Download iontoforesis

Andrology
Arch. Esp. Urol. 2012; 65 (8): 745-751
TRANSDERMAL IONTOPHORESIS WITH VERAPAMIL AND DEXAMETHASONE
IN THE ACUTE PHASE OF PEYRONIE´S DISEASE. OUR EXPERIENCE
Pablo Garrido Abad, Almudena Coloma, Luis Miguel Herranz, Milagros Jimenez, Carlos
Suarez, Maria Dolores Prieto1, Teresa Formoso1 and Manuel Fernandez Arjona.
Urology Department and Unidad de Enfermería de Urología1. Hospital del Henares. Coslada. Madrid. Spain.
Summary.- OBJECTIVES: To evaluate the treatment
of Peyronie´s disease (PD) with verapamil and
dexamethasone iontophoresis.
other parameters like erectile function (EF), intercourse
capacity or adverse effects of the treatment, which were
evaluated with questionnaires.
METHODS: Twenty nine patients with PD were treated
by means of a Miniphysionizer” dispositive 3 sessions a
week during 4 consecutive weeks. 5mL of a combination
of verapamil (10mg.) and dexamethasone (4mg.) were
transdermally administered with a 2.5 mA current
during 20 min. The aim is to evaluate treatment efficacy
in correcting penile curvature (Kelami test), plaque
size (penis ultrasound (US)) improvement of pain and,
RESULTS: All patients completed the treatment protocol
(12 sessions) and a total number of 348 sessions of
iontophoresis were performed. After treatment, 3 patients
(10.7%) continued with pain, but it disappeared in 25 of
them (89.3%). A decrease of the size of the plaque was
observed in 13 patients (44.8%), even disappearance in
4 patients (13.8%). No patient had curvature decrease
after treatment. However, EF (IIEF score) and ability
for intercourse improved in 3 (10.3%) and 4 patients
(13.8%) respectively.
CONCLUSION: Verapamil and dexamethasone
iontophoresis is a safe and reliable treatment resolving
painful erections in the acute phase of PD. However
its efficacy in solving penile curvature and erectile
dysfunction (ED) is more limited.
@
Keywords: Penis. Iontophoresis. Peyronie´s disease. Erectile Dysfunction.
CORRESPONDENCE
Pablo Garrido Abad
Urology Department
Hospital del Henares
Avda. Marie Curie, s/n.
Coslada. Madrid. (Spain).
[email protected]
Accepted for publication: July 4th, 2012
Resumen.- OBJETIVO: Evaluar el resultado del tratamiento de la Enfermedad de Peyronie (EP) mediante
iontoforesis de verapamilo y dexametasona.
MÉTODOS: Tratamiento de 29 pacientes con EP en 3
sesiones semanales durante cuatro semanas consecutivas mediante un dispositivo Miniphysionizer©. Administrando 5 mL de una combinación de 10mg de verapamilo y 4mg de dexametasona, aplicado transdérmico
a través de una corriente de 2.5 mA durante ciclos de
20 min. Se evalúa la eficacia del tratamiento mediante
corrección de curvatura peneana (test de Kelami), tamaño de la placa (ecografía peneana), mejoría del dolor
746
P. Garrido Abad, A. Coloma, L. M. Herranz, et al.
y otros parámetros, como, la función eréctil, capacidad
de penetración o efectos secundarios del tratamiento,
que fueron valorados mediante cuestionarios.
RESULTADO: Todos los pacientes completaron el protocolo de tratamiento (12 sesiones) y se efectuaron un
total de 348 sesiones de iontoforesis. Tras finalizar el
tratamiento completo, 3 pacientes (10.7%) continuaron presentando dolor, mientras que remitió en 25 de
ellos (89.3%). En 13 pacientes (44.8%) se observó una
disminución del tamaño de la placa, desapareciendo
incluso totalmente en 4 pacientes (13.8%). La curvatura
no se disminuyó en ninguno de los pacientes tras el
tratamiento.
Sin embargo, la función eréctil mejoró en 3 pacientes
(10.3%) según la puntuación del IIEF, y la capacidad
para la penetración mejoró en 4 pacientes (13.8%).
CONCLUSIONES: La iontoforesis con verapamilo y
dexametasona es un tratamiento seguro y eficaz en la
resolución del dolor con las erecciones en la fase aguda de la EP. Sin embargo la eficacia en la resolución de
la curvatura y la DE es más limitado.
Palabras clave: Pene. Iontoforesis. Enfermedad
de Peyronie. Disfunción Eréctil.
INTRODUCTION
In 1743 François de La Peyronie described
for the first time the concept induration penis plastica.
Since then, is named Peyronie´s disease (PD) (1).
PD is a complex of symptoms due to structural
modifications in penile corpora cavernosum, that
can result in penile deviation, painful erections, and
difficulties during intercourse.
The cause of penile curvature is the presence
of fibrotic plaques involving tunica albuginea.
Is a relatively common disorder among men
(40-70 year old), with a reported prevalence of 3.28.9%. However the actual prevalence of PD may be
even higher because many men are embarrassed to
complain about it (2,3).
Treatment for EP presents several approaches
with different results. Due to relatively high number of
patients in our daily andrology consultation, we think
is interesting to evaluate one of the most unknown
therapy for PD, the transdermal Iontophoresis.
Transdermal drug delivery has been suggested
to have advantages over oral or injection therapy by
eliminating first pass metabolism and minimizing the
pain of injection.
Transdermal Iontophoresis is the transport of
ions through the skin by an electric current, to reach
higher concentrations of drugs in the site of action.
METHODS
The study design
retrospective serie of cases.
was
a
one-center
A total of 29 patients were treated, with a
mean age of 62.7 year old (34-78), with PD in last
3 months. All treatments were completed between
February 2010 and September 2011.
Inclusion criteria were clinical evidence
of primary Peyronie’s disease including plaque,
deformity of the penis and pain on erection or
non-specific genital pain. Exclusion criteria were
recent treatment with calcium channel blockers or
corticosteroids, therapies interfering with these 2
drugs, and erectile dysfunction due to causes other
than Peyronie’s disease.
During study, patients were not allowed to
treat ED with pills or other treatments.
Electromotive drug administration treatment
was performed under the established protocol,
including thorough degreasing of the skin under the
active and dispersive electrodes with rubbing alcohol.
This step is important to decrease irregularities in skin
impedance to electric current and drug transfer. Then
a 5 cc plastic self-adhesive receptacle was filled with
of 4 mg. dexamethasone and 10mg. verapamil and
fixed to penis skin over plaque. The positive electrode
(anode) of the Miniphionizer® (model MP 2.0,
Physion, Italy) was connected to the receptacle and
the cathode was connected to a skin electrode fixed
to the thigh (Figure 1). A pulsed direct 2,500 Hz.
current of 2.5 mA. was performed for 20 minutes.
Complete treatment consisted of 3 weekly sessions
during 4 weeks (total of 12 weeks).
According to Cabello et al (4), following
parameters were assessed: penile deviation, plaque
size, curvature severity, erectile function, ability for
intercourse and presence of painful erections.
Penile deviation was classified in lateral or
dorsal/ventral, plaque size (cm.) was measured by
penis ultrasound before and after treatment (Figure
2). Grade of deviation by means of Kelami test
(autophotos in three different planes during complete
TRANSDERMAL IONTOPHORESIS WITH VERAPAMIL AND DEXAMETHASONE IN THE ACUTE PHASE OF PEYRONIE´S DISEASE...
747
Penis ultrasound were not all performed
by same radiologist, but all by urology-specialized
radiologist into the department.
During treatment adverse effects
assessed. All patients completed 12 sessions.
were
RESULTS
All patients completed treatment (12 sessions)
and a total of 348 iontophoresis sessions were
administered (Table I).
FIGURE 1. Treatment EMDA with MiniPhionizer©
applied over penile dorsal plaque.
erection) stratified in (<30º, 30-60º and >60º).
Erectile function was measured by means of score of
1-5 and 15 International Index of Erectile Function
questionnaire (IIEF). Ability for intercourse was
classified in possible, difficult and impossible, after
a questionaire, just as presence or ausence of painful
erections, according to a pain scale from 0 to 10 and
stratified (Ausence:0; Mild:1 a 3, Moderate:4 a 7,
Severe: 8 a 10).
All patients were assessed 1 month after
treatment.
None of them have received any other
treatment before for PD.
Most frequent deviation in our serie was
dorsal, in 19 patients (65.5%), and the rest 10
patients (34.5%) had lateral deviation.
Plaque presence was confirmed in all patients.
Proximal plaque location was the most prevalent, 16
patients (55.2%), medium in 10 patients (34.5%),
and distal in 3 patients (10.3%). After treatment
reduced plaque size was evidenced. Mean plaque
size before treatment measured by penis ultrasound
was 2.37 cm. (0.1-3.1), and 1.78 cm. (0.0-3.3) after
treatment. (p<0.001)
13 patients (44.8%) had a reduction in plaque
size, and totally disappear in 4 patients (13.8%). All
of this 4 patients had an initial plaque size < 0.8
cm.
28 patients (96.5%) have complained painful
erections before treatment. After 12 iontophoresis
sessions, 3 patients (10.7%) continued referring
FIGURE 2. Ultrasound before and after treatment with an important reduction in plaque volume.
748
P. Garrido Abad, A. Coloma, L. M. Herranz, et al.
pain, but disappeared in 25 of them (89.3%). 23
of these patients with pain disappearance, showed
this improvement after third treatment session. This
resolution of pain was registered in patients with
dorsal (16) as lateral (9), and in all groups of plaque
size, < 1cm (5), 1-2cm (2) and >2 cm (18).
After Kelami test, patients were stratified in
<30º (11), 30-60º (15) and >60º (3). Curvature did
not decrease after treatment in any patient, if it is true
that neither progressed. Erectile function (IIEF score)
improved only in 3 patients (10.3%), and ability for
intercourse in 4 patients (13.8%).
22)
Mean patient follow-up was 14.1 months (3-
No adverse events related to iontophoresis
were observed, except mild ecchymosis in skin
electrode site.
DISCUSSION
The true nature of PD is almost unknown,
but usually occurs after a penis trauma, autoinmune
mechanisms, genetic anomalies or abnormal activity
of fibroblasts (5).
The pathophysiology of PD and the
mechanism of plaque formation are largely unknown.
One paradigm is that PD begins with an inflammatory
process that leads to a progressive fibrosis, altough
exact mechanism is still not well known. Several
inflammatory mediators, growing factors and
matrix proteins responsable of plaque formation:
transforming growth factor beta 1 (TGF-β1), matrix
metalloproteinases, plasminogen 1 activator inhibitor
and growing factor for platelets A and B. (6-9)
Loss of elasticity in plaque site cause deviation
and/or penis deformity, and may interfere with venous
occlusion responsible of erection. (10)
Final result may be penile deformity, pain,
difficulties for intercourse and erectile dysfunction.
Clinically two well defined different phases: acute
and chronic. In acute phase, 12-18 months, patients
present painful erections, curvature or penile
deformity, palpable plaque, and often erectile
dysfunction. Whereas in chronic phase, penile
deformity stabilizes and pain goes down. However,
TABLE I.
Before treatment
Deviation
Type
Grade
After treatment
N
%
N
%
Dorsal
19
65.5%
19
65.5%
Lateral
10
34.5%
10
34.5%
Ventral
0
0%
0
0%
< 30º
11
37.9%
11
37.9%
30-60º
15
51.7%
15
51.7%
> 60º
3
10.3%
3
10.3%
Proximal
16
55.2%
14
48.3%
Medium
10
34.5%
9
31%
Distal
3
10.3%
2
6.9%
0
0
0%
4
13.8%
<1cm
5
17.2%
3
10.3%
1-2 cm
2
6.9%
8
27.6%
>2cm
22
75.9%
14
48.3%
Yes
28
96.5%
3
10.3%
No
1
3.5%
26
89.7%
Plaque
Location
Size
Pain
TRANSDERMAL IONTOPHORESIS WITH VERAPAMIL AND DEXAMETHASONE IN THE ACUTE PHASE OF PEYRONIE´S DISEASE...
exists a high variability in the PD development (5).
Natural evolution of PD is to progress in
30.3-48% of cases without treatment, but only 3.212% have a spontaneus resolution (11,12).
Despite a myriad of treatment options, PD
remains a considerable theraputic dilemma because
of the paucity of randomized, placebo-controlled
trials.
Iontophoresis is the electrokinetic transport
of charged ionic molecules by a electric source, to
overcome limitations of topical therapies. It is placed
into the non surgical therapies for PD.
Stancik et al recently demonstrated the
decreased expression of bFGF mRNA and bFGF
protein, as well as overexpression of TGF-β protein
and TGF-β receptor, in excised Peyronie´s plaques
after having undergone electromotive drug therapy
with dexamethasone, verapamil, and lidocaine when
compared with therapy naïve plaques (13).
It has been applied with different drugs and
dosages since several years ago.
Most used medications are: verapamil,
dexamethasone, lidocaine and orgotein.
Levine et al described in 2003 the presence
of verapamil in the tunica albuginea during plaque
surgery in PD patients after they have been treated
with EMDA (14).
Di Stasi in 2004 reported a prospective,
randomized study including 96 patients with PD treated
with 5mg. of verapamil + 8 mg. dexamethasone
iontophoresis versus a group treated with iontophoresis
of lidocaine 2%. 43% of patients of the verapamil +
dexamethasone group showed reductions in plaque
size or penile deviation, meanwhile lidocaine group
did not show significative changes (15).
In 2003, Di Stasi (16) reported a serie of
49 patients treated by iontophoresis with 5mg.
of verapamil and 8 mg. of dexamethasone with
an amazing results. He reported 73% of plaque
reduction, and 8% of total disappearance. Moreover
describes a deviation reduction in 84% of patients,
and 59% of improval in erectile function.
In 2007, Greenfield published his experience
with iontophoresis of verapamil 10mg. versus
saline. 65% and 58% of them, respectively, showed
a reduction in deviation (9.1º vs 7.6º), without
significative differences between both treatments.
749
Authors conclude that electric current, by itself, may
cause beneficial effects (17).
In Spain few series of patients with PD treated
by iontophoresis have been reported. In 2003 Pérez
Espejo et al (18) reported a serie of 61 patients
treated by iontophoresis with orgotein. 17 patients
(27.9%) showed improval in pain, while 4 patients
(6.5%) reduced penile deviation. In 2005 Cabello et
al (4) reported a retrospective serie of cases, with a
reduction in painful erections and plaque size in 80%
and 60% of patients, improval of erectile function in
10%, without reduction in penile deviation in any
patient.
Our results showed reduction in pain in 89%
of patients, as high as previously reported in other
series (28-96%) (10,15,16,18), and reduction of
plaque size in 45%, softly lower than reported by
other authors (53-100%) (10,15,16). It is surprising
the null response in penile curvature reduction in
our serie, according to Cabello et al (4), not seen in
any patient, meanwhile reaches up to 84% in other
reports.(16) In the same way, the mild improvement
of erectile function in our patients (10%), does not
belong with other series reported, with improvements
up to 60% (16).
This results may be due to a lower number of
patients included in our serie, or to a shorter followup.
Other non-surgical treatments for PD include
oral therapies, topical therapy, intralesional therapies,
local penile electroshock wave therapy (ESWT) and
penile traction devices.
Different oral therapies are used for PD
treatment, including vitamin E (tocopherol), potassium
aminobenzoate (potaba), colchicine, tamoxifen
citrate, acetyl esters of carnitine, phosphodiesterase
type 5 inhibitors, and pentoxifyline (5,19). All of
them fail to demonstrate efficacy in randomized
trials, except potassium aminobenzoate (potaba) that
demonstrated stablish progression of penile deviation
in Weidner et al (20).
Topical therapies include among others:
verapamil, hydrocortisone and aminopropionitrile
(19), although results are poor in nearly all of cases.
Several
intralesional
therapies
have
been used: corticosteroids, verapamil, orgotein,
collagenase and interferons (α-β). Among them,
corticosteroids are not recommended and verapamil
has not demonstrate efficacy in randomized,
controlled trials (21). Orgotein is forbidden in USA
750
P. Garrido Abad, A. Coloma, L. M. Herranz, et al.
and its use is not well recommended. Collagenase,
however, in a recent phase II trial (not yet published)
have demonstrated significative improval of painful
erections and curvature (22), while interferon
treatment have demonstrated efficcacy in resolution
of curvature, plaque size and pain, without effect in
erectile function (23).
*5.
ESWL have not demonstrated beneficial
effect. Currently ESWL has no current place in PD
treatment (24).
7.
6.
Penile traction devices and vacuum devices
have suggested benefits in PD treatment, but not yet
in RCT´s (25-27).
8.
In severe cases of PD, treatment may include
penile surgical procedures, like tunical shortening
procedures (plication), tunical lenghtening procedures
(grafting) or penile prosthesis implantation.
9.
CONCLUSION
Iontophoresis
with
verapamil
and
dexamethasone is a safe and reliable treatment in
resolving painful erections in acute phase of PD.
However its efficacy in resolving curvature and ED is
more limited.
This treatment should be recommended
to patients whose main symptom is pain and to
patients with mild curvature and those who do not
want to perform an intralesional injection or surgical
procedures.
10.
11.
12.
13.
14.
**15.
REFERENCES AND RECOMMENDED READINGS
(*of special interest, **of outstanding interest)
1. de la Peyronie F. Sur Quelques obstacles qui
s´opposent a l´ejaculation naturelle de la semence.
Mem Acad Royale Chir 1743;1:337-42.
2. Schwarzer U, Sommer F, Klotz T, Braun M, Reinfenrath B, Engelmann U. The prevalence of
Peyronie´s disease: results of a large survey. BJU
Int. 2001;88(7):727-30.
3. Mulhall JP, Creech SD, Boorjian SA, Ghaly S,
Kim ED, Moty A, y col. Sujective and objective
analysis of the prevalence of Peyronie´s disease in
a population of men presenting for prostate cancer
screening. J Urol. 2004.171;& Pt 1):2350-2353.
4. Cabello Benavente R, Moncada Iribarren I, de Palacio España A, Hernández Villaverde A, Monzó
JI, Hernández Fernández C. Iontoforesis transdér-
*16.
17.
18.
*19.
mica con dexametasona y verapamilo para la Enfermedad de La Peyrone. Actas Urol Esp 2005;29
(10): 955-960.
Vanni AJ, Bennett NE. Tratamiento y Manejo actual de la fase aguda de la Enfermedad de Peyronie. Arch. Esp Urol. 2009;62 (8):614-22.
Somers KD, Dawson DM. Fibrin deposition in Peyronie´s disease plaque. J Urol.
1997;157(1):311-315.
Lue TF. Peyronie´s disease: an anatomicallybased hypothesis and beyond. Int J Impot Res.
2002;14(5):411-413.
Davila HH, Ferrini MG, Rajfer J, González-Cadavid NF. Fibrin as an inducer of fibrosis in the
túnica albugínea of the rat: a new animal model of
Peyronie´s disease. BJU Int.2003;91(9):830-838.
Davila HH, Magee TR, Zuniga FI, Rajfer J, Gonzalez-Cadavid NF. Peyronie´s disease associated
with increase in plasminogen activator inhibitor
in fibrotic plaque. Urology. 2005;65(4):645-648.
Rield CR, Plas E, Engelhardt P, Daha K, Pflüger
H. Iontophoresis for treatment of peyronie´s disease. J Urol 2000:1696-1705.
Kadioglu A, Tefekli A, Erol B, Oktar T, Tunc M,
Tellaloglu S. A retrospective review of 307 men
with Peyronie´s disease. J Urol. 2002;168(3):10759.
Mulhall JP, Schiff J, Guhring P. An analysis of
the natural history of Peyronie´s disease. J Urol.
2006. ; 175:2115-8.
Stancik I, Schäfer R, Andrukhova O, Oeser R, Plas
E, Pflüger H. Effect of transdermal electromotive
drug therapy on fibrogenic cytokine expression in
Peyronie´s disease. Urology. 2009;74(3):566-70.
Levine LA, Estada CR, Shou W, Cole A. Tunica
albuginea tissue analysis after electromotive drug
administration. J Urol. 2003;169:1775-78.
Di Stasi SM, Giannantoni A, Stephen RL, Capelli
G, Giurioli A, Jannini EA. A prospective, randomized study using transdermal electromotive administration of verapamil and dexamethasone for
Peyronie´s disease. J Urol. 2004;171:1605-1608.
Di Stasi SM, Giannantoni A, Capelli G, Jannini EA, Virgili G, Storti L, y col. Transdermal
electromotive administration of verapamil and
dexamethasone for Peyronie´s disease. BJU Int.
2003;91(9):825-829.
Greenfield JM, Shah SJ, Levine LA. Verapamil
versus saline in electromotive drug administration
for Peyronie´s disease: a doublé-blind, placebo
controlled trial. J Urol. 2007;177:972-975.
Pérez Espejo MP, Campoy Martínez P, Pérez Pérez M, Argüelles Salido E, Rodríguez Pérez A,
Soltero González A. Iontoforesis en la enfermedad de Peyronie. Nuestra experiencia. Arch Esp
Urol. 2003;56(10):1133-1137.
Serefoglu EC, Hellstrom WJ. Treatment of
751
20.
21.
22.
23.
Peyronie´s Disease:2012 Update. Curr Urol
Rep.2011;12:444-452.
Weidner W, Hauck EW, Schnitker J. Potassium
paraaminobenzoate (POTABA) in the treatment
of Peyronie´s disease: a prospective, placebo-controlled, randomized study. Eur Urol.2005;47:530536.
Rehman J, Benet A, Melman A. Use of intralesional verapamil to dissolve Peyronie´s disease
plaque: a long-term single-blind study. Urology.1998;51:620-626.
Auxilium Pharmaceuticals. A phase 2b, doubleblind, randomized, placebo-controlled study of
the safety and effectiveness of AA4500 administered two times a week for up to three treatment
cycles (2x3) in subjects with Peyronie’s Disease.
En: Clinical Trials.gov [internet] Bethesda (MD):
National Library (VS). 2000-[cited 2011 Dec 21]
Available from: http://clinicaltrials.gov/show/
NCT00755222. NLM Identifier:NCT 00755222.
Hellstrom WJ, Kendirci M, Matern R, Cockerham
Y, Myers L, Sikka SC, y col. Single-blind, multi-
24.
25.
26.
27.
center, placebo controlled, parallel study to assess
the safety and efficacy of intralesional interferon
alpha-2B for minimally invasive treatment for
Peyronie´s disease. J Urol. 2006;176(1):394-398.
Taylor FL, Levine LA. Non-surgical therapy for
treatment of Peyronie´s disease. Asian J Androl.
2008;10(1):79-87.
Levine LA, Newell M, Taylor FL. Penile traction
therapy for treatment of Peyronie´s disease: a single-center pilot study. J Sex Med. 2008;5:14681473.
Gontero P, Di Marco M, Giubilei G, Bartoletti
R, Pappagallo G, Tizzani A, y col. Use of penile
extender device in the treatment of penile curvature as a result of Peyronie´s disease. Results of
a phase II prospective study. J Sex Med. 2009;6:
559-566.
Raheem AA, Garaffa G, Raheem TA, Dixon M,
Kayes A, Cristopher M, y col. The role of vaccum
pump therapy to mechanically straighten the penis
in Peyronie´s disease. BJU Int. 2010;106(8):11781180.