Pediatr Nephrol (2008) 23:269–274

DOI 10.1007/s00467-007-0440-3

ORIGINAL ARTICLE

Homotoxicological remedies versus desmopressin

versus placebo in the treatment of enuresis: a randomised,
double-blind, controlled trial
Pietro Ferrara & Giuseppina Marrone &
Valentina Emmanuele & Alessandro Nicoletti &
Antonio Mastrangelo & Eloisa Tiberi &
Antonio Ruggiero & Alfonso Fasano &
Fabrizia Paolini Paoletti

Received: 24 July 2006 / Revised: 1 December 2006 / Accepted: 22 December 2006 / Published online: 20 February 2007
# IPNA 2007

Abstract The aim of this trial was to compare the safety
and efficacy of homotoxicological remedies versus place-
bo and versus desmopressin (dDAVP) in the treatment of
monosymptomatic nocturnal enuresis (MNE). We con-
ducted a randomised, double-blind, double-dummy, con-
trolled trial in which 151 children with MNE were
randomly assigned to receive oral homotoxicological
remedies (n=50), dDAVP (n=50) or placebo (n=51).
The primary outcomes were: the reduction of wet nights
per week after 3 months of therapy; the evaluation of the
numbers and percentages of non-responders and respond-
ers; the number of children relapsing after initial response
and the number of children attaining 14 consecutive dry
P. Ferrara (*) : G. Marrone : A. Nicoletti : A. Mastrangelo :
A. Ruggiero
Department of Paediatric Sciences, Università Cattolica S. Cuore,
A. Gemelli Hospital,
Largo A. Gemelli, 8,
00168 Rome, Italy
e-mail: pferrara@rm.unicatt.it
nights during the treatment. The secondary outcome was
the detection of adverse effects. Baseline clinical charac-
teristics were similar in the three groups of patients. After
the 3 months of therapy there was a significant difference
between the three groups (P<0.001) in the mean number
of wet nights per week. The daily dose of dDAVP
produced a statistically significant decrease (62.9%) in
wet nights compared to placebo (2.4%) (P<0.001) and
compared to homotoxicological remedies (30.0%) (P<
0.001). There was a significant decrease in wet nights
among the group treated with homotoxicological medi-
cations if compared with placebo (P<0.001). The full
response achieved with homotoxicological remedies
(20%) was superior if compared with placebo (0%) (P<
0.001). Homotoxicology was superior to placebo (P<
0.001) with regard to the number of children attaining 14
consecutive dry nights during treatment. Our study
demonstrates that homotoxicology is safe and effective
when compared with placebo, even if it is significantly
less effective than dDAVP in this clinical condition.

V. Emmanuele : E. Tiberi Keywords Enuresis . Homotoxicology . Desmopressin .

Università “Campus Bio-Medico”,
Rome, Italy Treatment

A. Fasano
Department of Neurology,
Università Cattolica S. Cuore, A. Gemelli Hospital, Introduction
Rome, Italy
Nocturnal enuresis (NE) is a common disorder character-
F. Paolini Paoletti
Pediatrician of the National Health System, ised by repeated involuntary voiding of urine into bed or
Gualdo Tadino, Perugia, Italy clothes [1].
270
The terminology adopted is in accordance with the new
International Children_s Continence Society (ICCS) recom-
mendations. Monosymptomatic NE (MNE) means bed-
wetting without any other lower urinary tract symptom [2].
The involuntary leakage of urine during day time or while
awake, with or without nocturnal bedwetting, is called
urinary incontinence (UI).
The prevalence of NE is probably above 10% among 6-
years-old, around 5% among 10-years-old, and 0.5–1%
among teenagers and young adults [3–6]. An Italian
epidemiological study reported an overall NE prevalence of
3.8%, decreasing proportionately with increasing age [7].
In spite of this high rate of spontaneous remission, NE
may have a deep psychological and social impact on the
affected children and their families [5, 8]. Consequently, it is
important that NE is properly managed. Pharmacological,
psychological/behavioural and alternative interventions are
commonly used. The first-line therapy for a subgroup of
patients with MNE associated with nocturnal polyuria and
normal bladder function is desmopressin (dDAVP) [9].
Homoeopathy is a 200-year-old therapeutic method based
mainly on two principles. The principle of “similars” is that
small doses of a substance that can cause symptoms in a
healthy person can be used to cure similar manifestations of
disease in sick patients. The principle of “potencies” states
that remedies retain biological activity if they are diluted and
agitated or shaken between serial dilutions, even when
diluted beyond Avogadro’s number, at which no original
molecules remain. Even though homoeopathy is one of the
most controversial types of alternative medicines, several
studies have been conducted to assess the efficacy of
homoeopathy in different clinical conditions, reporting
positive results as well as the same placebo effect [10–13].
Homotoxicology was developed by the physician H.
Reckeweg. According to the concepts of homotoxicology,
any human disease is the result of toxins, which originate either
from within the body or from its environment. Each disease
process runs through specific phases and is the expression of
the body’s attempt to cope with these toxins [14].
Thus, homotoxicology is a form of therapy that uses
homoeopathically diluted remedies with the view of
eliminating toxins from the body, and it is strongly
influenced by (but not identical to) homoeopathy. An
important difference between homotoxicology and
homoeopathy is that the latter follows the “like cures like”
principle while homotoxicology does not. Moreover, many
homotoxicological remedies use medicines based on bio-
logical material from pigs, and others contain various
dilutions of the same material, which would be highly
atypical in homoeopathy [14].
The aim of this trial was to compare the safety and
efficacy of homotoxicological remedies, versus placebo and
versus dDAVP, in the treatment of MNE.
Pediatr Nephrol (2008) 23:269–274
Methods
Patients
Patients 6 years to 14 years of age (mean age 8.5 years)
were recruited from the Department of Paediatrics, Univer-
sity Hospital “A. Gemelli” of Rome, Italy, from January
2002 to December 2004. All patients met the ICCS
definition of NE, and none had received treatment for NE
or homotoxicological remedies within the previous
3 months. Exclusion criteria included NE associated with
day-time symptoms (urgency, frequency, UI, urinary tract
anomalies or infections). Each patient was asked about a
family history of bladder dysfunction and the number of
wet nights per week; in addition, each child was
investigated by urine analysis, urine culture and ultraso-
nography of kidney and bladder. The children and their
families were asked to participate in the study at the end
of the clinical evaluation. We investigated bladder func-
tion using a bladder diary that was completed by patients
or their parents. The bladder diary included the time and
the number of occasions the child micturated, urinary
volume, volume of fluid intake, number of changes of
clothes, urinary leakage, activities that provoked it and
sign of urge incontinence. The patients filled in this diary
for 3 months after the enrolment and during the period of
observation.
All parents or guardians gave written informed consent.
Study design
In this double-blind, double-dummy, randomised, con-
trolled, clinical trial children were enrolled by the inves-
tigators after the clinical evaluation, and patients who
experienced MNE, according to the ICCS definition, during
a 3-months observation period without treatment were
randomly assigned to receive oral homotoxicological
remedies (Solidago compositum-OTI; Biopax-OTI),
dDAVP (Minirin-Valeas) or oral matching placebo to
compare the efficacy of homotoxicology vs conventional
medicine and placebo in NE treatment.
Homotoxicological medications consisted of drops (Sol-
idago compositum) and tablets (Biopax). Drops were
composed of Solidago 4CH, Barberis 4CH, Urinary bladder
suis 8CH, Pyelon 4CH, Uretere suis 4CH, Urethra suis
4CH, Terebinthina chios 6CH, Mercurius corrosivus 6CH,
Arsenicum album 30CH, Cuprum sulphuricum 6CH, Buchu
8CH, Hepar sulphur 10CH, Capsicum 6CH, Orthosiphon
6CH, Equisetum hiemale 4CH, Pareira brava 6CH,
Cantharis 8CH, Apisinum 8CH, Baptisia 4CH, Natrum
pyruvicum 10CH, Pyrogenium 200CH, Sarsaparilla 6CH,
Colibacillinum 15CH, Coxsackie virus 8CH, Argentum
nitricum 6CH aa 1 ml, Alcohol 30% q.s. to 50 ml.
Pediatr Nephrol (2008) 23:269–274 271

Tablets were made of Phosphoric acid 4CH, Ignatia – partial responders if there was a 50% or more, but less
amara 4CH, Sepia officinalis 4CH, Psorinum 12CH, than 90%, decrease in the number of wet nights
Kalium bromatum 4CH, Zincum valerianicum 4CH, of compared to baseline
each 10 mg, excipients (lactose and saccharose) q.s. to – full responders if there was a 90% or more decrease in
100 g. Matching placebo consisted of placebo drops and the number of wet nights compared to baseline.
placebo tablets prepared, respectively, with a water–
Another primary outcome measure was the number and
alcohol solution and a lactose–saccharose substrate
percentage of non-responders, partial responders and full
without any active substance. The taste of both drops
responders after the first period of therapy, at the end of
and tablets was neutral.
the wash-out period and after the second period of
Study medications were prepared by the pharmacologi-
therapy.
cal and homotoxicological staff and randomly allocated to
Additional primary outcomes included the number of
coded bottles by a clerk, who held the code until the end of
children failing or relapsing after initial response and the
the study. Randomisation involved the use of computer-
number of children attaining 14 consecutive dry nights
generated random numbers in blocks of four prepared in
during both the first and second treatment periods. A
advance by personnel not involved in the study. All
secondary outcome was the detection of adverse effects due
medications were dispensed by the clerk in sets with the
to the study drugs. The parents were asked to report any
same form. The patients, the investigators and the pharma-
possible adverse event to the investigators, by telephone or
cological and homotoxicological staff were blind to the
during the check-up visits.
randomisation. Data were entered into Excel spreadsheets
by the investigators and was analysed before the conceal-
Statistical analysis
ment code was broken. The clerk was allowed to break the
code in case of adverse events attributed to the study
Based on a recent meta-analysis of 89 homoeopathic clinical
drugs. To achieve the blind, enrolled patients were given
trials [12], a total sample size of 150 was considered both
the following treatment: the first group received dDAVP
adequate and feasible. Data were expressed as mean ±
tablets 0.2 mg, once in the evening, plus placebo drops,
standard deviation. The comparison between number of wet
20 drops three times a day; the second group received
nights in different groups (dDAVP, homotoxicological
homotoxicological tablets, once in the evening, plus
remedies and placebo) was performed by analysis of
homotoxicological drops, 20 drops three times a day; the
variance (ANOVA) and Student’s t-test. When the response
third group received placebo tablets, once in the evening,
to therapy was considered, the alternative conditions of
plus placebo drops, 20 drops three times a day. The
“responder”, “partial responder” and “non-responder” were
treatment was started at different times for each patient,
compared by chi square (χ2) test using Fisher and Yates
and each one was treated for 3 months. The non-
correction when needed. Data were analysed with SPSS
responders to the therapy after the first 3-months period
software (version 10.1) and Statistica for Windows, with
were withdrawn from the study.
P<0.05 considered to indicate significance.

Outcome measures
Results
This was a preliminary study, and no literature data about
homotoxicological treatment in MNE were available, so
Patients
several outcome measures were evaluated to reveal treat-
ment failure after 3 months, 6 months and 9 months.
Of 185 patients who were screened, 151 underwent random
A primary outcome measure was the mean number of
allocation. Reasons for withdrawal in each group are shown
wet nights per week during the 3-months observation
in Fig. 1.
period without treatment (baseline) and after 3 months of
Fifty patients were randomly assigned to receive dDAVP,
therapy. Detailed daily diaries were maintained by the
50 patients to receive homotoxicological remedies and 51
patients and/or their parents throughout the study to make
to receive placebo.
notes on enuretic events.
There were no differences in gender, age or family
The children in the study were consequently classified
history of enuresis between the placebo and the treatment
as: [9]
groups (Table 1). The baseline severity of NE was similar
– non-responders if there was no decrease, or less than a in the three groups.
50% decrease, in the number of wet nights compared to The duration of follow-up was 3 months after the second
baseline period of treatment.
272 Pediatr Nephrol (2008) 23:269–274

The Consort E-Flowchart

185 patients screened

34 Excluded
25 for daytime symptoms
3 for urinary tract infection
1 for urinary tract mal-
151 underwent randomization formation
5 declined to participate

50 assigned to dDAVP 51 assigned to placebo 50 assigned to homotoxicological

remedies

32 entered phase 2 (2 weeks None entered phase 2 (2 weeks 13 entered phase 2 (2 weeks
wash-out) wash-out) wash-out)

18 did not re-enroll for any For no response to the 37 did not re-enroll for any
response to the therapy therapy response to the therapy

Fig. 1 Patients enrolled and followed up

Outcomes
The severity of NE was measured as the mean number of
wet nights per week during the observation period and was
compared among the three groups by ANOVA before and
after the first 3 months of therapy (Table 2).
The mean number of wet nights per week after the 3-
months drug-free observation period was at least six or
seven in all three groups.
The mean number of wet nights per week during
treatment was 2.4±2.8 in the children treated with dDAVP,
4.9±2.7 in those treated with homotoxicological remedies
and 6.4±0.7 in those receiving placebo.

Table 1 Baseline characteristics of the study patients

Table 2 Decrease (%) from baseline in number of wet nights
Characteristic dDAVP Homotoxicological Placebo
remedies Treatment Before After Decrease P
treatment treatment (%)
No. of patients 50 50 51 (wet nights (wet nights
No. of boys (%) 35 (70) 27 (54) 38 (74.5) per week) per week)
No. of girls (%) 15 (30) 23 (46) 13 (25.5)
Mean age in years 8.8 (7–13) 8.4 (6–14) 8.3 (6–13) dDAVP 6.5±0.7 2.4±2.8 62.9 <0.001
(range) Homotoxicological 6.7±0.5 4.9±2.7 30.0 <0.001
No. with family 41 (82) 38 (76) 39 (76.5) remedies
history of enuresis (%) Placebo 6.5±0.6 6.4±0.7 2.4 0.004
Pediatr Nephrol (2008) 23:269–274
After the 3 months of therapy there was a significant
difference between the three groups (P<0.001).
The efficacy variables in this study were decrease in
mean number of wet nights per week and response to
treatment categories.
The daily dose of dDAVP produced a statistically
significant decrease (62.9%) in the number of wet nights
compared to placebo (2.4%) (P<0.001) and compared to
homotoxicological remedies (30.0%) (P<0.001). There was
also a significant decrease in wet nights among the group
treated with homotoxicological medications (30.0%) if
compared with the placebo group (2.4%) (P<0.001).
After the first 3 months of therapy a full response was
achieved in 26 out of 50 (52%) of the children treated with
dDAVP compared with 10 out of 50 (20%) of those treated
with homotoxicological medications (P<0.001) and com-
pared with 0 out of 50 (0%) of the placebo group (P<0.001).
The full response achieved with homotoxicological
remedies (20%) was superior if compared with placebo
(0%) (P<0.001).
After an initial success with the first 3 months of therapy,
the number of children that relapsed was: 12 out of 26 full
responders (46%) and 6 out of 6 partial responders (100%)
in the group treated with dDAVP; 4 out of 10 full
responders (40%) and 3 out of 3 (100%) partial responders
in the group treated with homotoxicological remedies.
There was no statistically significant difference in the
percentage of relapse of the full and partial responders after
the wash-out period between the group treated with dDAVP
(46%) and the group treated with homotoxicological
medications (40%). All the partial responders (100%) of
each group, however, relapsed in the wash-out period.
After the second period of therapy there was no
significant difference between the dDAVP group and the
homotoxicology group in the percentages of full and partial
responders (Table 3).
The number of children attaining 14 consecutive dry nights
during treatment was 26 out of 50 of the children treated
with dDAVP, 10 out of 50 of those treated with homotoxico-
logical remedies and 0 out of 50 of the placebo group. The
Table 3 Treatment and wash-
out phases Treatments
dDAVP
Homotoxicological remedies
Placebo
dDAVP
Homotoxicological remedies
Placebo
273
difference was statistically significant for the dDAVP group
compared with the homotoxicology group (P<0.001) and
the placebo group (P<0.001). Homotoxicology was supe-
rior to placebo with regard to this outcome (P<0.001).
No adverse effects were reported in the 151 children
enrolled in the study.
Discussion
We evaluated a new approach to therapy, using homotox-
icological remedies, on the basis of the hypothesis that NE
is a complex and heterogeneous disorder. In fact, various
aetiological mechanisms of NE have been proposed in
recent years, and, consequently, various types of interven-
tions have been used. Pharmacological, behavioural and
“unconventional” interventions are commonly used for
people who wet the bed [15]. The popularity of alternative
and unconventional medicine is increasing worldwide.
Many surveys have estimated that between 30% and 70%
of patients in developed countries use these practices,
depending on the population and modality [16, 17].
Although homoeopathic treatments have been commonly
used for many decades, their efficacy is still controversial. No
scientific explanation for the mechanism of action of
homoeopathy is universally accepted, despite wide and often
controversial debate [18, 19]. To our knowledge, no random-
ized controlled trials have examined the effects of the use of
homotoxicological medications on children with NE.
The objective of this trial was to estimate the efficacy of
homotoxicological remedies when compared with placebo
and dDAVP in children with MNE. Our study revealed a
statistically significant trend for decreased numbers of wet
nights with the homotoxicological formulation, which was
superior to placebo. Homotoxicology was also superior to
placebo if we considered the number of children attaining
14 consecutive dry nights during treatment. These data
suggest that homotoxicological remedies are effective in the
short-term treatment for MNE, when compared with
placebo. The mechanism of action of our homotoxicolog-
Number Third months of therapy
Patients Full responders Partial responders Non-responders
50 26 (52%) 6 (12%) 18 (36%)
50 10 (20%) 3 (6%) 37 (74%)
51 0 0 51 (100%)
Relapse in wash out period (2 weeks)
Full responders Partial responders
32 12/26 (46%) 6/6 (100%)
13 4/10 (40%) 3/3 (100%)
0 0 0
274
ical medications remains unknown. It is unclear whether
only one of its components is biologically active or whether
the effects are due to the action of several components.
In homotoxicology, homoeopathically manufactured com-
bination products are designed to work with the body’s
defence mechanisms and facilitate the body’s elimination of
toxic substances. When used in combination formulations that
contain measurable amounts of homoeopathically prepared
active ingredients, they can be utilised by physicians to treat
specific indications. Moreover, while most homoeopathic
remedies are diluted to the point where pharmacological
actions are unlikely or impossible, homotoxicological reme-
dies could still be associated with pharmacological effects.
dDAVP was effective in reducing bed wetting during
treatment, compared with placebo and compared with
homotoxicology. However, there was no difference between
the two patient groups (dDAVP and homotoxicology) in the
percentage of relapses after the wash-out period and in the
second 3 months of therapy, probably due to the small
number of patients.
In our study the effect of dDAVP was immediate and
stable, but, interestingly, 36% of the patients did not
respond to the therapy, and, at the end of the first 3 months
of treatment, the relapse rate was high (46%). Recent data
have shown that the non-responders to dDAVP do not have
nocturnal polyuria, which is often present in the full and
partial responders. Furthermore, non-responders have been
shown to have a smaller functional bladder capacity than
other enuretic children [8].
The average cost/patient for 3 months of treatment was
€177,00 for dDAVP and €96 for the homotoxicological
remedies.
Our study may be useful to determine a new intervention
in order to guide choice of treatment in enuretic patients.
The use of homotoxicology could be considered a good and
safe treatment for NE, as there is an increasing demand for
alternative treatments in child healthcare, many parents are
afraid of the side effects of drugs, and NE is a common
disorder with a spontaneous cure [3]. Using homotoxico-
logical medications instead of the homoeopathic ones, we
used the same approach to treat the same clinical disorder,
which is essential to improve confidence and general-
isability of the findings. This study, however, has a
limitation due to a small sample size.
Our study demonstrates that homotoxicology is safe and
effective when compared to placebo, even if it is signifi-
cantly less effective than dDAVP in this clinical condition.
This study also contributed to several issues for further
research, such as the evaluation of the efficacy and safety of
long-term treatment with homotoxicological medications or
the evaluation of the effects on long-term efficacy if the
dosage is escalated. These issues will be elucidated in a
follow-up, long-term study.
Pediatr Nephrol (2008) 23:269–274
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