Download Table 2. Pain Relief

COMPARISON OF ANALGESIC EFFECT BETWEEN
DICLOFENAC SODIUM, KETOPROFEN, SPASMAVERINE AND
HYOSCINE N-BUTYL BROMIDE IN RENAL AND
URETERAL COLIC: A PROSPECTIVE DOUBLE-BLIND STUDY.
Hisham S. Abou-Auda*1, Sabah M. Al-Rayes2,
Adel M. Yousef3, Rafiq R. Abou-Shaaban4,
Abdelmoniem Koko3 and Tawfeeg A. Najjar1
1. Department of Clinical Pharmacy,
College of Pharmacy, King Saud University,
P.O.Box 2457, Riyadh-11451, Saudi Arabia.
Tel. 467-7470
Fax 467-6229
E-mail: [email protected]
2.
Ministry of Health, Riyadh, Saudi Arabia.
3.
Department of Urology, Riyadh Central Hospital,
P.O.Box 2897, Riyadh-11196, Saudi Arabia.
4. College of Pharmacy, Ajman University for Science
and Technology, Ajman, UAE
*
To whom correspondence should be addressed
Key Words: Renal colic, Ureteral colic, Diclofenac sodium, Ketoprofen, Spasmaverine,
Hyoscine N-butyl bromide, Saudi Arabia.
Abstract
Objective: To compare the analgesic effects of diclofenac sodium 75 mg IM, ketoprofen
100 mg IM, spasmaverine 40 mg IM or IV and hyoscine N-butyl bromide 20 or 40 mg
IM or IV.
Design: randomized, double-blind, prospective study.
Setting: the emergency department in Riyadh Central Hospital, Saudi Arabia.
Patients: 444 patients, 12-70 years of age, with moderate to severe pain due to renal or
ureteral colic.
Interventions: Subjects received a single dose of one of the test medications and patients
valuated their pain intensity and pain relief at 0 (baseline), 15, 30, 45 minutes and hourly
for 3 hours. If no improvement after 15 min, a second dose of the same medication is
administered.
Results: Significant differences (p<0.05) were found between the four groups with
respect to pain intensity difference (PID), mean pain relief and onset time of analgesia.
Diclofenac sodium and ketoprofen were equally effective, and both were significantly
(p<0.05) superior to spasmaverine and hyoscine N-butyl bromide in pain relief.
Significantly (p<0.5) fewer patients required a second dose in either diclofenac sodium
or ketoprofen-treated groups compared to the other two spasmolytic groups. The dose
and the route of administration of hyoscine N-butyl bromide and the route of
administration of spasmaverine had no significant (p>0.05) effect on the proportion of
patients with complete relief.
2
Conclusions: diclofenac sodium and ketoprofen can be safely used in the management
of acute renal and ureteral colic as an alternative to spasmolytic agents.
Introduction
The pain of ureteral and renal colic is a result of an acute upper urinary tract
obstruction leading to distention and an increase in tension within the walls of the ureter
and renal pelvis (1-2). It is suggested that prostaglandins play an important role in the
pathogenesis of ureteral and renal colic by stimulating secretion in the kidney, thus
raising the pressure in the renal tract above the ureteric obstruction (3-4). Inflammatory
edema is further increased by prostaglandins, namely PGE2, around the stone which
again increase the tension on the renal pelvic wall.
Analgesics are commonly employed in combination with spasmolytic drugs for
the treatment of renal and ureteral colic. The involvement of prostaglandins promoted
clinical experimentation to investigate the effectiveness of non-steroidal antiinflammatory drugs (NSAID) in alleviating the pain of renal and ureteral colic. These
drugs block the enzyme cyclo-oxygenase and hence, inhibit prostaglandins formation.
Several studies demonstrated that NSAID's such as diclofenac sodium (75 mg
intramuscularly) is more effective than pethidine (100 mg intramuscularly) (5-6), other
narcotic analgesics (7), spasmolytic agents (fenpipramide methbromide and pitofenone
hydrochloride) (8), pyrazolone-derived analgesics (e.g., dipyrone)(8-9), or placebo (1012) in the treatment of renal or ureteral colic. Ketoprofen, a phenylpropionic acid
derivative similar to ibuprofen, has never been compared with diclofenac sodium or
spasmolytics in this respect. Recently, the mode of action of ketoprofen, as with other
NSAID's, was shown to be the inhibition of prostaglandin synthesis, which is also
considered to be responsible for pain in renal colic (13). Intravenous administration of
ketoprofen (200 mg) has been reported to be effective in the treatment of pain due to
3
renal colic compared with lysine acetylsalicylates (1 g IV) (14). Although the efficacy of
spasmolytic agents in renal and ureteral colic has been debated, they are widely used
alone or in combination with narcotic analgesics in many countries including Saudi
Arabia. In a renal colic study, a single 20-mg intravenous dose of hyoscine Nbutylbromide demonstrated that this spasmolytic agent has a low analgesic effect when it
is used as single therapy or with a 2.5-gm dose of dipyrone (15). Spasmaverine
(alverine), a musculotropic antispasmodic similar to papaverine, has a direct action
unrelated to muscle innervation. It is one of the most widely used drugs for renal and
ureteral colic in Saudi Arabia and some European countries.
The aim of our study was to compare the therapeutic efficacy, safety and
tolerability of two NSAID's, namely, diclofenac sodium and ketoprofen, and two
spasmolytic drugs, namely, spasmaverine and hyoscine N-butylbromide in the treatment
of renal and ureteral colic. Due to intense pain involved with renal colic, the use of a
control group (placebo) was disregarded. Most of the reported studies were conducted
with a small sample size. This study emphasizes the use of a large patient population of
both sexes to ensure statistical reproducibility allowing to draw meaningful conclusions.
Materials and Methods
Patients:
A randomized and prospective double-blind design was used. Patients with moderate to
severe renal or ureteral colic admitted to emergency room (ER) at Riyadh Central
Hospital were recruited to the study. Patients with documented evidence of previous
episodes owing to calculi or execretory urographic results substantiating this diagnosis
were also included in the study.
4
Patients with another severe concomitant disorders, or with a history of renal
malfunction, cardiac failure, asthma, dyspepsia, peptic ulceration or hepatic disorder, or
those with documented allergy to any of the study medications, or those who received
any analgesic within 6 hours before the study were excluded. Pregnant or breast-feeding
women and those who were younger than 12 or older than 70 years were also excluded
from the study.
Six hundred and sixty patients were included. Each patient underwent a
comprehensive examination including a complete medical history, urinalysis (RBC,
crystals and pus), and X-ray. The nature of the study was explained fully to each
participant and informed consent was obtained. A permission to conduct the study was
obtained from the research committee at Riyadh Central Hospital.
Patients were randomly assigned to one of 4 treatment groups: (1) Diclofenac
sodium (75 mg intramuscularly), (2) ketoprofen (100 mg intramuscularly), (3)
spasmaverine
(40 mg intramuscularly or intravenously) and (4) Hyoscine N-
butylbromide (20 or 40 mg intramuscularly or intravenously). Spasmaverine was given
by slow intravenous push in 30 patients and intramuscularly in 58 patients. On the other
hand, hyoscine N-butyl bromide was given intravenously in 62 patients and
intramuscularly in 47 patients. The route of administration for both drugs as well as the
dose of hyoscine N-butyl bromide were determined randomly by the investigator.
Type of pain was also evaluated by the investigator as: acute (1), subacute (2) or
chronic (3). Pain intensity was evaluated verbally by each patient just before receiving
medication (baseline control) and at 15, 30 and 45 minutes. Patients were asked to
evaluate pain intensity as: no pain (0), mild (1), moderate (2) or severe pain(3).
Furthermore, patients were also asked to evaluate pain intensity at the designated
intervals using an analog pain intensity scale consisting of a 100-mm line whose ends
5
represented no pain (0 mm, pale pink) and very severe pain (100 mm, red). Pain relief
was also evaluated by patients as: no relief (0), mild relief (1), moderate relief (2) or
complete relief (3). A second dose of the same test medication was usually given if the
pain intensity was not improved after 15 minutes or if pain had returned. If pain
persisted for another 15 minutes, a dose of the other test drugs (from different group)
was considered, i.e.; if the first drug was a NSAID, the replacement drug should be a
spasmolytic. Whenever significant pain relief was not observed within 45 minutes, a
standard analgesic, pentazocine, was given. Those patients with moderate or complete
pain relief after the first or second dose were continued to be monitored at 15, 30, and 45
minutes and hourly for 3 hours. Figure 1 shows the study protocol. Throughout the
period of the study, efforts were made to maintain double-blind conditions and random
selection of replacement drug(s). The onset of action (the time required to reduce pain
intensity score to "mild") for each dose of the test medication was reported in minutes.
Pain relief (%) (Analgesic Efficacy) for each patient was calculated using the
following formula:
%R 
100 ( I o  I t )
Io
eqn. 1
where, I o is the baseline pain intensity score before administering the test medication,
and It is the pain intensity score after 15 minutes from drug administration. Pain
intensity difference (PID) was defined as the baseline pain intensity minus the observed
pain intensity. Furthermore, patients were asked at each assessment interval to describe
any side effect. Patients were also asked to give an estimate of the onset of complete
analgesia in minutes. For patients who had no pain relief for more than 3 hours, a score
of 240 minutes (4 hours) was assigned.
Statistical Analyses:
6
Statistical analysis of data was performed using SPSS-PC+ (Statistical Package
for Social Sciences) program on an IBM PC/AT computer equipped with 80386
microprocessor. Homogeneity of test groups was determined using one way analysis of
variance for continuous data, and chi-square with and/or without Yates' correction for
continuity, Kruskal-Wallis, and Scheff‚ tests for discrete data.
To avoid interobserver variability, only two physicians participated in
determining pain intensity and type of pain. Therapeutic efficacy was assessed by
analyzing the onset of analgesia by the analysis of variance with a factorial design. Pain
relief was compared for the four test groups using Kruskal-Wallis analysis of variance.
Chi-square test was also performed to test the effect of sex, concomitant disease, initial
pain intensity, type of pain, stone availability and history of pain on the observed results.
In few cases, Mann-Whitney “U” test was used to compare each pair of test medications
with respect to pain intensity difference (PID), while the Kruskal-Wallis test was
performed to confirm the results of PID for the four treatment groups.
Results
Six hundred sixty patients, 559 males and 101 females, ranging in age from 12 to
70 years (mean þ SD; 34.18  9.72 years) and in weight from 34 to 172 kg (mean  SD;
69.12  15.4 kg) were included in the study. Of those patients, 312 received diclofenac
sodium, 149 received ketoprofen, 89 received spasmaverine and 110 were given
hyoscine N-butyl bromide. Baseline pain intensity scores were either 2 (moderate) or 3
(severe) for all patients and were comparable among the four treatment groups, with
mean value of 2.58, 2.52, 2.57 or 2.38, respectively. There were no statistically
significant differences (p>0.05) in the demographic characteristics of baseline pain
assessment of patients in the four treatment groups. Table 1 summarizes patients'
7
demographic data and the results of homogeneity of test groups. No significant
differences (p>0.05) were found to exist between the four treatment groups with respect
to age , sex, weight, type of pain, the presence of other diseases or associated signs and
symptoms, urinalysis, stone availability, pain evolution time before treatment (pain
intensity) or the site of pain. Complete pain relief was achieved in 267 of 312 patients
(85.6 %) who received diclofenac sodium, 125 of 149 patients (83.9 %) who received
ketoprofen, 44 of 89 patients (49.4 %) who received spasmaverine and 52 of 110
patients (47.3 %) who received hyoscine N-butyl bromide as the first injection. Worse
pain or no change in pain intensity was observed in 51.8 %, 48.3 %, 12.1 % and 9.3 % of
patients on hyoscine N-butyl bromide, spasmaverine, ketoprofen and diclofenac sodium,
respectively.
Mean pain relief scores derived from equation 1, for diclofenac sodium or
ketoprofen were significantly (p<0.05) higher than those observed for spasmaverine and
hyoscine N-butyl bromide. Figure 2 shows a plot of pain intensity difference (PID) for
each treatment group. The mean scores for diclofenac sodium and ketoprofen were
significantly (p<0.05) superior to those for spasmaverine or hyoscine N-butyl bromide at
10, 30, 45 minutes, 1 and 2 hours.
Patients who had worse pain, no change or moderate relief were given a second
dose of their assigned medication. Thus 75 patients required a second dose; 17 (5.45 %),
6 (4.03 %), 26 (29.2 %), and 26 (23.6 %) of those patients were on diclofenac sodium,
ketoprofen, spasmaverine and hyoscine N-butyl bromide respectively. None of the
patients who had a second dose of ketoprofen required an alternative drug from the other
group. One patient on diclofenac sodium took an alternative medication (hyoscine Nbutyl bromide). Four patients needed an alternative drug after receiving a second dose of
spasmaverine (2 ketoprofen and 2 diclofenac sodium), while 9 patients on hyoscine N-
8
butyl bromide received an alternative drug from the other group (7 diclofenac sodium
and 2 ketoprofen). Table 3 shows pain relief before and after the second dose. The mean
onset time of analgesia ranged from 39.8 min for diclofenac sodium, 40.04 min for
ketoprofen, 46.33 min for hyoscine N-butyl bromide, to 50.12 min for spasmaverine. A
statistically significant difference (p<0.025) was found to exist between the four
treatment groups with respect to the onset of analgesia after the administration of the
first dose. Insignificant pain relief or insufficient response to treatment was observed in
14 patients after 45 minutes; 4 in each of the NSAID-treated groups and 3 in each of the
spasmolytic-treated groups. Pentazocine, a standard analgesic with a known efficacy,
was given to those patients. Evaluation of pain intensity by patients using the visual
analog scale (VAS) linearly correlated (r=0.8832) with pain assessment by clinicians
using the discrete pain intensity scale.
The route of administration of spasmaverine and hyoscine N-butyl bromide had
no effect on the outcome of the treatment (p>0.05) as shown in table 4. Moreover, the
dose of hyoscine N-butyl bromide recommended by the manufacturer (20 mg IV) is said
to be inadequate. We found no statistically significant difference (p>0.05) between the
20-mg and 40-mg doses of hyoscine N-butyl bromide in terms of improvement of pain
intensity (Table 5). Pain at venipuncture site was observed to be statistically (p<0.05)
more frequent in the two spasmolytic groups compared with the NSAID groups. Type of
pain has no effect (p>0.05) on pain relief in the four treatment groups.
Tolerability of the drugs was demonstrated by the absence of relevant side
effects. One patient from each group experienced some kind of notable side effects.
Discussion
9
This study reveals that diclofenac sodium and ketoprofen can be used
successfully in the treatment of renal and ureteral colic. They are superior to the
spasmolytic agents used in this study. In most cases, a single dose of NSAID's produced
rapid and effective pain relief and was practically devoid of significant side effects.
Diclofenac sodium and ketoprofen are equally effective in terms of improvement
of pain intensity and the proportion of patients obtained complete relief of pain at 15
min. In addition to the anti-inflammatory and analgesic effects, like other NSAID's, a
central action has been considered for ketoprofen (16). Our results demonstrated that
NSAID's provide a faster and greater pain relief as indicated by the larger PID scores at
10, 30 and 45 minutes and by the smaller mean onset time for diclofenac sodium and
ketoprofen.
The results of spasmolytic treatment are usually inconsistent and transient and
require high doses which result in significant side effect (17-18). However, larger doses
of hyoscine N-butyl bromide did not achieve a statistically significant (p>0.05)
improvement in pain relief compared with the dose recommended by the manufacturer.
Moreover, significantly (p<0.05) fewer patients required a second dose in either the
diclofenac sodium or ketoprofen-treated groups than in the spasmaverine and hyoscine
N-butyl bromide-treated groups.
In conclusion, this study demonstrated that the administration of NSAID's,
especially diclofenac sodium and ketoprofen, could offer clinicians another option for
renal and ureteral colic pain management as an alternative to the relatively less effective
spasmolytic drugs.
10
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1957.
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placebo-controlled pilot study. Clin Ther 1984; 6:483-7.
11
15. Lloret J, Munoz J, Monmany J, Puig X, Bonastre M, Brau J, Sola J, Domingo P,
Jane F. Treatment of renal colic with dipyrone. Curr Ther Res 1987; 42:1119-26.
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infusion. Clin Pharmacokin 1987; 12:214-21.
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colic. Eur J Clin Pharmacol 1991; 40: 543-6.
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12
28. Maier R, Menasse R, Riesterer L, Pericin C, Ruegg M, Ziel R. The pharmacology of
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13
Table 1: Patients’ Characteristics
Drug
Diclofenac
M
n=89
F
n=22
Ketoprofen
M
n=100
n=13
Spasmaverine
F
M
n=95
n=15
F
Hyoscine NBB
M
n=87
p
F
n=22
Sig
Age (yr):
Mean :
SD :
34.7
8.8
28.3
9.0
35.8
9.7
25.9
7.7
34.9
8.8
25.5
8.1
35.1
9.1
31.7
11.0
0.72a
NS
Weight (kg):
Mean :
SD :
67.7
14.5
63.1
12.6
72.1
17.7
55.2
12.6
69.8
13.1
64.7
20.7
66.9
13.4
72.4
15.5
0.39a
NS
Type of Pain:
a)
Acute:
b)
Subacute:
c)
Chronic:
50
21
18
13
8
1
54
35
11
5
6
1
59
21
14
10
5
0
57
20
10
15
4
3
0.16b
NS
Other Diseases:
a)
Present:
b)
Absent:
3
86
0
22
1
99
0
13
1
93
0
15
0
88
0
22
0.281b
NS
Urinalysis:
A) RBC:

Positive :

Negative :
40
49
9
13
32
68
3
10
43
52
5
10
27
61
7
15
0.93b
NS
B) Pus:

Positive:

Negative :
43
46
11
11
15
85
2
11
23
72
4
11
14
74
3
19
0.097b
NS
C) Crystals:

Positive:

Negative :
4
85
0
22
7
93
2
11
2
93
0
15
7
81
1
21
0.119b
NS
X-Ray:
a) Stone:
b) No stone:
16
73
2
20
11
89
2
11
15
80
0
15
13
75
5
17
0.691b
NS
Pain History:
a) Never before:
b) One week:
c) 2-3 weeks:
d) >4 weeks:
72
6
2
9
20
0
0
2
90
1
2
7
12
1
0
0
81
2
6
5
15
0
0
0
76
2
2
8
19
0
1
2
0.307b
NS
NS= Statistically significant, M=Males, F=Females
a. One-way analysis of variance (males and females combined)
b. Chi-square test (males and females combined)
14
Table 2. Pain Relief
Pain relief
NSAID
SPASMOLYTICS
Worse Pain
DS
n (%)
1 (0.9)
KET
n (%)
1 (0.9)
SPV
n (%)
18 (16.4)
HBB
n (%)
19 (17.3)
No Change
3 (2.7)
12 (10.6)
31 (28.2)
38 (34.5)
Moderate Relief
7 (6.3)
5 (4.4)
2 (1.8)
1 (0.9)
Complete Relief
100 (90.1)
95 (84.1)
59 (53.6)
52 (47.3)
111
113
110
110
Total
p< 0.0001 (S)
15
Table 3.
Pain relief before (b) and after (a) the second dose for patients who required a
second dose of the drug.
Treatment outcome
(No. of Patients)
Worse Pain
No Change
Moderate Relief
Complete Relief
Total
DS
KET
SPV
HBB
b
a
b
a
b
a
b
a
n
1
0
0
0
11
1
13
3
%
100
0
0
0
39.3
3.6
50
11.5
n
0
0
4
0
15
5
13
13
%
0
0
80
0
53.6
17.9
50
50
n
0
0
1
0
1
0
0
1
%
0
0
20
0
3.6
0
0
3.8
n.
0
1*
0
5
1
22
0
9
%
0
100
0
100
3.6
78.6
0
34.6
n
1
1
5
5
28
28
26
26
%
100
100
100
100
100
100
100
100
* Pain recurred after the first pain relief assessment.
p (before)=0.1113 (NS)
p (after) =0.0042 (S)
16
Table 4. Pain Intensity Difference (PID) (mean ± SEM)
Drug
Time
5 min
10 min
30 min
45 min
1 hr
2 hr
3 hr
DS
1.00 ± 0.18
1.63 ± 0.18
1.50 ± 0.40
1.53 ± 0.11
1.43 ± 0.11
1.31 ± 0.10
1.60 ± 0.05
KET
1.00 ± 1.00
0.83 ± 0.58
1.46 ± 0.18
1.36 ± 0.12
1.52 ± 0.17
1.25 ± 0.08
1.00 ± 0.18
SPV
-
1.00 ± 1.00
1.26 ± 0.67
0.73 ± 0.63
1.29 ± 0.22
1.00 ± 0.30
1.33 ± 0.19
HBB
-
0.77 ± 0.90
1.10 ± 0.35
1.33 ± 0.33
1.11 ± 0.16
1.00 ± 0.19
-
Table 4. Effect of route of administration of spasmaverine and hyoscine N-butyl
bromide on pain relief.
Treatment
Outcome
SPV
HBB
IV
IM
IV
IM
n (%)
n (%)
n (%)
n (%)
Worse Pain
6 (16.7)
12 (16.2)
8 (12.9)
11 (22.9)
No Change
11 (30.6)
20 (27)
22 (35.5)
16 (33.3)
Moderate Relief
1 (2.8)
1 (1.4)
0 (0)
1 (2.1)
Complete Relief
18 (50)
41 (55.4)
32 (51.6)
20 (41.7)
p (Sig)
Total
NS = Not Significant
0.9160 (NS)
36 (100)
74 (100)
0.3254 (NS)
62 (100)
48 (100)
Table 5. Effect of hyoscine N-butyl bromide dose on pain relief.
Treatment Outcome
Dose
20 mg
40 mg
n (%)
n (%)
Worse Pain
7 (17.1)
12 (17.4)
No Change
12 (29.3)
26 (37.7)
Moderate Relief
0 (0)
1 (1.4)
Complete Relief
22 (53.7)
30 (43.5)
p = 0.6399 (NS)
19
Table 6. Blood pressure and Heart rate results.
Drug
Blood Pressure (mm Hg)
Heart Rate
Systolic
Diastolic
(Beat/min)
Diclofenac sodium
123.4 ± 16.4
79.3 ± 9.8
82.0 ± 10.5
Ketoprofen
132.0 ± 18.5
85.0 ± 10.4
80.2 ± 11.1
Spasmaverine
128.5 ± 18.5
84.4 ± 10.7
84.7 ± 10.1
Hyoscine N-Butyl Br
129.4 ± 16.1
84.0 ± 9.6
83.7 ± 11.7
p (sig)
<0.001 (S)
0.0027 (S)
0.013 (S)
Total
128.4 ± 17.6
83.2 ± 10.4
82.6 ± 11.0
S=Statistically Significant.
20
Figure 1. Study Protocol
Patient with suspected RENAL or
URETERAL COLIC in ER
Diagnosis
Exclude
NO
Renal or
Ureteral Colic
confirmed?
YES
Lab Tests
& X-ray
Assign Medication
Randomly
Give First Dose
DISCHARGE
Pain after
15 min?
YES
Give Second Dose
NO
Monitor
Patient
Assess
Medication
NO
Pain after
15 min?
NO
YES
Pain after
15 min?
YES
Give Pentazocine
21
Give a Drug from
SECOND GROUP