Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1779_Библиотеки_им_академика_М_И_Перельмана.pdf
109
Which is the best site of GTN application? Are there any exclusion criteria like
secondary changes or migraine?
As already mentioned, anal fissure patients are characterized by a high degree of
tolerance (Table 11.2). Eight trials comprising 491 patients, who have been treated
with GTN, mention a period of suffering that lies between 1.9 and 240 months.
Anal Resting Pressure
To lower anal resting pressure, Bassotti et al. (2000) treated 12 anal fissure patients
perianally with 0.2% nitrate ointment and saw a significant decrease after
20 minutes.
According to Brisinda et al. (1999), resting pressure in 25 patients dropped from
83.4 ± 15.0 to 69.5 ± 16.8 mm Hg after the application of a 0.2% GTN ointment for
1 month. Loder et al. (1994) were able to show a decrease in anal resting pressure
of 27% after perianal application of 0.2% GTN in 10 patients. Lund et al. (1997)
noticed a significant decrease in anal resting pressure in 23 anal fissure patients
20 min after the application of 0.2% GTN. In 95% of all anal fissure patients, 0.2%
GTN ointment lowered anal resting pressure by 20% or more (Thornton et al. 2005).
Only GTN reduced effectively the anal resting pressure, but not Vaseline, xylocaine,
or hydrocortisone (Maan et al. 2004).
The behavior of anal squeeze pressure under GTN therapy is not uniform
(Table 11.3).
Healing Rates
Healing rates between 41% and 85% could be achieved in 12 clinical GTN trials
with a total of 469 patients. The study design, however, was not uniform
(Table 11.4).
Table 11.2 Duration of symptoms in 491 patients before GTN treatment for anal fissure
Author (year)
Anal fissure
patients (n)
Duration of symptoms
before GTN therapy months
Bacher et al. (1997) 20 6
Bacher et al. (1997) 15 5.5
Lund and Scholefield (1997) 38 12 (2–240)
Richard et al. (2000) 38 1.9 ± 2.75
Richard et al. (2000) 44 2.3 ± 3.65
Altomare et al. (2000) 59 10.5 ± 9
Altomare et al. (2000) 60 15 ± 21
Evans et al. (2001) 27 6–8
Evans et al. (2001) 33 6–8
Colak et al. (2002) 52 18 (3–36)
Colak et al. (2002) 37 14 (6–24)
Mustafa et al. (2005) 10 8.95 (4–24)
Mustafa et al. (2005) 10 7.65 (4–22)
Schiano et al. (2006) 16 17.5 (6–31)
Schiano et al. (2006) 16 16.88 (8–34)
Schiano et al. (2006) 16 15.19 (7–31)
Total 491
11.2 Conservative Therapy
110
Table 11.3 Anal resting pressure and squeeze pressure in 229 patients before and after GTN
therapy (in mm Hg or cm H
2
O)
Author (year)
mmHg cmH
2
O Patients (n)
Anal resting
pressure
Squeeze
pressure
Bacher et al. (1997) × 35
Before 110 177
After GTN therapy 87 157
Brisinda et al. (1999) × 25
Before 83 ± 15.0 79 ± 26
After GTN therapy 71 ± 17 86 ± 31
Brisinda et al. (2007) 50
Before 89 74
After GTN therapy 72 79
Kennedy et al. (1999) × 24
Before 125 ± 8 n/a
After GTN therapy 107 ± 7
Loder et al. (1994) × 11
Before 103 n/a
After GTN therapy 79
Lund et al. (1996) × 21
Before 118 n/a
After GTN therapy 70
Lund and Scholefield (1997) × 39
Before 122 ± 44 n/a
After GTN therapy 72 ± 33
Mustafa et al. (2005) × 10
Before 113 ± 13 n/a
After GTN therapy 70 ± 13
Schiano et al. (2006) × 16
Before 129 ± 18 218 ± 37
After GTN therapy 96 ± 17 168 ± 26
Table 11.4 Healing
rates after GTN
treatment in 12
uncontrolled trials with
469 patients (in %)
Author (year)
Patients (n)
Healing rate after
GTN therapy (%)
Dorfman et al. (1999) 27 56
Gorfine (1995) 12 83
Gorfine (1995) 30 77
Hasegawa et al. (2000) 40 50
Hyman and Cataldo (1999) 17 41
Jonas et al. (1999) 49 45
Jonas et al. (2002) 93 61
Lund and Scholefield (1997) 39 85
Lund and Scholefield (1998) 41 73
Palazzo et al. (2000) 45 73
Pitt et al. (2001) 64 41
Ward et al. (2000) 12 66
Total 469
11 Therapy for Chronic Anal Fissure
111
Anodermal Perfusion
Laser Doppler flowmetry of anodermal perfusion was carried out before and after
the application of GTN ointment in six anal fissure patients (Kua et al. 2001). Before
therapy began, a significant reduction of blood flow in the area of the anal fissure
was noticed in comparison with other sectors of the anoderm. After the application
of GTN, a significant increase of perfusion was observed in the anal fissure area
within the first hour.
The following controlled trials deal with the effect of GTN ointment in compari-
son with other therapeutic measures.
GTN Versus Self-Bougienage
Schiano et al. (2006) compared two groups of 16 patients each: one group practiced
self-bougienage with an anal cryothermal dilator, and the other was treated with
0.25% GTN. The authors saw healing in 56% of cases in the first group compared
to 62.5% in the second group. Sileri et al. (2007) achieved similar results in a total
of 156 patients. The healing rate of those who used anal dilators was 46% compared
to 40% of those who received a 0.2% GTN treatment.
GTN Versus Instrumental Anal Dilatation
Boschetto et al. (2004) treated 18 patients with GTN ointment and 18 with a hydro-
pneumatic dilatation which was performed only once. The healing rate was 39% in
the first group and 95% in the second one. Tranqui et al. (2006) also performed
pneumatic dilatation in combination with GTN ointment in 21 patients. They com-
pared the healing rate in this group with that of 56 patients who had received botu-
linum toxin together with nifedipine ointment. The healing rate was 71% in the first
group and 94% in the second group.
GTN Versus Placebo
The analysis of seven trials with 227 verum patients and 221 placebo controls
revealed healing rates of 24–79% in the verum group, and of 8–52% in the placebo
group (Table 11.5).
Table 11.5 Healing
rates after GTN therapy
in seven controlled trials
with 227 patients
Author (year)
Patients (n)
Healing rate
(GTN %)
Altomare et al. (2000) 59 49
Carapeti et al. (1999) 23 67
Chaudhuri et al. (2001) 10 70
Graziano et al. (2001) 22 79
Kennedy et al. (1999) 24 46
Lund and Scholefield (1997) 38 68
Scholefield et al. (2003) 51 24
Total 227
11.2 Conservative Therapy
112
GTN Local Versus GTN Transdermal
Colak et al. (2003) treated 37 patients with GTN ointment and 52 with GTN patches.
They saw healing rates of 79 and 81%, respectively. Zuberi et al. (2000) treated 18
patients with GTN ointment and 19 patients with GTN patches, and observed heal-
ing rates of 67 and 63%, respectively.
GTN Versus Nifedipine
Ezri and Susmallian (2003) compared the effect of GTN ointment and nifedipine oint-
ment in 26 patients each, and saw healing rates of 58 and 89%, respectively. Mustafa
et al. (2005) tested the oral dose of nifedipine in comparison with GTN ointment in
two groups of 10 patients each. The healing rate in both collectives was 50%.
GTN Versus Diltiazem (DTZ)
The authors above (Table 11.6) treated one collective each with GTN or diltiazem
locally. Healing rates were not significantly different.
Sajid et al. (2008, 2012) proved by meta-analysis that both substances are simi-
larly effective and have the same recurrence rates. GTN, however, produces more
side effects.
GTN Versus Xylocaine/Vaseline/Hydrocortisone
Bacher et al. (1997) treated eight patients with GTN ointment and five patients with
xylocaine ointment. The anal fissures healed in 12% of cases in the GTN group and
in 0.0% in the xylocaine group. Four groups of 16 anal fissure patients each were
treated with GTN ointment, xylocaine ointment, Vaseline, or hydrocortisone.
Healing rates were 94%, 69%, 25%, and 75%, respectively.
GTN Versus Botulinum Toxin (BTX)
Two collectives of 130 patients each were given either GTN ointment or a BTX
injection. Both therapies showed healing rates of 59%. In a meta-analysis, Sajid
et al. (2007) proves that GTN is just as efficient as BTX (Table 11.7).
GTN Versus Sphincterotomy
The analysis of seven trials with 388 patients (Table 11.8) shows healing rates after
GTN treatment (n = 200) between 30% and 90%, and after sphincterotomy (n = 188)
between 85% and 100%.
Table 11.6 Healing rates in five trials: GTN versus diltiazem therapy with 275 patients (in %)
Author (year)
Patients with Healing rate after
GTN therapy
(n)
DTZ therapy
(n)
GTN therapy
(%)
DTZ therapy
(%)
Ala et al. (2012) 36 25 60 91
Bielecki and
Kolodziejczak (2003)
21 22 86 90
Jonas (2002) 39 12 69 58
Kocher et al. (2002) 29 31 86 78
Shrivastava et al. (2007) 30 30 73 80
TOTAL 155 120
11 Therapy for Chronic Anal Fissure
113
Complication “Headache” After GTN Therapy
Table 11.9 shows that the complication “headache” rate lies within a range between
16% and 100% of patients in 19 trials with a total of 775 individuals.
Recurrence Rates
Nineteen trials with a total of 535 patients show recurrence rates between 6% and
64% (Table 11.10).
Conclusion
GTN ointment is regarded as first-line therapy for chronic anal fissure with the
intention of pain relief. The differing results concerning healing and relapse rate are
probably due to methodological shortcomings of the clinical trials with regard to
varying galenics, dosage, and the unknown bioavailability of the preparations which
are mostly magistrally produced.
11.2.2 Isosorbide Dinitrate
Isosorbide dinitrate (ISDN) is used in the prevention and long-term therapy for
angina pectoris. It is not approved for use in the local treatment of anal fissure. In
Germany, it is available in pharmacies as Isoket ointment or TD spray Iso Mack
®
.
Only Lysy et al. (1998) use an officinal Isoket spray in their clinical trials. Schouten
Table 11.7 Healing rates in five trials: GTN versus BTX therapy (in %)
Author (year)
Patients with Healing rate after
GTN therapy
(n)
BTX therapy
(n)
GTN therapy
(%)
BTX therapy
(%)
Brisinda et al. (1999) 25 25 60 96
Brisinda et al. (2007) 50 50 70 92
De Nardi et al. (2006) 15 15 67 57
Fruehauf et al. (2006) 25 25 52 24
Jones et al. (2006)
a
15 15 47 27
Total 130 130
a
+BTX/+placebo
Table 11.8 Healing rates in seven studies on GTN therapy versus sphincterotomy (in %)
Author (year)
Patients treated with Healing rate after
GTN (n) Sphincterotomy (n) GTN (%) Sphincterotomy (%)
Brown et al. (2007) 27 24 41 100
Evans et al. (2001) 34 31 61 97
Hashmat and Ishfaq (2007) 28 28 64 100
Libertiny et al. (2002) 35 35 54 100
Mishra et al. (2005) 20 20 90 85
Oettlé (1997) 12 12 90 100
Richard et al. (2000) 44 38 30 90
Total 200 188
11.2 Conservative Therapy
114
Table 11.9 Headache after GTN therapy in 19 trials with 775 anal fissure patients (in %)
Author (year)
Anal fissure
patients (n)
Headache after
GTN therapy
(n) (%)
Colak et al. (2002) 37 6 16
Loder et al. (1994) 11 2 18
Richard et al. (2000) 44 8 18
Kennedy et al. (1999) 24 6 25
Mustafa et al. (2005) 10 3 30
Altomare et al. (2000) 68 23 33
Brisinda et al. (2007) 50 17 34
Bacher et al. (1997) 126 50 40
Ezri and Susmallian (2003) 26 10 40
Fruehauf et al. (2006) 25 13 50
Lund and Scholefield (1997) 80 47 58
Kocher et al. (2002) 29 17 59
Hasegawa et al. (2000) 56 34 60
Libertiny et al. (2002) 19 12 62
Dorfman et al. (1999) 27 17 63
Carapeti et al. (1999) 46 33 72
Zuberi et al. (2000) 18 13 72
Hyman and Cataldo (1999) 33 29 88
Hashmat and Ishfaq (2007) 46 46 100
Total 775 386
Table 11.10 Recurrence rates after GTN therapy in 22 trials with 535 patients (in %)
Author (year)
Anal fissure
patients (N)
Recurrence after
GTN therapy (%)
Altomare et al. (2000) 26 19
Bacher et al. (1997) 18 22
Brown et al. (2007) 27 41
Carapeti et al. (1999) 23 33
Colak et al. (2003) 48 15
Colak et al. (2003) 34 9
De Nardi et al. (2006) 15 33
Dorfman et al. (1999) 15 27
Evans et al. (2001) 20 45
Ezri and Susmallian (2003) 26 31
Hasegawa et al. (2000) 13 8
Hasegawa et al. (2000) 7 57
Hashmat and Ishfaq (2007) 28 33
Jonas (2002) 25 64
Kocher et al. (2002) 26 8
Libertiny et al. (2002) 35 9
Lund et al. (1996) 21 19
Lund and Scholefield (1997) 31 16
Lund and Scholefield (1997) 38 8
Richard et al. (2000) 13 38
Schiano di Visconte et al. (2006) 16 19
Shrivastava et al. (2007) 30 32
TOTAL 535
11 Therapy for Chronic Anal Fissure
115
Table 11.11 Details of five local ISDN therapy studies with 221 patients
Author (year)
Anal
fissure
Patients
(n)
Percent
ISDN therapy
Treatment
in weeks
Follow-up
weeks
Schouten et al. (1996) Chronic 34 1.0 6–12 12
Lysy et al. (1998) Chronic 41 Spray (three times a day) 4 11
Werre et al. (2001) n/a 20 1.0 (five times a day) 5 20
Songun et al. (2003) Acute/
chronic
100 1.0 (five times a day) 8 48
Parellada (2004) Chronic 26 0.2 (three times a day) 10 96
Table 11.12 Healing and recurrence after local ISDN therapy in five trials with 155 patients
Author (year)
Patients (n)
Healing after local
ISDN therapy (%)
Recurrence
(%)
Schouten et al. (1996) 34 88 7.0
Lysy et al. (1998) 41 83 14.6
Werre et al. (2001) 20 85 10.0
Parellada (2004) 27 67 n/a
Berkel et al. (2014) 33 33 28.0
Total 155
et al. (1996) and Songun et al. (2003) embedded ISDN in lanolin, white Vaseline, or
liquid paraffin, while Parellada (2004) incorporated it in white Vaseline. Werre et al.
(2001) gave no details on the ointment carrier they employed. ISDN must be dis-
solved in an acid environment to ensure its full effect. It is therefore uncertain
whether the preparations mentioned above have any effect at all.
ISDN releases nitrogen monoxide and has a relaxing effect on the internal anal
sphincter muscle (Parellada 2004; Lysy et al. 1998; Schouten et al. 1996; Werre
et al. 2001). It has a vasodilatory effect, too, and leads to a better perfusion
(Schouten et al.). This relaxation should facilitate a “reversible chemical sphincter-
otomy.” Headache frequently occurs in the course of treatment. It generally stops
some days after further application. Table 11.11 shows the details of five ISDN
therapy studies.
However, the trials as such are hardly comparable because chronic anal fissures,
for instance, and also both acute and chronic anal fissures are dealt with simultane-
ously, or no details whatsoever are given to explain the type of anal fissure. Differing
concentrations (0.2–1.0%) of the topical medication were used, which were applied
between three and eight times per day. The duration of therapy varied between 4 and
12 weeks. Healing rates lay between 67% and 100%, and the relapse rate could
reach 14.6% (Table 11.12).
Conclusion
Only few and, in addition, not comparable clinical trials on local ISDN therapy are
known. Therefore, ISDN therapy cannot be recommended.
11.2 Conservative Therapy
116
11.2.3 Diltiazem
Diltiazem is a calcium channel blocker which leads to relaxation of smooth muscu-
lature and vascular dilation.
Carapeti et al. (2000) and Jonas et al. (2001) noticed a significant drop in anal
resting pressure after local application of 2% diltiazem gel. Headache, frequently
observed after employment of GTN and ISDN, does not seem to play a role in the
use of diltiazem. Only one author (Kocher et al. 2002) reports this side effect.
However, perianal pruritus is described in 7% of cases after diltiazem treatment,
probably caused by the basic component of the topical medication (Knight et al.
2001; Jonas et al. 2001). Therefore, diltiazem should be incorporated in basic cream
DAC (Neues Rezeptur-Formularium 2007).
Table 11.13 shows that the relapse rate after diltiazem therapy seems to be lower
than that after GTN application: 12.5% vs. 32% (Shrivastava et al. 2007) and 0.0%
vs. 2.5% (Kocher et al. 2002).
Diltiazem is available as 2% gel, cream, or ointment. Yet, the basic compo-
nents of the topical medication are not revealed. Diltiazem was applied peria-
nally, intra- anally, or both perianally and intra-anally two or three times a day.
Topical treatment lasted between 6 and 12 weeks, and healing rates (n = 441) lay
between 41% and 94%. These differing results probably depend on the different
basic components of the topical medications, the differing sites of application,
the duration of therapy varying in length, and on the disunity in defining chronic
anal fissure.
Conclusion
Headache does not occur after treatment with a diltiazem topical medication. The
healing rate is a little higher than that after GTN therapy, and the relapse rate seems
to be lower.
Table 11.13 Details of 11 topical diltiazem therapy studies with 441 patients
Author (year) Patients (n) DTZ therapy application
Duration
weeks
Healing
(n) (%)
Carapeti et al. (2000) 15 2% gel, three times a day 8 10 67
Jonas et al. (2001) 26 2% gel, twice a day 8 17 65
Knight et al. (2001) 64 2% gel, twice a day 9 47 73
Kocher et al. (2002) 31 2% cream, twice a day 6–8 22 71
DasGupta et al. (2002) 23 2% gel, three times a day 12 3 48
Jonas et al. (2002) 39 2% gel, twice a day 8 19 49
Griffin et al. (2002) 47 2% cream, twice a day 8 23 48
Bielecki et al. (2003) 22 2% ointment, twice a day 8 19 86
Bader et al. (2006) 32 2% gel, twice a day 6 30 94
Nash et al. (2006) 112 2% cream, twice a day 6 46 41
Shrivastava et al. (2007) 30 2% ointment 6 24 80
Samim et al. (2012) 74 2% cream, twice a day 12 32 43
Total 515 292
11 Therapy for Chronic Anal Fissure
117
11.2.4 Nifedipine
Nifedipine is a calcium antagonist. The agent has an effect particularly on the
smooth musculature and leads to a vascular dilation. An oral dose of 20 mg nifedip-
ine results in a significant reduction in anal resting pressure in healthy as well as in
anal fissure patients, but not in squeeze pressure (Agaoglu et al. 2003; Cook et al.
1999; Mustafa et al. 2005). The active agent is highly sensitive to light. In Germany,
nifedipine is approved for the treatment of both chronic stable and vasospastic
angina, and also of essential hypertension. Depending on the dose, there have been
hints at an increase of complications of the cardiovascular system, like myocardial
infarction, and at rising mortality rates. Headache, flush and peripheral edemata are
very often reported in the course of the treatment.
Therefore, an oral dose administered for the treatment of chronic anal fissure is
unjustified because of low healing rates and partly grave side effects. The local
application of 0.2–0.5% nifedipine, however, appears to result in a high healing rate
and a lower complication rate (Tables 11.14 and 11.15).
Conclusion
An evaluation of the local nifedipine therapy requires the results of further random-
ized controlled trials.
11.2.5 Indoramin
Indoramin is an alpha-1-adrenoreceptor blocker which is used in the treatment for
hypertension.
In 2000, Pitt et al. treated chronic anal fissure patients and healthy controls with
an oral dose of indoramin, and afterwards found a significant reduction of anal rest-
ing pressure for the duration of 3 h.
A year later, they saw a significant drop in anal resting pressure in a double-blind
randomized placebo-controlled trial with a total of 23 patients. Six weeks later, they
Table 11.14 Healing rate after oral or local nifedipine application in nine trials with 444 patients (in %)
Author (year)
Nifedipine
application Patients (n)
Healing
(n) (%)
Agaoglu et al. (2003) Oral 10 5 50
Ho and Ho (2005) Oral 41 7 17
Mustafa et al. (2005) Oral 10 5 50
Golfam et al. (2014) Oral 65 29 49
Antropoli et al. (1999) Local 141 134 95
Ezri and Susmallian (2003) Local 26 23 89
Perrotti et al. (2002) Local 55 25 45
Katsinelos et al. (2006) Local 31 26 84
Golfam et al. (2014) Local 65 43 73
Total 444 297
11.2 Conservative Therapy
118
Table 11.15 Details of three local nifedipine therapy studies with 138 patients
Author (year)
Patients (n)
Nifedipine
applied (%)
Additional therapy
application
Healing duration
weeks
Healing
rate (%)
Follow-up
(Months)
Complications
(%)
Recurrence
rate (%)
Perrotti et al. (2002) 55 0.3 1.5% Lidocaine 6 94.5 12 0.0 5.0
Ezri and Susmallian (2003) 52 0.2 None 24 89.0 4.5 5.0 42.0
Katsinelos et al. (2006) 31 0.5 Dietary fiber 8 96.7 19 50.0 6.6
Total 138 92.7 13.7 17.4
11 Therapy for Chronic Anal Fissure