Immunology and Homeopathy. 4. Clinical Studies—Part 2

Oxford Journals Medicine Evidence-based Compl. and Alt. Medicine
Volume 3, Number 4 Pp. 397-409
eCAM Advance Access originally published online on July 31, 2006
eCAM 2006 3(4):397-409; doi:10.1093/ecam/nel046
This Article

© 2006 The Author(s).
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Immunology and Homeopathy. 4. Clinical Studies—Part 2

Paolo Bellavite1, Riccardo Ortolani2, Francesco Pontarollo1, Valeria
Piasere1, Giovanni Benato2 and Anita Conforti3
1 Department of Scienze Morfologico-Biomediche Piazza L.A. Scuro,
37134 Verona, Italy, 2 Association for Integrative Medicine ‘Giovanni
Scolaro’ Piazza L.A. Scuro, 37134 Verona, Italy, and 3 Department of
Medicina e Sanità Pubblica, University of Verona Piazza L.A. Scuro,
37134 Verona, Italy

   Abstract

The clinical studies on the effectiveness of homeopathy in respiratory
allergy (18 randomized trials and 9 observational studies) are
described. The literature of common immunologic disorders including
also upper respiratory tract infections (URTI) and otorhinolaryngology
(reported in part 1), is evaluated and discussed. Most of initial
evidence-based research was addressed to the question of whether
homeopathic high dilutions are placebos or possess specific effects,
but this question has been often equivocal and is still a matter of
debate. The evidence demonstrates that in some conditions homeopathy
shows significant promise, e.g. Galphimia glauca (low dilutions/
potencies) in allergic oculorhinitis, classical individualized
homeopathy in otitis and possibly in asthma and allergic complaints,
and a few low-potency homeopathic complexes in sinusitis and
rhinoconjunctivitis. A general weakness of evidence derives from lack
of independent confirmation of reported trials and from presence of
conflicting results, as in case of homeopathic immunotherapy and of
classical homeopathy for URTI. The suitable methods to evaluate
homeopathy effectiveness, without altering the setting of cure, are
also analyzed.

Keywords: allergy – asthma – evidence-based homeopathy – homeopathic
immunotherapy – homeopathic medications – homeopathy – immunology –
isopathy – rhinoconjunctivitis

   Introduction

In the first part of this review (1) the evidence-based research on
homeopathy in common upper respiratory tract infections (URTI) or in
otorhinolaryngologic complaints has been described. We shall here
describe studies performed in the field of allergology and, more
specifically, in oculorhinitis (hayfever) and allergic asthma. The
methods of analysis and the criteria of classification are the same as
described in the first part of the review.

Finally, the global body of evidence regarding the effectiveness of
the different therapeutic approaches, in the conditions considered in
this review, is presented in the Discussion. Here, the classification
of the therapeutic approaches is made according to a grade of evidence
in six levels, which was developed by Natural Standard, an
international research collaboration that aggregates and synthesizes
data on complementary and alternative therapies (http://
www.naturalstandard.com/index.asp). A summary of these criteria is
reported in Table 1.

  Table 1 Synthesis of the levels of evidence of therapeutic efficacy

   Allergic Conditions

Allergies are the most common immunological diseases among general
population, and increasing evidence suggests that incidence of
allergic disorders is rising dramatically. The results of several
studies indicated that patients before seeking homeopathic care for
their allergic symptoms were unsatisfied within conventional health
care system and that their choice was mostly motivated by assumption
of few side-effects or by a wish to ‘try everything’ (2–7).
Approximately 50% of asthma patients in the UK have used some form of
complementary therapy for their asthma at some stage, and most of
these patients have indicated that they derived at least some benefit
(8).
Several studies using homeopathy have reported beneficial effects from
treating allergy-related conditions, other studies have not found
benefits over placebo. A summary of these papers in chronological
order is given in Table 2, here in the text they will be grouped
according to different modalities of therapy that have been
investigated.

  Table 2 Homeopathic clinical studies of allergy and asthma

Classic Individualized Homeopathy
According to this approach each patient received his/her single
medicine (‘simillimum’). In many reports using classic individualized
prescription, there is an indication of most frequently used
medicines.

In starting this brief analysis of results obtained in allergology, we
cite a retrospective study, reported at a homeopathic conference (13),
which included children treated with individualized homeopathy. The
results appeared to be encouraging, since 44.2% of patients had a
‘satisfactory reaction’, 36.7% a ‘manifest improvement’, 18.3% a
‘relative improvement’ and 0.8% showing ‘no reaction’. The remedies
prescribed most frequently were Lycopodium clavatum, sulphur,
Pulsatilla and Silicea.

Castellsagu (16), retrospectively evaluated a series of children who
had suffered from allergic bronchial asthma, and who were treated with
a single drug in accordance with classical homeopathic method. Twenty-
two different drugs were prescribed (the most used were sulphur,
Calcarea carbonica, Lycopodium and Pulsatilla), at different
potencies. After 3 years of treatment, the results showed a complete
cure in 58% of cases, improvements in 23% and failures in 19%. In
brief, the results obtained in such a serious chronic disease are
encouraging, but the open and uncontrolled nature of the trial makes
it impossible to draw definite conclusions.

A further retrospective study evaluated patients suffering from
bronchial asthma (both children and adults) and under individualized
homeopathic treatment for more than 3 years (22). A statistically
significant decrease in frequency and severity of attacks before and
after treatment was reported. There was also a marked decrease in the
use of conventional medication. The most frequently prescribed
remedies were Arsenicum album, Nux vomica, sulphur, Pulsatilla and
Silica.

A communication in a conference of International Homeopathic Liga
reported a trial on the effectiveness of classical individualized
treatment of asthmatic people who were allergic to dermatophagoides
(23). Symptoms and immunologic parameters were evaluated before and
after an 8 months treatment. Significant decrease in number of
exacerbations, of spirometric tests and immunologic markers was
observed in active homeopathic group. A full report would permit a
detailed evaluation of the trial.

A trial on individualized homeopathic therapy in asthma was published
in a Mexican homeopathic journal (25). The study was double blind and
controlled with placebo but the randomization was not specified. The
main result was a reduction of asthma attacks after 4 months of
therapy, with a significant difference in favor of homeopathy.

A pharmacoeconomic study (not reported in Table 2 because it does not
concern effectiveness) assessed the homeopathic treatment in allergic
diseases in a health maintenance organization (4). The computerized
medication charts of each patient were evaluated for conventional
medication consumption 3 months before and 3 months after homeopathic
intervention, with each patient serving as his or her own control. The
results showed that 56% of patients reduced their use of conventional
medication following homeopathic intervention. The most significant
reduction was in anti-histamine use, followed by decreases in
bronchodilator use and steroids, with an average saving of $24 per
patient in the 3 month period following homeopathic intervention.

Negative Trial, Questionable Method

The effects of individualized homeopathic remedies as an adjunct to
conventional treatment were compared with placebo medication in
children with mild to moderate asthma (33). There were no clinically
relevant or statistically significant changes in active quality-of-
life score. Scores of severity of symptoms indicated relative
improvements but the sizes of effects were small. The authors
concluded that adjunctive homeopathic remedies are not superior to
placebo in improving the quality of life of children with mild to
moderate asthma. This is a study that raised high media coverage as a
proof of inefficacy of homeopathy, but various authors have raised
doubts that the parameters used were sensitive enough to differentiate
between children who have no asthma and those who have only mild
asthma (38–40). In fact, included patients had very mild or lacking
symptoms, which hardly could be ameliorated. Therefore, this study
should be interpreted with caution.

Effectiveness in ‘Real World’

An observational study where outcome and costs of homeopathic therapy
were compared with those of conventional treatment in routine care has
been published (36). Since all children included in this study were
affected by allergic diseases (homeopathic therapy: 54 atopic
dermatitis, 20 allergic rhinitis, 17 asthma; conventional therapy: 64
atopic dermatitis, 11 allergic rhinitis, 12 asthma), the results of
this subset of patients may be of interest for this review. Allergic
children were treated either with classic homeopathic approach or with
conventional therapies provided by doctors selected from an address
list of general practitioners. The two groups were not randomized but
their disease grade at baseline was similar. After 12 months of cure,
symptom severity scores decreased more significantly in homeopathic
group than in conventional group. There was also a trend to a better
improvement of quality of life in the homeopathic group, but not
statistically significant after diagnosis-specific adjustment.

A series of cases of respiratory allergy treated with individualized
and constitutional homeopathy in a private homeopathic practice was
recently reported (37). The author estimated an overall success rate
of 87.6% for homeopathic treatment in these conditions. Only two cases
of ear, nose and throat allergies out of a total of 105 showed no
improvement, no patients deteriorated. Two cases with worsening and
three without improvement were noted out of 42 cases of pulmonary
allergies.

Homeopathic Immunotherapy

One of the most extensive lines of research in homeopathy was the
attempt to utilize high dilutions of substances, known to cause
allergy, to prevent or cure the same allergies. This is an application
of the ancient isopathic principle (41) that has been also termed
‘homeopathic immunotherapy (HIT)’ (11,14,42). The chosen model, use of
pollen in hay fever, actually comes from the work of a homeopath—Dr
Charles Blackley—who, in the 1870s, first identified pollen as the
cause of respiratory seasonal allergies (42).

To start the description of these results, it is worth citing a first
report in a non-indexed journal by Hardy in 1984 (9). The authors
showed a relief of oculorhinitis symptoms in patients allergic to
house dust by homeopathic potencies of house dust. The same approach
characterized long-lasting and deep investigations by a group led by
D. Reilly. A double-blind study, published as preliminary report in
1985 (43) and as a full paper in 1986 (11), compared the effects of
placebo and of a 30c homeopathic preparation designed as Pollen
because it contained a mixture of 12 pollens. The results were
positive insofar as patients receiving the homeopathic treatment had
significantly fewer symptoms and used half of anti-histamine rescue
treatment than controls.

The same group published the results of a study on patients with
severe atopic asthma requiring daily administrations of
bronchodilators, most of whom were being treated with steroids (14).
Patients received a placebo for 4 weeks and were then randomly divided
into two groups, one of which continued the placebo, whereas the other
was treated with a 30c homeopathic preparation of the main allergen to
which each patient was sensitive. The patients revealed a
statistically significant difference in favor of the active treatment.
These studies, enriched by further statistical analyses and a meta-
analysis of all of patients, were published in 1994 (15) and showed an
extremely high probability (P = 0.0004) that the homeopathic effect
was not due to a placebo effect. The time-course of symptoms
improvement of this trial series is reported in Fig. 1. A clear
difference can be seen between HIT and placebo, but the effect may be
considered quite small for therapeutic purposes.

   Figure 1 Effect of homoeopathic immunotherapy (HIT) on visual
analogue scale (VAS) scores averaged over four trials. On average,
there was a mean reduction of the visual analogue scale score of 10.9
mm in the homoeopathy group compared with 1.1 mm in the placebo group
(P < 0.001). Reproduced with permission from Taylor et al, reference
28.

A trial of the homeopathic medication Lung histamine 5c used
prophylactically in children with asthma also reported promising
results in reducing the frequency of attacks (44), but the design of
study did not allow persuasive evidence (42). An uncontrolled study
conducted in Belgium observed the effect of Pollen 30c (prepared from
a mixture of 12 grass pollens) combined with Apis mellifica 15c and
Lung histamine 15c, in allergic oculorhinitis (17). The regimen was
one tablet per day and progress was monitored for 6 months by
registering nasal and ocular symptoms as well as by doctor's
assessment. From 69 to 86% of patients—according to the parameter
evaluated—showed clinical improvements.
Further Multicenter Studies

Reilly's group has subsequently organized a multicenter study on
patients affected by allergic rhinitis (28). The study involved
administration of a 30c potency of the main allergen or (in control
group) an indistinguishable placebo. The results demonstrated a
significant improvement in nasal air flow in treated patients in
comparison with those receiving placebo (P = 0.0001). Subjective
symptoms improved but not in a statistically significant manner. It is
interesting to note that the group treated with homeopathic
preparations of allergen more frequently reported an initial
worsening, that is well known in homeopathy. This study offered
further proof that high homeopathic dilutions cannot be assimilated to
a simple placebo. However, as underlined by the authors themselves,
this does not mean that their proposed HIT is an efficacious
homeopathic therapy for chronic rhinitis (also because classic
homeopathy requires individualized treatment).

Unsuccessful Replications

A study of HIT, with essentially negative results, was published in
2002 by an independent group led by G. Lewith (32). Patients with
asthma and positive skin prick tests for house dust mite entered the
trial. After a 4 week baseline assessment, participants were
randomized to receive oral HIT, made with their specific allergen, or
placebo, and then assessed over 16 weeks by means of three visits and
diary assessments every other week. There was no difference in most
final outcomes between placebo and HIT, but there was a different
pattern of change during the trial in diary assessments concerning
morning peak expiratory flow, visual analogue scale and mood. In
brief, the homeopathic medicine caused a slight but statistically
significant worsening during the early phases of treatment than
placebo, while at the end of experimental period the effectiveness of
HIT was not significantly different from placebo. This study sparked a
considerable discussion in the same Journal (45). In a subsequent
paper, some of the authors of the past negative trial of HIT have
discussed their data of the same trial using complexity theory (46).
This is an evidence for a different oscillation in outcome (both
physiological and subjective) of verum treatment with respect to
placebo (see Fig. 2). The authors suggest that such time dynamics are
consistent with a complexity theory interpretation of how the body
functions as a whole and speculate that these oscillatory phenomena
require a different trial methodology from that currently employed.

   Figure 2 Oscillatory effects in a homeopathic clinical trial.
Although the study failed to show a clinical improvement at the end of
the trial period, there was nevertheless a significant difference
between active treatment compared to placebo: the pattern of data
indicate that verum, compared to placebo, approximates to an
oscillation. PEF, peak of expiratory flow; VAS, visual analogue scale.
Reproduced with permission from Hyland and Lewith, reference 46.

A series of double-blind, randomized, placebo-controlled trials on
preventive and therapeutic effectiveness of pollen of Betula (HIT)
were conducted by a Norwegian group. In the first study (29), the
effect of the homeopathic remedy Betula 30c versus placebo for adult
patients with birch pollen allergy was tested. No statistically
significant difference between groups was found, except for a brief
period when those receiving verum having fewer and less serious
symptoms. For some days these differences were statistically
significant. Surprisingly, the verum group also reported some
aggravation after medication, more than did placebo group, a result in
agreement with that of previously mentioned trials (28,32). The second
study (30) involved children and gave uncertain results, according to
the authors possibly because the pollen count was very low during
treatment period and only 3 days were high enough to provoke allergic
symptoms. This time the verum-treated patients fared worse than
placebo group; they used more rescue medication and had higher symptom
scores during these 3 days. The authors suggested that the findings
may document a putative ‘aggravation response’, but certainly do not
support the usefulness of the tested homeopathic prophylaxis for this
condition. The third paper (31) with similar protocol with addition of
a crossover of treatments showed a consistent response in both verum
and placebo groups, with no consistent clinical advantage of HIT.
Other authors communicated, in a letter (34), to have obtained
negative findings in an open study in which they assessed the effects
of HIT in children with stable asthma. This could be because of the
small sample size (n = 12) or because the lack of efficacy of remedy.

New Positive Findings

A recent double-blind trial showed significantly positive effects of
HIT of seasonal allergic rhinitis (35). The drug was prepared from
common allergens (tree, grass, weed species) specific to Southwest
region of US, which was compared with placebo. Study outcomes included
allergy-specific symptoms using the rhinoconjunctivitis quality-of-
life questionnaires. The subjects reported no adverse effects during
the 4 weeks intervention period.

Fixed Prescription of Low-Potencies

The treatment of allergic patients using low potencies (4x or 6x)
extract from the plant G. glauca has been investigated for many years
by Wiesenauer's group (10,18,47). In a double-blind, randomized study
of patients with seasonal allergic rhinitis, Wiesenauer and Gaus (10)
used G. glauca 6x without individual homeopathic prescriptions. After
1 month of treatment, an improvement in eye symptoms was observed in
80% of patients in the homeopathic group, in 65% of patients in the
placebo group and in 66% of patients in the group receiving the
dilution alone, without dynamization. The data were promising but
there was not clear cut statistical difference.

Two years later, Wiesenauer and Ludtke (12) published the results of
another double-blind, randomized, placebo-controlled study of the
effects of G. glauca in allergic rhinitis. After 1 month of treatment,
there were clear improvements in the experimental group in terms of
eye symptoms and nasal symptoms. As in the 1985 study, the authors
confirmed the efficacy of Galphimia in seasonal allergic rhinitis, and
suggested that it should be used only after homeopathic identification
of sensitive individuals in order to minimize the number of non-
responders. Wiesenauer subsequently continued the experiments and his
group has published a number of papers concerning the efficacy of G.
glauca, the most effective potency being the 4x (18,48,49).

Complex Formulations

A group of investigators tested the effectiveness of two homeopathic
complexes in bronchial asthma. In the first clinical trial the complex
Engystol-N (tablets) was studied (19–21). Patients were randomly
assigned to verum or placebo groups, under blind conditions. During
observation period, those treated with homeopathic complex showed
greater improvement of respiratory function. In another paper (26),
they described a double-blind, randomized, placebo-controlled study of
patients with allergic bronchial asthma already being treated with
steroids, bronchodilators and other drugs. One vial of complex Asthma
H Inj. Plfugerplex (a mixture of low dilutions of many homeopathic
plants and minerals) was administered subcutaneously every week for 9
months. The administration of Triamcinolone decreased in treated group
and increased in placebo group. The treated group also showed a
significant reduction in contracted infections and in cationic protein
levels, a marker of local inflammation. There was no change in
spirometric parameters (FEV and FVC), possibly because patients were
advised to take the lowest cortisone dose compatible with the absence
of cough and resting dyspnea.

Micciché et al. (24) carried out an open study of children with
allergic oculorhinitis comparing conventional anti-histaminic and
cortisone treatment with a homeopathic protocol based on three drugs
(Dolisosbios No. 15, an organotherapeutic, Mn-Cu Oligodrop and
Histaminum 4c) initiated after the start of pollen season in order to
evaluate their acute phase efficacy. After 2 months of treatment, 30
out of 35 children in homeopathic group were cured, 2 received only a
slight benefit and 3 were switched to conventional treatment because
of relapses. In conventional treatment group, 21 out of 35 children
were cured, 7 showed a slight improvement and 7 had to discontinue
treatment because of toxic effects. As in other reports from
‘equivalence’ studies, the effectiveness of homeopathy is clearly
demonstrated when it is compared with conventional therapies. However,
the validity of results is limited by the fact that this was not a
randomized study.

Weiser et al. (27) have reported a study of seasonal allergic
rhinitis, using a complex product (Luffa compositum) in nasal spray
formulation. The homeopathic remedy consisted of a fixed combination
made up of Luffa operculata and G. glauca (in 4x, 12x, 30x potencies),
plus histamine and sulfur (in 12x, 30x, 200x potencies). There was a
reference group of patients without homeopathic therapy who were
treated only with standard intranasal therapy based on chromolyn
sodium. The results of the study demonstrate a quick and lasting
effect of the treatment, which produced a nearly complete remission of
hay fever symptoms. Adverse systemic effects did not occur. Local
adverse events appeared in 3 patients among a total of 146. In
conclusion, the authors suggested that, for the treatment of hay
fever, the homeopathic nasal spray is as efficient and well tolerable
as conventional therapy with chromolyn sodium.

Systematic Reviews of Allergy and Asthma

A meta-analysis of seven randomized clinical trials (RCT) to assess
the efficacy of homeopathic preparations of G. glauca in treatment of
allergic rhinitis was published by Ludtke and Wiesenauer (50). The
data are consistently in favor of a statistically significant effect
of the low-dose homeopathic medicine over placebo, particularly in
relief of eye symptoms. Verum estimate of success is reported of 80%.
The validity of these experimental studies was confirmed also by
independent meta-analyses (51,52).

The review of Kleijnen et al. (53) and the meta-analysis of Reilly of
his own studies (28) suggested that HIT was effective in the treatment
of rhinitis. There have been a few reviews of randomized, controlled
trials published regarding the use of homeopathy for asthma treatment.
Six trials were included in a recent review (54,55). These trials were
of variable quality and the results of the studies are conflicting in
terms of effects on lung function. The authors underlined that
standardized treatments in these trials are unlikely to represent
common homeopathic practice where treatment tends to be
individualized. More and larger trials are therefore urgently needed
to assess properly the role of homeopathy in management of asthma, but
experts (51,56,57) suggested that as well as randomized trials, there
is a need for observational data to document the different methods of
homeopathic prescribing and how patients respond. Further studies
could assess whether individuals respond to a ‘package of care’ (i.e.
the effects of medication as well as consultation, which is considered
a vital part of individualized homeopathic practice) rather than the
homeopathic medicine against placebo alone.

   Discussion

While complementary medicine and homeopathy are becoming an
increasingly prominent part of health care practices, there is paucity
of controlled studies concerning their effectiveness. Traditional
knowledge has been accumulating for over 200 years, but only in past
few decades modern research methods such as RCT, rigorous
observational studies and equivalence studies comparing homeopathy
with conventional standard therapies have been applied.

Few well-designed studies have been reproduced by independent research
teams for two main reasons: lack of sufficient funding and lack of a
sufficient number of well-trained homeopaths who are qualified and
interested in research. As a matter of fact, the debate on efficacy of
homeopathy is still very hot, as shown by a series of reviews
(51,52,58,59) and chiefly by the controversial meta-analysis published
by the Lancet (60,61) and by the significant expert reactions to the
latter (62–64).

Even though the number of papers published in peer-reviewed journals
is increasing, the results of many clinical studies on effectiveness
of homeopathy are characterized by low standards of methodology
(52,53,65). The major problems in most trials were the description of
allocation concealment, imprecise outcomes and the reporting of drop-
outs and withdrawals. Other concerns are publication bias (tendency to
publish more positive than negative trials, a problem that is also
present in conventional medicine) and lack of independent replications
of most conducted studies.

This review summarizes the trial data for or against homeopathy as a
treatment for a series of diseases due to disorders of immune system
and/or dysregulation of local inflammatory processes. We are confident
that the reported studies represent a large majority of available
literature in this field, although some omission cannot be excluded.
Clearly, the few dozens of papers reported are highly heterogeneous in
terms of disease conditions, drug used and experimental designs.

There was great heterogeneity in the nature of the homeopathic
intervention applied: mostly fixed combinations or complexes, several
individualized homeopathy with single remedies, some isotherapy
studies in allergy. In Table 3 the studies concerning the disorders of
immune system considered in this review are grouped according to
clinical condition and type of homeopathic treatment; the clinical
evidence of the major groups of treatments was classified according to
criteria that have been reported in Table 1.

  Table 3 Summary of the levels of evidence of clinical homeopathic
studies in immunoallergology

The best evidences of effectiveness appearing in the top two rows of
Table 3 and are G. glauca (low potencies) in allergic oculorhinitis,
classical individualized homeopathy for otitis, Euphorbium compositum
for rhinitis–sinusitis, Traumeel in post-chemotherapy stomatitis. The
use of homeopathy in those conditions is indirectly supported also by
evidence in basic science, animal studies or theory [(89,90) and P.
Bellavite, R. Ortolani, F. Pontarollo, G. Pitari, A. Conforti,
unpublished data]. In grade C (unclear or conflicting evidence) there
are many studies, because positive results reported by some authors
were not replicated by others. The classical individualized therapy of
allergy and asthma was shown to be effective in a number of studies
and not effective only in one trial, but several positive trials were
of lower quality and published in non-indexed journals; so, as a
caution, we considered the scientific evidence as still unclear
according to the criteria of Table 1. The number of homogeneous trials
is too small to attempt pooling and meta-analysis.
In synthesis, there are many promising studies supporting clinically
demonstrable activity of homeopathic medicines in immunoallergology
but the database of high-quality homeopathic research in various
fields is very small. Most studies here reviewed suggest that
homeopathic medicines in high dilutions, prescribed by trained
professionals, are safe and are unlikely to provoke severe adverse
reactions, in agreement with previous reports (91–93).

Placebo and Effectiveness, Different Questions

Clinical research on homeopathy has been initially focusing on the
question of placebo. The first relevant RCT published by top medical
journals came out in 1986 with the title ‘Is homeopathy a placebo
response?’(11) and 20 years later a meta-analysis published in this
field meaningfully had the title ‘Are the clinical effects of
homeopathy placebo effects?’ (61) (Fig. 3). This clearly indicates
that we still do not have a consensus, but possibly also because the
question is not correct, and this is the case for those medicines that
contain low dilutions, i.e. ponderal doses, of active principles. The
latter medicines by definition cannot be considered as inert placebos,
but the distinction was ignored by the famed Lancet's meta-analysis
(61) and its related editorial (60).

   Figure 3 Titles of Lancet's two publications on homeopathic
trials. Reproduced with permission from Lancet 1986;2:881–6 (A) and
from Lancet 2005;366:726–32 (B).

On evaluating the evidence in favor and against clinical effectiveness
of a therapy, it should be pointed out that the placebo question is
exceedingly important but is not equivalent to the question of whether
a therapeutic approach is clinically effective. The evidence of
specific activity of a drug over placebo is usually achieved in double-
blind RCT. Epidemiologists agree that this ‘artificial’ setting may
have high internal validity but often fails to reproduce the ‘real
life’ application of the method. Patients and physicians need also an
answer to the empirical question of whether and how much the
homeopathic therapy, considered as a whole system of cure, may help to
decrease symptoms, improve quality of life and may substitute other,
often more toxic, forms of therapy. More pragmatic studies aimed at
‘improving’ instead of ‘proving’ homeopathy have been suggested
(45,51,94).
To Blind or Not to Blind

The blinding procedure that is often related to the problem is
utilized in clinical research. This procedure has been so widely
employed in evidence-based research on conventional drugs that there
is the tendency to consider it as the gold standard for any clinical
research. However, randomized trials have important limitations in
interventions that require particular skills (95) and finding the
correct homeopathic simillimum depends on in-depth anamnesis and
atmosphere of trust, which is disrupted by randomization (96). In
homeopathy, the parameters of evaluation follow specific rules that
imply consideration of the totality of a patient's symptoms which
includes the disease's symptoms and a continuous follow-up that often
requires careful evaluation of response by the clinician, and often
change of medicine, particularly in chronic cases. To successfully
discriminate between complex responses to a homeopathic treatment it
is important to know the characteristics of the substance given to the
patient and the healing steps of this modality.

We consider the great importance that is given by classic homeopathy
to the interactions such as those between patient–doctor–medicine and
environment–body–mind (97,98). It has been suggested that, according
to the theory of ‘entanglement’ (99–102), the remedy would act in the
context of a tripartite relationship with the patient and the
practitioner. What may be the physical basis of such an entanglement
is still a matter of speculation, but this point forces us to take
into account the ‘context’ of cure (e.g. patient–physician
interactions) and therefore to seriously question the double blinding
for testing homeopathy: this method by definition would disrupt those
interactions (103).

According to these premises, one can assume that in homeopathic cure a
complex interaction of these mechanisms occurs: (i) a small physical
action of extremely low-dose remedy, (ii) the activation of centers
responding to ‘placebo effect’ due to beliefs, expectations of the
patient and (iii) the endogenous healing mechanisms (99,100,104–108).
If this is the case, the therapeutic effect is due not to the sum of
these factors but to their product and any procedure decreasing or
shuting down one of them (as blinding undoubtedly does) may markedly
affect homeopathic cure, much more than allopathic drug effect. As a
consequence of the interference with everyday routine homeopathic
practice, more false negative findings are expected in homeopathic
double-blind studies than in allopathic ones (109).

Observational Research

Observational research of uncontrolled homeopathic practice documents
consistently strong therapeutic effects and sustained satisfaction in
patients (59). An observational study showed that over 70% of patients
attending a homeopathic hospital out-patient unit recorded positive
changes in a wide range of chronic diseases (110). Superimposable to
this finding is the report showing that 7 out of 10 patients visiting
a Norwegian homeopath reported a meaningful improvement in their main
complaint 6 months after the initial consultation (111). Similar or
even higher percentages of patients declaring their satisfaction with
homeopathic cure were reported by others (112–116). Interestingly, a
study was undertaken to investigate the preferences of patients with
asthma for various treatment modalities showed that the extent to
which the doctor treated the patient as a whole person was also a
statistically significant attribute for the choice of homeopathic
therapy versus conventional therapy, even if clinical results are
perceived as equivalent (8).

So, we are in the situation that if we adopt the strict criteria of
evidence-based medicine, which were initially developed for chemical
drugs, the analysis of published literature on homeopathy finds little
evidence of superiority of homeopathic medicines over placebo. If we
accept observational studies and equivalence studies as valuable tools
of investigation, we find many proofs of effectiveness of homeopathy.
In any case this is valuable information from a pragmatic standpoint
because it enables the decision based on other factors like patient's
personal preference, adverse effects, availability and costs. The
integration of RCT, observational prospective studies and
pharmacoeconomic analyses are the future of research in this field.

Conclusions and Prospects

In summary, there is an efficacy/effectiveness paradox (similar to
that found in several other areas of complementary medicine research)
with a weak evidence in favor of homeopathy when studies are done in
randomized and double-blind conditions, but yet there is documented
effectiveness in equivalence studies comparing homeopathy and
conventional medicine and documented usefulness in general practice
(59): the therapy is useful when applied in open practice and produces
substantial effects, even in patients with chronic diseases (117,118).
This paradox leads to two conclusions: (i) additional clinical
research, both experimental and observational, including studies using
different designs, is necessary for further research development in
homeopathy and (ii) it is conceivable that the discrepancies are due
to lack of a consistent theory concerning the action mechanism of
homeopathy (59), so that additional basic research and innovative
approaches to this problem are urgently warranted.

Nevertheless, the growing public interest in homeopathy (probably due
more to a ‘liking’ for this therapeutic system as a whole and the use
of small doses rather than to any scientific certainty concerning its
effectiveness) allows us to hope that also this section of medicine
will also receive greater attention from the competent authorities and
the scientific world. Rigorous clinical studies examining
effectiveness of homeopathy like other complementary and alternative
medicines are needed (119). It will be necessary to adapt research
methodologies to the homeopathic field in order to respect the
complexity of its diagnostic procedure, but it is equally necessary to
ensure that protocols include objective measurements of clinical and
laboratory parameters, as well as adequate control groups of untreated
subjects or subjects treated with conventional therapies.

  Footnotes

For reprints and all correspondence: Paolo Bellavite, University of
Verona, 37134 Verona, Italy. Tel: +39-045-8202978; Fax:
+39-045-8202978; E-mail: paolo.bellavite@univr.it

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Received March 6, 2006; accepted June 9, 2006

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P. Bellavite, R. Ortolani, F. Pontarollo, G. Pitari, and A. Conforti
Immunology and Homeopathy. 5. The Rationale of the 'Simile'
Evid. Based Complement. Altern. Med., June 1, 2007; 4(2): 149 - 163.

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