of the
TROMETHAMINE
KETOROLAC
at 1 hour single
and
study
Patients
was
set
and
up
as
dose.
a multicenter
a target
who
were
study
of a minimum
eligible
for
with
of 100
entry
were
pa-
those
who were suffering pain due to renal colic, and who described that pain as at least moderate according to a 4-point verbal rating scale. The diagnosis of renal colic required radiological evidence of a renal stone or acute renal obstruction. Patients were to be aged between 18 and 75 years and have a weight between 45 kg and 100 kg. The study protocol allowed entry of fit, healthy patients, including women with adequate contraceptive protection and excluding patients with a known history of allergy or previous adverse reaction to salicylates or nonsteroidal antiinflammatory drugs; patients known to abuse alcohol, narcotics or other drugs; and patients with a temperature above 37.5#{176}C. Study
Medications
The doses administered in the study were single intramuscular doses of 10 mg (1 ml of 1% solution) or 90 mg (3 ml of 3% solution) of ketorolac, or 100 mg (2 ml of 5% solution) of pethidine. To maintain the double-blind
technique
nature
was
of the
used;
the
study,
test
a double
dose
was
observer
administered
by a person who was not involved in the assessment of the patient, and the nature of the given medication was not disclosed to the observer. If insufficient analgesia was reported following the test medication, the clinician was allowed to prescribe his usual standard analgesic, and the time of administration was recorded.
Schedule
of Assessments
When a patient presented with pain typical of renal colic, he/she was asked to assess the severity of the pain according to a 4-point verbal rating scale (none, mild, (VAS).
moderate, The VAS
severe), was 100
and
a visual
analogue
scale
vertical line marked at the bottom with ‘no pain’ and at the top with ‘the worst pain imaginable.’ Patients who assessed their pain as moderate or severe on the verbal rating scale (VRS),
were
entered
into
test medication as an the gluteus maximus.
ANALGESIC/ANTI-IN
PETHIDINE
12
Population
five centers tients.
AND
One hour after administration of the test medication, the severity of pain was assessed by the investigator. Pain severity was assessed using the VRS and VAS as before. The patient was next assessed by the investigator approximately twelve hours after administration of the test medication, when time to next analgesia was recorded. Volunteered adverse events were recorded at each assessment. Sedation was separately assessed using a 3-point scale (no sedation, mild sedation/ drowsiness, asleep), at 1 hour and 12 hours after the
test dose. At 12 hours the nursing staff were asked to assess the overall degree of sedation over the study period, using the same assessment scale. Vital signs were measured and recorded at baseline and at the 1 hour assessment.
Statistical
Analysis
The primary efficacy variables were the pain intensity difference from the VAS, and the pain severity (VRS). The time between the test drug and the next analgesic dose was also analyzed. For each of these variables, a linear additive model, including treatment center and their interaction, was fitted in order to test the difference between treatments and the consistency of this difference across centers. Pain intensity differences derived from the VAS scores were analyzed using a 2-way analysis of variance. The 95% confidence intervals for the differences between each pair of treatments are quoted. Pain severity (VRS) was analyzed by fitting a proportional odds model,4 each pair of treatments being analyzed separately. For time from test dose to the next analgesic, results for each treatment group were summarised using the Kaplan-Meier estimator.5 Analysis was carried out using the Cox proportional hazards model.5 For sedation scores at 1 hour, two of the three categories (mild sedation/drowsiness and asleep), were combined because of the low frequencies in the asleep category and analysis was carried out using All
logistic statistical
regression.5 tests were
two
tailed
with
a 5%
level
of significance. RESULTS
mm
the
study
intramuscular
FLAMMATORY/IMMU
and
received
injection
the
into
NOSUPPRESSIVES
Patient
Population
125 patients included in
were the
entered safety
into analysis
were excluded from all the ses. One patient’s pretrial
the but
study. four
All were patients
primary efficacy analypain was described as
337
OOSTERLINCK
ET AL
any TABLE Summary
I
of Patients
Female
of Demography
Pain
Ketorolac 10mg
Ketorolac
Pethldine
90mg
100mg
45
37
32 (7 1%)
29 (78%)
39 29 (74%)
13 (29%)
8 (22%)
10 (26%)
40 21-71
41 21-69
39 18-70
70 45.5-90 1
Height (cm) Median
172.5
Range Missing
152-187 1
between
Intensity
73.2 47.7-100 0 172
155-196 0
73 54-95.5 0
The mean baseline pain scores from the VAS were high for all groups being 80 mm, 82 mm and 80 mm for ketorolac 10 mg, ketorolac 90 mg and pethidine 100 mg respectively. A marked decrease in VAS pain scores was seen in all three groups, and the mean VAS pain intensity differences at 1 hour after dosing were 54 mm, 65 mm and 57 mm for ketorolac 10 mg, ketorolac 90 mg and pethidine 100 mg respectively. Paired comparisons showed no difference between ketorolac 10 mg and pethidine 100 mg (P = .4), for which the estimated difference between treatments was 5 mm in favor of pethidine with a 95% confidence interval of -7 mm to 17 mm. However, there was evidence of a difference between ketorolac 90
175
152-190 0
Assessment mild, thereby making him ineligible. One patient was found not to have renal colic, and for two patients, pain assessments were not completed. Thus 121 patients were included in the efficacy analysis; 45 in the ketorolac 10 mg group, 37 in the ketorolac 90 mg group and 39 in the pethidine 100 mg group. All 121 patients were included in the analysis of the time to the next analgesic. Several were excluded from the analyses at either I or 12 hours. At 1 hour, nine patients were excluded (6 from ketorolac 10 mg, one from ketorolac 90 mg and 2 from pethidine 100 mg). In five cases this was because the assessment time was different from the scheduled 1 hour (a time of 45 minutes to 90 minutes postdosing was permitted), in two cases because the assessment time was not given, and in two cases because rescue analgesia had been given after only 30 minutes. At 12 hours, patients were included in the analysis whether or not rescue analgesia had already been given. However, of the total 121 patients 18 patients (7 ketorolac 10 mg, 6 ketorolac 90 mg, 5 pethidine 100 mg), were excluded. In one case this was because the patient discharged himself before the assessment time, for one the assessment time was unknown and for the other 16 the assessment was carried out outside 10-14 hours. Details of the patient population are summarized in Table I for all patients. Ninety (74%) were men with ages ranging from 18 to 71 years. Weights ranged from 45.5 to 100 kg. There was no evidence of
5
J Clin Pharmacol
1990;30:336-341
groups
centers.
TABLE
338
treatment
Group
Age
Median Range Weight (kg) Median Range Missing
differences
or between
Treatment
Number Sex Male
marked
II
of Pain IntensIty
Visual Analogue
Scale
BaselIne Scores: Treatment Ketorolac 10mg
Ketorolac
Pethldine
90mg
100mg
80
82
80
Mean
SD Range N
20 11-100 39
VAS Pain intensity
Group
Differences
11 57-100 35 from BaselIne Treatment
Ketorolac 10mg
Mean SD N Not recorded Comparison
54 26 39 0
13 52-100 37 at 1 hour Group
Ketorolac
Pethldine
90mg
100mg
65 18 35 1
57 26 37 0
of Treatments:
95% Estimated
SIgnificance K90-K10 P100-Kb K90-P100
P= P= P=
Dlfference*
Confidence
Interval
.02
14
2,26
.4 .12
5 10
-7, 17 -2,22
SD Standard deviation; K10 ketorolac 10 mg; K90 = ketorolac 90mg: P100 = pethidine 100 mg; * A positive value indicates a greater decrease in pain for the first treatment mentioned.
INTRAMUSCULAR
KETOROLAC
mg and each of the other two treatments, in both cases favouring ketorolac 90 mg. The difference from ketorolac 10 mg was statistically significant (P = .02), the estimated difference being 14 mm in favor of ketorolac 90 mg with a 95% confidence interval of 2 mm to 26 mm. The difference from pethidine 100 mg was less marked and was not statistically significant (P = .12). The estimated difference was 10 mm in favor of ketorolac with a 95% confidence interval of -2 mm to 22 mm. Table II summarizes the results of the VAS assessment of pain intensity. Table III summarizes the results of the assessment of pain intensity using the verbal rating scale. On entry the proportion of patients with severe pain was highest in the ketorolac 90 mg group (72%) and lowest in the ketorolac 10 mg group (59%). At 1 hour after dosing about one third of the patients had no pain (41%, 33% and 30% in the ketorolac 10 mg, ketorolac 90 mg and pethidine 100 mg groups respectively), and few still had moderate or severe pain. The comparison of each pair of treatments showed no differences between them (P> .4). Comparison of the assessment of pain relief at one hour
TROMETHAMINE
Assessment Baseline
of Pain
III
Intens ity Verbal
Analysis
Pethidine
90mg
100mg
16 (41%) 23 (59%)
10 (28%) 26 (72%)
13 (35%) 24 (65%)
Pain SeverIty Treatment Ketorolac 10mg
None Mild Moderate/Severe
16 (41%) 16 (41%) 6/1 (18%)
Group
Ketorolac
Pethidine
90mg
100mg
12 (33%) 19 (53%) 4/1 (14%)
11(30%) 20 (54%) 3/3 (16%)
Comparison of Treatments: Significance
K90-K10 P100-Kb K90-P100 =
from Study Drug Admin istration to Next Analgesic Treatment
Time to Next Analgesic 10 hours Unknown Estimated
27 1*
Group
Ketorolac 90 mg 6 (17%)
30 it
Pethidine 100 mg 18 (47%)
20 b
time
(mins) by which 25% had received rescue anaIgesic Comparison
355
670
300
of Treatments”: Significance
K90-K10 P100-Kb
P=0.08 P> 0.5
K90-P100
P=0.015
Study
completed
at 9 hours
50 minutes.
t Study completed at 9 hours 40 minutes. No times given; excluded from the analysis. § Kap!an-Meier estimate without adjustment for differences between I By Cox regression adjusting for differences between centers. K10 = Ketorolac 10mg; K90 = Ketorolac 90mg; P100 Pethidine
also
Ketorolac
Severe
at One Hour:
Group
Ketorolac 10mg
Moderate
KI 0
of Time
IV
centers. 100mg.
Assessment:
Treatment
Scores
Rati ng Scale
PETHIDINE
TABLE
*
TABLE
AND
P>.5 P= .4 P>.5 ketorolac
10 mg; K90
=
ketorolac 90 mg; P100
ANALGESIC/ANTI-INFLAMMATORY/IMMUNOSU
=
pethidine
100 mg.
PPRESSIVES
revealed
no
significant
differences
between
treatments In order ministration tients who the study summary requiring edly lower either the idine 100
to compare the time from study drug adto next analgesic, the number of parequired an analgesic within 10 hours of drug administration has been used as a measurement (Table IV). The percentage an analgesic within this time was markin the ketorolac 90 mg group (17%), than ketorolac 10 mg group (39%), or the pethmg group (47%). The figure shows graphi-
cally
estimated
the
(P>
.2).
proportion
of patients
who
had
not the
yet received rescue analgesia against time from administration of the study drug. Each pair of treatments was compared and there was no evidence of any difference between ketorolac 10 mg and pethidine 100 mg (P .5), but there was a statistically significant difference between ketorolac 90 mg and pethidine 100 mg (P = .015), and a difference approaching statistical significance between the two doses of ketorolac (P = .08). In each case, the difference favored ketorolac 90 mg. The proportion of patients with no sedation at 1 hour was higher in the two ketorolac groups (54%,
339
OOSTERLINCK
ET
AL
100
90
-
L#{149}:
80
70
60
%
50
KETOROLAC
90mg
40 30 20
PETHIDINE
10
100mg
KETOROLAC
0.
10mg
I 0
5
10
15
20
25
TIME SINCE STUDY DRUG (hours) Figure.
Estimated
percentage
of patients
who
have
not yet received
for 10 mg and 90 mg respectively), than the pethidine 100 mg group (35%). None of the comparisons of the treatment groups were statistically significant (P> .1). Sedation during the study period was recorded at 12 hours. Results are summarized in Table V for patients who had not yet received rescue analgesia. For ketorolac 90 mg, the proportion with no sedation was higher (81%) than either of the other two groups, which were similar to each other (61% for 10 mg ketorolac and 59% for 100 mg pethidine). No clinically important changes occurred in the vital signs. Adverse effects were recorded in 32 of the patients, eight in the ketorolac 10 mg group, 10 in the ketorolac 90 mg group and 14 in the pethidine group. 47%
These
are
summarized
in Table
The standard treatment for renal colic is usually parenteral administration of a narcotic. This has inherent problems due to the adverse event profile; nausea and vomiting are particular problems in patients who are likely to be predisposed to these symptoms. The use of a narcotic in this emergency situation
#{149} .1 CiIn Pharmacol
1990;30:336-341
analgesia.
may
also
be
open
to abuse,
both
by
the
attendants
and malingering patients. The active control group chosen in this study was 100 mg pethidine, an accepted standard in the treatment of renal colic. Two doses of ketorolac, 10 mg and 90 mg were studied in order to identify firstly whether ketorolac shows efficacy in this indication and secondly whether there is any dose-effect rela-
TABLE Summary
of Degree
V
of Sedation
During
Assessed by the Nursing Staff (Recorded Treatment
VI.
DISCUSSION
340
rescue
Not yet received analgesia No sedation Mild sedation/ drowsiness Asleep
Group
Ketorolac 10mg
Ketorolac
Pethidine
90mg
100mg
14 (61%)
17 (81%)
10 (59%)
8 (35%) 1(4%)
3 (14%) 1(5%)
5 (29%) 2 (12%)
0
2
1
Missing Patients
the Study as at 12 Hours)
whose assess ments
were outsi de 10-14
hours
were excluded.
KETOROLAC
INTRAMUSCULAR
TABLE Summary
of Adverse
Events Group
less
Ketorolac 10mg
Ketorolac 90mg
Pethidine
46
38
41
10 (26%)
14 (34%)
8 (17%)
5 2 2 1 1
5 (11%) 2 (4%) 1 (2%) 0 0
A previous
relationship
study
has
100mg
7 (17%) 7 (17%) 0 0 0
(13%) (5%) (5%) (3%) (3%)
shown
a dose-effect
postoperatively.1
In this study, I hour after drugs had displayed efficacy
their administration in relieving pain.
all Of the
two scales used to assess pain intensity, only the visual analogue scale revealed a significant difference between any treatments, and that was between the two ketorolac groups, in favor of 90 mg. Comparison of the assessment of pain intensity using the verbal rating scale showed that by 1 hour few patients
in
any
severe
pain.
The tance
time in the
group
were
still
suffering
moderate
or
to next analgesia is of practical emergency situation, as it has
imporimplicaFor 100 mg
tions concerning patient management. pethidine it was estimated that 25% of the patients required further analgesia within 5 hours of dosing. The time for 10 mg ketorolac was 6 hours, and for 90 mg ketorolac was 11 hours. This result combined with the overall assessment for 90 mg where the mean percentage of time that pain relief was good or complete was 82% indicates that 90 mg ketorolac was a better overall treatment than 100 mg pethidine, despite an initial lack of difference at 1 hour. A similar conclusion was reached in postoperative pain with morphine as a comparator.2 Statistical significance was seen in the difference between 90 mg ketorolac and 100 mg pethidine for both the overall pain relief assessment and the time to next analgesic. The differences between 10 mg and cally
90 mg of ketorolac significant and
ketorolac
were
similar
were pethidine
in this
large, 100
but mg
respect.
ANALGESIC/ANTI-INFLAMMATORY/IMMUNOSUPPRESSIVES
PETHIDINE
not statistiand 10 mg
frequent
with
of adverse events was low. were the most frequently overall and were noted for (especially vomiting), were
ketorolac.
These
references
to
somnolence were spontaneous reports. This feature was also particularly investigated with a sedation scale. At I hour after dosing there was no difference between the groups. At the 12-hour visit, sedation over the whole study period was assessed by the nursing staff. Among patients who had not received a rescue analgesia, 81% of the ketorolac 90 mg group showed no sedation compared to approximately 60% in both of the other two groups. CONCLUSIONS The
tionship.
AND
The overall incidence Somnolence and vomiting reported adverse events all groups. These effects
VI
Treatment
Number of patients Number (%) with Adverse Events Adverse Events Somnolence Vomiting Injection site pain Taste perversion Nausea
TROMETHAMINE
results
of
the
study
show
that
intramuscular
ketorolac is efficacious in the treatment of renal colic. A dose of 10 mg ketorolac is equivalent in efficacy to 100 mg pethidine, a standard treatment in this indication. Although not recommended for repeat dosing a supra-maximal single dose of 90 mg ketorolac showed better pain relief at one hour after dosing. Of greater clinical significance was the significantly longer period of pain relief for this dose. The overall incidence of adverse events was low with all drugs, notably so for the occurrence of vomiting after ketorolac. Acknowledgments are due to the following: Mr. C. McArdle (Consultant Surgeon, The Royal Infirmary, Glasgow); Mr. Scott (Consultant Urologist, Glasgow Royal Infirmary); Mr. P. Freeman (Accident and Emergency Consultant, New Cross Hospital, Wolverhampton); Dr. Moore (Accident and Emergency Consultant, University College Hospital, London); Mr. B. Birch (London Stone Clinic) and Mr. J. Parry (Whittington Hospital, London).
REFERENCES 1. O’Hara DA. Fragen RI, Kinzer M, Pemberton D: Ketorolac methamine as compared with morphine sulphate for treatment post-operative pain. Clin Pharmacol Ther 1987;41:556-561.
troof
2. Yee JP, Koshiver JE, AlIbon C, Brown CR: Comparison of intramuscular ketorolac tromethamine and morphine sulphate for analgesia of pain after major surgery. Pharmacotherapy 1986;6: 25 3-261. 3. Brandon-Bravo LJC, Mattie H, Spierdijk J, Bovill JG, Burm AGL: The effects on ventilation of ketorolac in comparison with morphine. Eur J Gun Pharmacol 1988;35:491-494. 4. Agresti A: Analysis Wiley, 1984.
of Ordinal
5. Cox DR, Oakes D: Analysis and Hall, 1984. 6. Cox DR: Analysis of Binary
Categorical
of Survival Data.
Data.
London,
Data. London, Chapman
New
York.
Chapman and
Hall.
1974.
341
