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Phlebology Suppl.

I (1994) 4D-43
1994 The Venous Forum of the Royal Society
of Medicine and Societas Phlebologica Scandinavica

Double Blind Placebo Controlled Evaluation of Clinical Activity and


Safety of Dation 500 mg in the Treatment of Acute Haemorrhoids
M. Cospite
Division of Angiology, Department of Surgical and Anatomical Sciences, Palermo University, Italy

ABSTRACT

Objective: Efficacy of treatment of acute haemorrhoidal

crisis by Daflon 500 mg (0500) in comparison to a


placebo (PI).
Design: Prospective, double blind, placebo controlled
trial with randomization into two parallel groups.
Setting: In- and outpatients at a University Hospital.
Patients: One hundred patients with a history of haemorrhoidal disease, suffering from an acute haemorrhoidal attack.
Interventions: Administration of Daflon 500 mg or
placebo at a dose of three tablets b.i.d. for the first 4
days and two tablets b.i.d. for the following 3 days.
Mainoutcome measures: Improvement of symptoms and
signs measured by a score and patient acceptability.
Results: Overall improvements of symptoms was greater
in the 0500 group than in the PI group, from day 2 up to
day 7. The clinical severity of proctorrhagia, anal
discomfort, pain and anal discharge diminished in both
groups, but to a greater extent in the 0500 group
(p <0.001). Inflammation, congestion, oedema and
prolapse were more markedly improved in the 0500
group than in the PI group. Duration and severity of the
current haemorrhoidal episode, as assessed by patient
self-evaluation, were less important in the D500 group
compared with previous episodes. Use of analgesics
and topical medications diminished in both groups, with
a major reduction in the D500 group from day 4
(p <0.001). Acceptability was good in both groups: no
patient experienced major side-effects.
Conclusion: Treatment with D500 resulted in a quicker
and more pronounced relief of signs and symptoms of
acute haemorrhoids than with the placebo.
Keywords: Haemorrhoids; Haemorrhoidal disease;
Treatment

Also registered as Capiven, Detralex, Arvenum 500 mg.

Introduction
Haemorrhoidal disease is characterized by recurrent
acute congestive episodes of the anal region. The onset
of these episodes is often triggered by mechanical and
vascular factors: arteriovenous shunts may open up
suddenly under certain conditions, such as ingestion of
highly spiced food, alcohol and substances altering the
vasomotor function in the gut and pelvis [1,2].
In addition to hygiene and dietary recommendations,
pharmacological treatment is aimed at treating the
acute haemorrhoidal crisis and preventing relapse [3].
Bioflavonoids, including diosmin, show specific efficacy
in the treatment of haemorrhoidal disease because of
their phlebotonic, capillaroprotective activity and antagonism of the biochemical mediators of inflammation
[4,5].
The present study was carried out to evaluate the
therapeutic efficacy and acceptability of Daflon 500
mg", a purified and micronized flavonoid fraction consisting of diosmin (90%) and hesperidin (10%), in the
treatment of symptoms and signs of a haemorrhoidal
crisis [6].

Materials and Methods


This double-blind, placebo-controlled study included
100 patients suffering from a haemorrhoidal crisis. The
patients were randomly allocated to two parallel
groups, one treated with Daflon 500 mg (D500) and the
other with placebo (PI). The inclusion criteria were the
following: adult outpatients or inpatients of any sex and
age, with known haemorrhoidal disease, diagnosed by
proctoscopy, suffering from an uncomplicated acute
haemorrhoidal crisis without any previous treatment for
a maximum of 3 days. For inclusion in the study, the
patients had to suffer from symptoms such as bleeding,
anal discomfort, pain and pruritus, and objective
proctoscopic signs.
Patients requiring a surgical procedure, suffering
from an anal fistula or rectal prolapse, receiving phle-

41

Evaluation of Dation 500 mg in Treatment of Acute Haemorrhoids

botropic, anticoagulant, antiplatelet or anti-inflammatory drugs and patients receiving non-authorized


analgesic and/or topical medication were not included.
Additional treatments that were permitted were glafenine tablets 200 mg (maximum four tablets per day) and
lidocaine 5% ointment.
The duration of the study was 7 days and the dosage
was six tablets a day (three b.i.d.) for the first 4 days and
fo.u~ tablets a day (two b.i.d.) for the following 3 days. A
clinical assessment was undertaken on the initial day
(DO) to record the patient's anamnesis, age, intensity
a~d frequency of haemorrhoidal crises during the preVIOUS year, the risks and triggering factors, any previous
treatment and the outcome. A clinical examination was
carried out in order to score the subjective and objective
symptoms (bleeding, anal discomfort, pain and proctitis): 0, none; 1, mild; 2, significant; and 3, severe. From
DO to the last day of treatment (D7), the patients kept a
diary, noting daily the degree of improvement of their
symptoms as: 0, none; 1, mild improvement; 2, significant improvements; 3, disappearance of symptoms.
The compliance of patients was evaluated on the basis
of the number of tablets returned on D7. Patients who
did not comply with the protocol and/or patients who
did not complete the treatment were excluded from the
final analysis. The therapeutic activity was evaluated
from the evolution of subjective and objective
symptoms and from the use of analgesic and topical
medication.

Table 1. Baseline characteristics of the patient population

No. of patients
Sex
Age (years)
Mean (SEM)
Range
Weight (kg)
Mean (SEM)
Range
Height (em)
Mean (SEM)
Range

Homogeneity

Dation 500 mg

Placebo

50
27M, 23 F

50
22M, 28 F

44.6 (1.7)
(24-79)

42.6 (1.5)
(23-67)

p=0.389
NS

69.9 (1.6)
(45-103)

68.7 (1.9)
(45-115)

p=0.650
NS

167.5 (1.1)
(152-180)

168.9 (1.2)
(150-189)

p=0.404
NS

p=0.317
NS

NS, not significant.

Efficacy

The overall improvement in symptoms was greater in


the D500 group than in the PI group; this improvement
was obvious from D2 (p <0.001) and was sustained up
to D7 (Table 2). The scores used to evaluate bleeding,
anal discomfort, pain and pruritus decreased significantly in both groups, but a substantially greater
decrease was observed in the D500 group in comparison
with the PI group (p <0.001) (Table 3). The proctitis
was significantly improved in both groups but the
improvement was significantly better in the D500 group
compared with the PI group (p <0.001).
Statistical Analysis
An improvement in clinical findings (inflammation,
congestion, oedema or prolapse) was observed in 47 out
Student's r-test for independent series and variance of 50 patients in the D500 group versus 29 out of 50
analysis was used for quantitative variables;
test, a patients in the PI group (p <0.001). The duration and
MacNemar test or G test were used for qualitative intensity of the present crisis, in comparison with
previous crises, were significantly reduced in the D500
variables.
group in comparison with the PI group (p <0.001)
(Table 4).
The use of the permitted analgesics significantly
decreased in both groups (p <0.001). The reduction of
Results
topical medication use was significant only in the D500
One hundred patients entered the study and were group. The comparison between the two groups showed
randomly allocated to the Daflon 500 mg group (n = 50) a significant decrease from D3 onwards in the D500
or to the placebo group (n = 50) (49 males, 51 females
including 22 pregnant women). The two groups were Table 2. Delay of therapeutic activity and degree of improvement of
not statistically different for anthropometric and crisis
general characteristics, for haemorrhoidal risk factors,
Placebo
Comparison
for the previous haemorrhoidal attacks (except for their Day Dation 500 mg
(p values)
intensity, which was more marked in the D500 group),
No. of Scores
No. of Scores
for the characteristics of the present crisis, or for the
patients
patients
time and circumstances of occurrence of the clinical
0
2 3
0
symptoms (Table 1).
2 3
One patient in the D500 group and five patients in
the PI group withdrew because of lack of therapeutic 2
50
29 21 0 0 50
47 3 0 0 <0.001
efficacy. Two patients in the D500 group and four 3
50
12 23 15 0 50
32 15 3 0 <0.001
50
3 23 24 0 50
22 22 5 1 <0.001
patients in the PI group (NS) complied poorly with the 4
50
3 11 28 8 50
18 19 12 1 <0.001
treatment. All of these patients attended the medical 56
49
0 6 23 20 45
9 19 14 3 <0.001
examination at D7 and were included in the final 7
49
1 2 17 29 45
11 17 14 3 <0.001
evaluation.

M. Cospite

42
Table 5. Side-effects

Table 3. Clinical status at day 7


Symptom
scores

Daflon 500 mg

Bleeding

0
1
2
3

Anal discomfort
0
1
2
3

Pain

0
1
2
3

Pruritus

0
1
2
3

Proctitis

0
1
2
3

Placebo

Comparison
of groups

Daflon

Placebo

3
2

500mg

19
1
0
0

95
5
0
0

9
4
4
1

50
22
22
6

p=0.OO6

19
26
3
1

39
53
6
2

3
25
16
5

6
51
33
10

p<O.OOl

42
5
2
1

84
10
4
2

8
24
15
3

16
48
30
6

p<O.OOl

21
5
0
0

81
19
0
0

30
48
22
0

p<O.OOl

27
18
2
0

57
38
4
0

17
56
23
4

p<O.OOl

11

5
0

No. of patients with one or more side-effects


Gastralgia
Diarrhoea
Dyspepsia
Abdominal pain
Nausea
Headache

diastolic blood pressures were not significantly altered


during the treatment in both groups.
The overall acceptability of both treatments was
assessed as satisfactory by patients and physicians. Four
patients in each group gave a 'poor' score; the results
were scored by Physicians as 'poor' in four patients in
the D500 group and in three patients in the PI group
(NS).

Discussion

Pharmacological treatment with micronized diosmin


(Daflon
500 mg) was effective in the treatment of a
11
haemorrhoidal
crisis. A statistically significant improve2
ment of both subjective and objective assessment of
symptoms (bleeding, anal discomfort, pain, pruritus
and anusitis) from D2 onwards was observed in the
Table 4. No. of patients with a decrease in duration and intensity of D500 group in comparison with the PI group. Moreover,
a significant reduction of duration and intensity of the
crisis vs. the previous crises
haemorrhoidal crisis and a significant improvement of
the clinical findings was demonstrated in the D500
Comparison
Daflon 500 mg Placebo
group in comparison with placebo.
A hypothetical explanation of the results obtained
12 (25%)
p<O.OOI
38 (78%)
Duration
from this study is that Daflon 500 mg has a protective
p<O.OOl
44 (90%)
19 (39%)
Intensity
effect on vascular permeability and oedema; it reduces
the level of the main biochemical mediators of inflamTBX 2, histamine, bradykinin,
mation (PGE2, PGF2~,
group for the analgesic tablets (p = 0.013) and for the LTB 4 and oxygen free radicals) [7,8]. Daflon 500 mg
topical medications (p = 0.041), still present at D7 contains micronized diosmin, owing to a new technique
that decreases the size of the particles of the active
(p <0.001).
component (diameter less than 2 j.lm). It has been
r.ecently demonstrated that micronization ensures a
Acceptability
better gastrointestinal absorption [9], thus leading to
better clinical results in comparison with non-microAs far as therapeutic results are concerned, 84% of the nized diosmin in the field of chronic venous insufficiency
patients treated with Daflon 500 mg were very satisfied [10] as well as haemorrhoidal attacks [11].
or satisfied in comparison with 42% in the PI group;
In summary, this drug (Daflon 500 mg) can be
86% of the clinicians considered the results as very good considered as a useful pharmacological agent against
in the D500 group in comparison with 32% in the PI the clinical symptoms of a haemorrhoidal crisis.
group. Thus, the overall evaluation of the therapeutic
efficacy by both patients and clinicians showed a significant difference (p = 0.001) in favour of the D500 group.
Four patients in the D500 group and three patients in References
the PI group experienced mainly mild digestive side1. Denis J. Etude numerique de quelques facteurs etiopathogenetieffects; no patient was obliged to stop the treatment
ques des troubles hemorroidaires de l'adulte. Arch Fr Mal App
Dig 1976;56:529-36.
because of major side-effects (Table 5). Systolic and
8
27

Evaluation of Daflon 500 mg in Treatment of Acute Haemorrhoids


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3. Smith LE. Hemorrhoids. A review of current techniques and
management. Gastroenterol Clin North Am 1987;16:79--91.
4. Damon M, Flandre 0, Michel F, Perdrix L, Crastes de Paulet A.
Effect of chronic treatment with a purified flavonoid fraction on
inflammatory granuloma in the rat. Arzneim Forsch/Drug Res
1987;37(11), 10:1149-53.
5. Galley P. Etude de l'activite de Daflon 500 mg sur la resistance
capillaire. J Int Med 1987; 88 (suppI.):25-6.
6. Duchene-Marullaz P, Amiel M, Barbe R. Evaluation of the
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suppI. ):25-32.

43
7. Duhault J, Crastes de Paulet A, et al. Daflon 500 mg: activite
protectrice vis-a-vis des mediateurs biochimiqucs irnpliques dans
la reaction inflammatoire (etudes de pharmacologie et de
pharmacocinetique. Compte rendu d'expertise). 1990.
8. Labrid C, Duhault J, Vix C. Proprietes pharmacologiqucs de
Daflon 500 mg. J Int Med 1987;85 (suppl.):3G-6.
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Bertrand M. Absorption de la diosmine chez Ie lapin: interete de
la micronisation. Arteres et Veines 1982;11:163-5.
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chronic venous insufficiency. Phlebology 1992;7:(suppI. 2):45-9.
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500 mg. Phlebology 1992, 7 (suppl. 2): 53-6.

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