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Randomised controlled tr ial of homoeopathy versus
placebo in perennial allerg ic rhinitis with overview of
four tr ial series
Morag A Taylor, David Reilly, Robert H Llewellyn-Jones, Charles McSharry, Tom C Aitchison
Abstract
Objective To test the hypothesis that homoeopathy is
a placebo by examining its effect in patients with
allergic rhinitis and so contest the evidence from
three previous trials in this series.
Design Randomised, double blind, placebo
controlled, parallel group, multicentre study.
Setting Four general practices and a hospital
ear, nose, and throat outpatient department.
Participants 51 patients with perennial allergic
rhinitis.
Intervention Random assignment to an oral 30c
homoeopathic preparation of principal inhalant
allergen or to placebo.
Main outcome measures Changes from baseline in
nasal inspiratory peak flow and symptom visual
analogue scale score over third and fourth weeks after
randomisation.
Results Fifty patients completed the study. The
homoeopathy group had a significant objective
improvement in nasal airflow compared with the
placebo group (mean difference 19.8 l/min, 95%
confidence interval 10.4 to 29.1, P = 0.0001). Both
groups reported improvement in symptoms, with
patients taking homoeopathy reporting more
improvement in all but one of the centres, which had
more patients with aggravations. On average no
significant difference between the groups was seen on
visual analogue scale scores. Initial aggravations of
rhinitis symptoms were more common with
homoeopathy than placebo (7 (30%) v 2 (7%),
P = 0.04). Addition of these results to those of three
previous trials (n = 253) showed a mean symptom
reduction on visual analogue scores of 28% (10.9 mm)
for homoeopathy compared with 3% (1.1 mm) for
placebo (95% confidence interval 4.2 to 15.4,
P = 0.0007).
Conclusion The objective results reinforce earlier
evidence that homoeopathic dilutions differ from
placebo.
Introduction
Do homoeopathic serial dilutions, containing no mol-
ecules of the original substance from which they were
prepared, show intrinsic therapeutic effect? This trial,
the fourth in a series, was designed in response to a
challenge from an independent clinical team to contest
the evidence from the three preceding trials that
homoeopathic dilutions seem to differ from placebo.
1–3
These were not trials of treatments; they were designed
to address the placebo hypothesis, using allergy as a
model. In this study, as before, patients with atopic
inhalant allergies received, randomly and double blind,
either an oral 30c homoeopathic preparation of their
principal allergen or a placebo. The previous trials
studied effects in atopic patients with hay fever
12
and
asthma,
3
whereas this study focused on perennial aller-
gic rhinitis. We report the results of this fourth trial and
an overview of the series.
Participants and methods
Volunteers were recruited in London from four
general practices and the ear, nose, and throat
outpatient department of Northwick Park Hospital.
The prescribers were familiar with homoeopathic
principles but were not experienced in homoeopathic
immunotherapy. All patients gave written informed
consent, and the trial was approved by Hillingdon and
Harrow Health Authorities’ ethics committees.
Patients meeting the admission criteria (box) were
screened for symptoms and compliance during a two
week qualification period.
6
Although drugs for rhinitis
were stopped two weeks before entry, patients could
use them during the trial if required, and asthma drugs
were not altered. No new allergen avoidance measures
were permitted during the trial.
Trial design
The trial was a randomised, double blind, placebo con-
trolled study of two parallel groups (fig 1). Crossover
was precluded because of possible carry over effects
from homoeopathy. We recruited participants over six
weeks from the middle of February so that the
prospectively defined stopping time was before the
start of the local pollen season.
At the start of the qualification period the doctor
assessed each patient’s history, allergy status, and nasal
obstruction. The principal allergen determining the
prescription was then chosen on the basis of the largest
skin test weal concordant with the allergy history. In
seven cases in which the prescriber had difficulty in
University
Department of
Medicine, Glasgow
Royal Infirmary,
Glasgow G31 2ER
Morag A Taylor
research associate
David Reilly
honorary senior
lecturer in medicine
Department of
Psychological
Medicine,
University of
Sydney, New South
Wales 2006,
Australia
Robert H
Llewellyn-Jones
lecturer
University
Department of
Immunology,
Western Infirmary,
Glasgow G11 6NT
Charles McSharry
pr incipal
immunologist
Department of
Statistics, University
of Glasgow,
Glasgow G12 8QQ
Tom C Aitchison
senior lecturer in
statistics
Correspondence to:
D Reilly, Academic
Departments,
Glasgow
Homoeopathic
Hospital, Glasgow
G12 0XQ
davidreilly1@
compuserve.com
BMJ 2000;321:471–6
471BMJ VOLUME 321 19-26 AUGUST 2000 bmj.com
determining the principal allergen, telephone advice
was given by a doctor experienced in prescribing
homoeopathic immunotherapy. The first of three phials
of placebo corresponding to the principal allergen was
then administered by the doctor on to the patient’s
tongue. Patients were unaware that the phials contained
placebo, although the researchers were not blinded.
The following two weeks served jointly as the quali-
fication and baseline period. At the second visit, quali-
fying patients were randomised by a restricted
technique of permuted blocks of two,
7
generated from
random number tables and stratified for the indicated
allergen. A double blinded prescription was immedi-
ately dispensed. The trial ended with a follow up visit
four weeks later.
Allergy and respiratory tests
Operators were trained to test sensitivity to house dust
mite, cat fur, dog hair, tree pollens, grass pollens, and
cladosporium by skin prick testing with preloaded lan-
cets (Phazets, Pharmacia, Milton Keynes) and to
aspergillus, feathers,and house dust using a needle and
allergen solution (Bencard, Welwyn Garden City).
Negative and positive histamine controls were used. A
weal reaction of 3 mm or more in its greatest diameter
after 15 minutes was taken as positive. To confirm the
diagnosis, allergen specific serum IgE was measured by
radioimmunoassay according to the manufacturer’s
instructions (Pharmacia). Samples were tested in
batches to avoid interassay variability.
Patients were taught to use a Youlten nasal inspira-
tory peak flow meter (Clement Clark, Harlow),
8
which
is an objective, sensitive, valid, and reliable indicator of
nasal obstruction.
9–12
This measure decreases after
nasal challenge in allergic rhinitis.
11 13
In clinical trials
increases of 13 l/min after low dose desensitisation
14
and 18.5 l/min after topical steroids
15
have been corre-
lated with clinical improvements.
Study diaries
At the same time each morning and evening patients
recorded three successive nasal inspiratory peak flow
measurements. Before making these measurements
patients oriented themselves by noting each morning
(ona0to4integer scale) how their symptoms had
interfered with their sleep and, each night, rating
blocked, runny, or itchy nose symptoms, sneezing, and
any eye and chest symptoms. Patients then recorded
their daily overall visual analogue scale score. To allow
comparison with our previous trials
1–3
the identical
wording was used: “Overall today I felt . . .” on a scale of
0-100 mm, where 0 is fine and 100 is terrible. Visual
analogue scale scores are a recommended measure of
the severity of rhinitis.
16
Adverse events, including
initial aggravations of symptoms as observed in our
previous rhinitis trial,
2
were documented by the
patients, clarified by the doctor, and recorded on
standard adverse experience report forms. Any use of
conventional drugs was also noted.
Medication preparation and administration
Using original standard allergen material from the Pas-
teur Institute in Paris, a homoeopathic laboratory
(Boiron, Lyons, France) prepared the drugs according to
the French homoeopathic pharmacopoeia through 30
stages of 1 in 99 serial agitated dilutions to produce a
30c dilution, as reported previously.
3
Each treatment
consisted of three identical phials containing 1 g of
lactose-sucrose globules that had been impregnated
with either a 30c homoeopathic dilution of the principal
allergen or placebo. The three phials constituted a split
single dose that was to be taken equally spaced over 24
hours to cover any diurnal variation in the patient’s sen-
sitivity to treatment and to ensure compliance. Only one
dose was taken. The placebo dilution consisted of the
same batch of diluent identically diluted and vibrated
but without the starting allergen. The treatments were
indistinguishable in packaging,taste,and smell. Random
samples of drug phials were checked by independent
laboratories for the presence of extraneous house dust
mite allergen (der p1) by enzyme linked immuno-
sorbent assay (ELISA)
17
(University of Virginia, Char-
lottesville) and for antiallergy drugs by gas
chromatography-mass spectrometry (MD800, Fisons,
Manchester). No such contamination was found.
Criteria for eligibility
Inclusion
Age > 16 years
Atopic: reactive to inhaled allergens with positive skin
test results
More than 1 year history of perennial rhinitis
4
Exclusion
Deterioration during grass pollen season
Nasal abnormalities causing obstruction
Previous homoeopathic immunotherapy for perennial
rhinitis
Allergen avoidance in past 6 weeks
Away from usual environment for more than 1 week
during trial
Respiratory infection
Severe concomitant disease
Pregnancy, breast feeding, or likelihood of pregnancy
Oral or parenteral steroids in past 6 months
5
Conventional desensitisation in past 3 months
Washout periods
Long acting antihistamines in past 4 weeks
Topical steroids, cromoglycate, vasoconstrictors, or
antihistamines in past 2 weeks
Case note review and poster recruitment
patients seen for screening (n=121)
Received homoeopathy as allocated
(n=24)
Eligible to enter qualification period
(n=56)
Ineligible for randomisation (n=5)
(1 chest infection, 4 non-compliance)
Eligible for randomisation (n=51)
Completed trial (n=23)
(1 lost to follow up)
Received placebo as allocated
(n=27)
Completed trial (n=27)
Randomisation
Fig 1 Recruitment of patients and their progress through the trial
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472 BMJ VOLUME 321 19-26 AUGUST 2000 bmj.com
The coded drug packages were sent to the
pharmacy department of Glasgow Royal Infirmary
where, to augment blinding, each one was recoded
with a unique number according to the randomisation
schedule and then delivered to the pharmacy
department of Northwick Park Hospital for distribu-
tion to each centre. The codes were held by both the
French laboratory and a hussier de justice (notary) and
remained unbroken until the analyses were completed.
Analysis
The prestudy power calculation was based on the
results of the hay fever trial,
2
from which a mean differ-
ence of 15 mm between the groups on visual analogue
scale scores and a corresponding standard deviation of
29 were obtained. With a choice of 5% significance and
80% power, we estimated that 60 patients would be
required in each group to avoid false negative results.
No interim analysis was carried out. The predefined
main measures of outcome were the changes from
baseline in mean visual analogue scale scores and nasal
inspiratory peak flow (use of mean values supported by
Wihl and Malm
18
) over the third and fourth weeks after
randomisation, when initial aggravations would be
likely to be over and any treatment effects evident. Pre-
defined secondary measures of outcome were differ-
ences between the groups in reports of adverse events,
including initial aggravations of symptoms and use of
drugs for rhinitis. Intention to treat analysis was used.
Variables with normal distributions (nasal inspiratory
peak flow and visual analogue scale) were analysed by
using two tailed, two sample t tests and confidence
intervals. ÷
2
tests were applied to categorical compari-
sons and proportions, but if any cell in a contingency
table was less than 5, Fisher’s exact test was used. The
independent statistician verified the coded data entry,
confirmed all analyses, and then carried out a repeated
measures analysis of covariance on the changes from
baseline over the four weeks after randomisation for
each variable. The possible terms for inclusion in the
model were treatment, time into study, and treatment-
time interaction; the baseline score was included as a
potential covariate.
Overview
To summarise our results, the original data
19
from all
four trials were pooled and analysed by an independ-
ent worker using Cochrane Collaboration meta-
analysis software (Revman 3.0). All available visual
analogue scale scores from every randomised patient
in the four trials were used on an intention to treat
basis, with each patient acting as his or her own control.
The four trials had been designed as a series to address
the hypothesis that homoeopathy is a placebo
response. Each trial studied atopic inhalant allergies
and assessed subjective effects in the same way over the
third and fourth weeks after randomisation. They had
also all used homoeopathic immunotherapy at 30c
potency. The studies should therefore have a good
degree of clinical homogeneity. Statistical heterogen-
eity was assumed to be present when the P value for
heterogeneity was less than 0.10, and therefore the
random effects model was used.
20
The weighted mean
difference was used as an estimate of the treatment
effect (average change on homoeopathy minus average
change on placebo).
21
To aid presentation the overall
daily graph was plotted with smoothed values by using
simple robust non-linear procedures.
22
As the main
objective measure varied across the studies we
compared them in a simple overview.
Results
Participants
Fifty one patients successfully completed qualification
screening and were randomised (fig 1). Because of the
exacting screening, strict qualification criteria, and the
prospectively defined requirement to stop enrolment
before the pollen season, we did not recruit the
number of patients that the power calculation had esti-
mated we required.
At baseline, clinical characteristics (table 1) and
main measures of outcome (table 2) were similar in
both groups. One patient (homoeopathy group) was
subsequently lost to follow up despite repeated postal
reminders.
Nasal inspiratory peak flow
We found a clear objective difference between the
effects of placebo and homoeopathy on nasal airflow
Table 1 Baseline clinical characteristics of study participants. Values are numbers
(percentages) of participants unless stated otherwise
Homoeopathy (n=24) Placebo (n=27)
Mean (SD) age (year) 31 (10) 36 (13)
Sex (male : female) 6 (25) : 18 (75) 9 (33) : 18 (67)
Mean (SD) duration of rhinitis (years) 13 (11) 16 (11)
Taking orthodox drugs before trial 4 (17) 6 (22)
Used orthodox treatments previously (used:effective) 23 (96) 26 (96)
Topical steroids 8 (35) : 3 (13) 12 (46) : 5 (19)
Cromoglycate 6 (26) : 2 (9) 3 (12) : 2 (8)
Vasoconstrictors 12 (52) : 9 (39) 7 (27) : 4 (15)
Antihistamines 15 (65) : 9 (39) 12 (46) : 7 (27)
Immunotherapy 5 (22) : 3 (13) 3 (12):2(8)
Surgery 4 (17) : 1 (4) 4 (15) : 2 (8)
Over the counter 20 (87) : 9 (39) 20 (77) : 13 (50)
Used alternative therapies before 6 (25) : 0 5 (19):2(7)
Principal allergen:
House dust mite 17 (71) 18 (67)
House dust 5 (21) 5 (19)
Feathers 1 (4) 3 (11)
Cat 1 (4) 1 (4)
Mean (SD) specific IgE (units/ml) 4.6 (5.4) 4.1 (5.8)
Mean (SD) skin test weal (mm) 6.8 (4.2) 6.8 (4.2)
Time after treatment (weeks)
Mean change from baseline (min)
01
Baseline
234
-5
5
10
15
20
25
30
Homoeopathy
0
Placebo
Fig 2 Mean (SE) weekly change from baseline in nasal inspiratory
peak flow
Papers
473BMJ VOLUME 321 19-26 AUGUST 2000 bmj.com
(table 2 , fig 2). Patients in the homoeopathy group had
an overall improvement from baseline averaging 21%
compared with 2% in the placebo group over the third
and fourth weeks after randomisation. This difference
was significant (P = 0.0001) and was confirmed by
repeated measures analysis of covariance. The improve-
ment was consistent across all recruitment centres.
Visual analogue scale
Subjectively, both treatments resulted in improvement,
with no significant difference between them (table 2).
This change began during the single blind placebo
run-in period, decreasing the baseline value by the time
of randomisation. Subsequently both groups showed
further improvement. The individual symptom scores
echoed these trends. Centre by centre analysis showed
that in all but one of the centres the homoeopathy
group improved more than the placebo group. This
anomalous result seemed to be related to the increased
frequency of aggravations and later entry in that centre.
Other measures
Non-respiratory adverse events were minor, and no
difference was found between the groups. Initial aggra-
vations of rhinitis symptoms were provoked more by
homoeopathy than by placebo. By 48 hours after ran-
domisation seven (29%) patients in the homoeopathy
group reported a worsening of rhinitis, two with
wheeze, compared with two (7%) patients in the
placebo group, neither of whom had wheezing
(P = 0.04, Fisher’s exact test). By 14 days, 11 (46%)
patients in the homoeopathy group had reported
adverse events, 10 of whom had rhinitis related aggra-
vations, compared with seven (26%) in the placebo
group, five of whom had rhinitis related aggravations
(÷
2
= 3.28, P = 0.07). In general, most aggravations were
short lived, averaging four days, and all had resolved by
day 16. Aggravations of rhinitis in patients who
received homoeopathy seemed to point to a good out-
come. Initial deterioration was followed by subjective
improvement and a corresponding improvement in
nasal inspiratory peak flow. Only one patient in each
group resorted to conventional rhinitis drugs,and both
took them for less than four days.
Overview
Figure 3 compares the underlying patterns from the
four trials based on daily visual analogue scale data
from all 253 randomised patients and the main objec-
tive measures. The subjective changes measured by the
visual analogue scale show a therapeutic response
from homoeopathy across the four trials. There was a
lesser and more variable response in the placebo
groups, which probably accounts for the evidence of
some statistical heterogeneity (÷
2
= 9.04, df = 3,
P = 0.03). The pooled estimate of the treatment effect
(middle column, fig 3) showed an average improve-
ment in visual analogue scores in the homoeopathy
group compared with the placebo group (improve-
ment 11.1 mm, 95% confidence interval 3.3 to 18.8;
P < 0.01). Thus, overall, the trend of the individual trial
results and pooled data point towards homoeopathy
differing from placebo. The trends in the objective
measures all follow the same direction as the subjective
measures (fig 3), again indicating a difference between
a homoeopathic dilution and placebo.
Figure 4 shows the average response to homoeo-
pathic immunotherapy over time in the four trials. A
distinct separation emerges between the action of
homoeopathy and placebo. On average, over the last
two weeks after randomisation, patients who received
homoeopathy had a 28% improvement compared with
3% among those in the placebo group. 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 (95% confidence interval
for difference 4.2 to 15.4, P = 0.0007; two sided, two
sample t test).
Discussion
We found that homoeopathy and placebo had different
effects. Compared with placebo, homoeopathy pro-
voked a clear, significant, and clinically relevant
improvement in nasal inspiratory peak flow, similar to
that found with topical steroids.
15
However, the subjec-
Table 2 Baseline scores and mean change from baseline over third and fourth week after randomisation for subjective and objective
measures of severity of rhinitis
Mean (SD) baseline average score Mean (SE) change from baseline
Homoeopathy
(n=24)
Placebo
(n=27) P value
Homoeopathy
(n=23)
Placebo
(n=27)
Difference between groups
Mean (95% CI) P value
Visual analogue scale (mm) 39.5 (12.9) 38.1 (18.7) 0.76 −5.0 (3.3) −4.0 (2.8) 1 (−9.8 to 7.8) 0.82
Nasal inspiratory peak flow (l/min):
Morning 98.1 (34.5) 103.2 (32.9) 0.62 25.1 (5.9) −0.3 (3.0) 25.4 (11.7 to 39.2) 0.0008
Evening 110.7 (46.7) 115.0 (42.2) 0.75 19.5 (5.7) 5.4 (3.3) 12.1 (0.6 to 27.6) 0.04
Total 104.4 (41.1) 109.1 (37.9) 0.58 22.3 (4.1) 2.5 (2.3) 19.8 (10.4 to 29.1) 0.0001
-40 -30 -20 -10 0
Pilot
Hay fever
1
Hay fever
2
Asthma
3
Perennial
rhinitis
No of "escape"
antihistamine
tablets
Homoeopathy
Placebo
Bronchial hyper-
responsiveness
log
10
PC
20
mg
histamine
Nasal inspiratory
peak flow (l/min)
Composite
10 20
-40 -30 -20 -10 0
-6
0.4
0.3
0.2
0.1
0.1
0.2
0.3
-5
-4
-3
-2
-1
-10
10
20
30
40
0
Change from entry to final weekChange from baseline over final two weeks
Main objective measuresVisual analogue scale scores
Overview OverviewPooled analysis
10 20
Fig 3 Overview and pooled analysis of four trials of homoeopathic immunotherapy
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474 BMJ VOLUME 321 19-26 AUGUST 2000 bmj.com
tive improvement was less clear. Although the objective
measure consistently improved in all five centres, the
subjective results were better than placebo in only four
of the five centres and overall there was no difference
between the groups. If the objective results are valid the
discrepancy in the subjective measurements may be
partly due to under recruitment compounded by
aggravations and possible initial placebo responses
during the run-in period in both groups, perhaps
reflecting the positive expectations of the participants.
23
Patients with rhinitis are keen to enter studies in their
quest for better symptom control.
24
Subjective
improvement began before the end of the placebo
run-in phase in both groups, and this lessened the
chance of distinguishing between the groups.
25 26
A
larger sample size may have shown a subjective differ-
ence between the groups.
More initial aggravations occurred in patients who
received homoeopathy, and this may have further
complicated the subjective results. The pattern of tem-
porary worsening followed by improvement, seen in
this trial and observed in clinical homoeopathy for
over 200 years,
27 28
is not typical of placebo.
Validity of results
Like any other therapy, homoeopathy requires
rigorous scientific testing, and one study is insufficient
evidence. Some perspective may be gleaned by viewing
the results of this trial in the context of the series of
which it is part. Except for the subjective measure in
this fourth trial, the subjective and objective results
show a trend across these four trials clearly pointing to
homoeopathy being different from placebo. If the
results were due to chance then some trends in favour
of placebo would be expected. So does homoeopathy
work or are our results due to some other factor?
Recent attempts to resolve the controversy sur-
rounding homoeopathy have centred on the 180 or so
controlled trials to date. A criteria based review in 1991
found that the evidence was positive but not conclusive.
29
In a 1997 update, other workers concluded that 73% of
the existing trial data supported homoeopathy being
more effective than placebo, with the pooled odds ratio
from a criteria based meta-analysis of 89 trials
suggesting homoeopathy showed around twice the
overall mean effect of placebo. The difference was
significant and proved robust in sensitivity analyses that
included correction for publication bias.
30
A third work-
ing group, independently set up by the European Com-
mission, selected 17 comparisons in 2001 patients for a
meta-analysis. The pooled P value was highly significant,
and the group commented that “it is likely that among
the tested homeopathic approaches some had an added
effect over nothing or placebo.”
31
Are these findings
“meta-errors” or, however implausible, does something
tangible lie at the core of homoeopathy?
To interpret these findings as arguing for
homoeopathy having an effect may now be more
plausible than our previous hypothesis of serial false
positive results.
332
For now, we conclude that this study
has failed to confirm our original hypothesis that
homoeopathy is a placebo.
We thank the patients who took part in the study, their doctors
(Janet Gray, Ian Isaac, John Porterfield) and R Auerbach of
Northwick Park Hospital, London, for ear, nose, and throat
assessment. We thank Laboratoires Boiron for preparing the
drugs, Angela Mahoney for help with randomisation, Neil Beat-
tie for prescription advice, Peter Langhorne for independent
pooled analysis, Andrew Jenkins for computer programming
and graphics, and J H McKillop for his support. We also thank S
McIntosh of the Institute of Biochemistry, Glasgow Royal Infir-
mary, for screening for anti-asthma drugs and T G Merrett of
the Allergy Analysis Centre, Gwynedd, Wales, for screening for
house dust mite antigen.
Contributors: MAT was project manager, participated in the
design, and conducted most of the analysis. DR conceptualised
and developed this series of trials and was involved in the design
and analysis of this trial. RHL-J instigated this trial, acted as
clinical coordinator while working in London, and contributed
to design and analysis. CMcS participated in the design and car-
ried out immunological analysis. TCA advised on the design of
the project and implemented further independent analysis. The
paper was written mainly by MAT and DR with important con-
tributions from the other authors. MAT and DR are guarantors.
Funding: Fondation Française pour la Recherche en Homeo-
pathie, Blackie Foundation Trust, British Homoeopathic Associ-
ation, and Scottish Homoeopathic Research and Education Trust.
The project was initially part of a research fellowship created by
the Research Council for Complementary Medicine in partner-
ship with the Medical Research Council and the King’s Fund.
Competing interests: MAT’s salary was partly paid by the
Blackie Foundation Trust, British Homoeopathic Association,
and Scottish Homoeopathic Research and Education Trust
administered by Glasgow University. She was reimbursed for
attending a symposium organised by the Blackie Foundation
Trust.DR beganthis research programme before using homoeo-
10
5
0
-5
-10
-15
-20
-25
-30
Daily mean change from basleline VAS (mm)
1 7 14 21 28
Baseline
Placebo
Homoeopathy
Days after randomisation
Fig 4 Effect of homoeopathic immunotherapy and placebo on visual
analogue scale scores averaged over four trials
What is already known on this topic
Much scepticism exists about the effectiveness of extreme
homoeopathic dilutions
Several trials have suggested that homoeopathic dilutions have more
effect than placebo
What this study adds
Patients with allergic rhinitis who received homoeopathy had
significantly better nasal air flow than those in the placebo group
More patients in the homoeopathic group had initial symptom
aggravations
Overall, no difference was seen in subjective measurements on a visual
analogue scale, with both groups showing improvement
When the results are combined with those of three similar studies,
homeopathy is different from placebo on both subjective and objective
measures
Papers
475BMJ VOLUME 321 19-26 AUGUST 2000 bmj.com
pathy or developing education. He uses homoeopathy in clinical
care. He accepts occasional lecture and teaching fees but has no
consultancy work. He has declined all direct industry grants for
research and has used intermediary regulatory organisations to
ensure independence.
1 Reilly DT, Taylor MA. Potent placebo or potency? A proposed study
model with initial findings using homoeopathically prepared pollens in
hay fever. Br Homoeopathic J 1985;74:65-75.
2 Reilly DT, Taylor MA, McSharry C, Aitchison T. Is homoeopathy a
placebo response? Controlled trial of homoeopathic potency, with pollen
in hayfever as model. Lancet 1986;ii:881-6.
3 Reilly DT, Taylor MA, Beattie NGM, Campbell JH, McSharry C, Aitchison
TC, et al. Is evidence for homoeopathy reproducible? Lancet 1994;
344:1601-6.
4 Mygind N. Nasal allergy. 2nd ed. Oxford: Blackwell, 1979:224-5.
5 Vithoulkas G. Homoeopathy. Wellingborough: Thorsons, 1985:72.
6 Knipschild P, Leffers P, Feinstein AR. The qualification period. J Clin Epi-
demiol 1991;44:461-4.
7 Pocock SJ. Clinical trials. Chichester: Wiley, 1983.
8 Youlten LJF. The peak nasal inspiratory flow meter: a new instrument for
the assessment of the response to immunotherapy in seasonal allergic
rhinitis. Allergol Immunopathol (Madr) 1980;8:344.
9 Jones AS, Viani L, Philllips D, Charters P. The objective assessment of
nasal patency. Clin Otolaryngol 1991;6:206-11.
10 Gleeson MJ, Youlten LJF, Shelton DM, Siodlak MZ, Eiser NM, Wengraf
CL. Assessment of nasal airway patency: a comparison of four methods.
Clin Otolaryngol 1986;11:99-107.
11 Holmström M, Scadding GK, Lund VJ, Darby YC. Assessment of nasal
obstruction. A comparison between rhinomanometry and nasal inspira-
tory peak flow. Rhinology 1990;28:191-6.
12 Fairley JW, Durham LH, Ell SR. Correlation of subjective sensation of
nasal patency with nasal inspiratory peak flow rate. Clin Otolaryngol
1993;18:19-22.
13 Krayenbuhl MC, Hudspith BN, Scadding GK, Brostoff J. Nasal response
to allergen and hyperosmolar challenge. Clin Allergy 1988;18:157-64.
14 Scadding GK, Brostoff J. Low dose sublingual therapy in patients with
allergic rhinitis due to house dust mite. Clin Allergy 1986;16:483-91.
15 Malmberg H, Holopainen E, Simola M, Boss I, Lindqvist N. A comparison
between intranasal budesonide aerosol and budesonide dry powder in
the treatment of hay fever symptoms. Rhinology 1991;29:137-41.
16 Linder A. Symptom scores as measures of the severity of rhinitis. Clin
Allergy 1988;18:29-37.
17 Luczynska CM, Arruda LK, Platts-Mills TAE, Miller JD, Lopez M,
Chapman MD. A two-site monoclonal antibody ELISA for the
quantification of the major Dermatophagoides spp allergens Der p1 and
Der f1. J Immunol Methods 1989;118:227-35.
18 Wihl J-A, Malm L. Rhinomanometry and nasal peak expiratory and
inspiratory flow rate. Ann Allergy 1988;61:50-5.
19 Stewart LA , Parmar MKB. Meta-analysis of the literature or of individual
patient data: is there a difference? Lancet 1993;341:418-22.
20 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin
Trials 1986;7:177-88.
21 Bracken MB. Statistical methods for analysis of effects of treatment in
overviews of randomised trials. In: Sinclair JC, Braken MB, eds. Effective
care of the newborn infant. Oxford: Oxford University Press, 1992:13-8.
22 Velleman P. Definition and comparison of robust non-linear data
smoothing algorithms. J Am Stat Assoc 1980;75:609-15.
23 Shapiro AK, Shapiro E. The powerful placebo. Baltimore: Johns Hopkins
University Press, 1997:226.
24 Aby JS,Pheley AM, Steinberg P. Motivation for participation in clinical trials
of drugs for the treatment of asthma, seasonal allergic rhinitis and
perennial nonallergic rhinitis. Ann Allergy Asthma Immunol 1996;76:348-54.
25 Kiene H. A critique of the double-blind clinical trial
—
1. Alternative Thera-
pies in Health and Medicine 1996;2(1):74-80.
26 Kiene H. A critique of the double-blind clinical trial
—
1. Alternative Thera-
pies in Health and Medicine 1996;2(2):59-64.
27 Hahnemann H. Essay on a new principle for ascertaining curative pow-
ers of drugs and some examinations of the previous principles. Hufeland’s
Journal 1796;ii:391-439, 465-561.
28 Bellavite P, Signorini A. Homoeopathy. Berkeley, CA: North Atlantic Books,
1995.
29 Kleijnen J, Knipschild P, ter Riet G. Clinical trials of homoeopathy. BMJ
1991;302:316-23.
30 Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV, Jonas
WB. Are the clinical effects of homoeopathy placebo effects? A
meta-analysis of placebo-controlled trials. Lancet 1997;350:834-43.
31 Homoeopathic Medicine Research Group. Report to the European
Commission directorate general XII: science, research and development.Vol1
(short version). Brussels: European Commission, 1996:16-7.
32 Reilly’s challenge [editorial]. Lancet 1994;344:1506.
(Accepted 25 April 2000)
Commentary: Larger trials are needed
Tim Lancaster, Andrew Vickers
High quality randomised trials are welcome in the
evaluation of homoeopathy, as in other branches of
health care. The methods used by Reilly and colleagues
in their study of homoeopathy for perennial allergic
rhinitis were rigorous, and it is unlikely that their
results arose from methodological bias.
Are they correct to argue that they have reinforced
the evidence that homoeopathy is more than a
placebo? The current trial is the fourth in which this
group evaluated a similar treatment, comparator,
patient group, and outcome measure. As with the pre-
vious studies, the primary outcome used to calculate
the sample size was a visual analogue score measuring
patients’ perceived improvement in symptoms. In con-
trast to the earlier studies, they detected no effect of
homoeopathic treatment on the visual analogue score.
These data do not strengthen the conclusion that
homoeopathy differs from placebo. In fact, the effect of
including the current study in their meta-analysis with
data from the three earlier trials is to weaken (though
not overturn) this conclusion.
The authors report a significant effect of homoeo-
pathy on a second outcome measure, the nasal peak
inspiratory flow. This result, like that of the meta-analysis,
is challenging to those who believe that homoeopathy is
always equivalent to placebo. However, it is difficult to
place this finding in the context of the previous studies
as they did not measure this outcome.
Clinical trials are particularly important in
homoeopathy as they are nearly the only evidence
that treatment can have effects different from placebo.
Unlike many medical interventions, there are no
established animal models, mechanisms of action, or
examples of similar treatments of proved benefit.
Moreover, homoeopathy is biologically implausible
because of the use of medicines diluted beyond the
Avogadro limit. It is therefore reasonable to ask for a
high level of randomised evidence before concluding
that homoeopathy exerts specific effects. A meta-
analysis based on all the controlled trials identified by
a systematic search showed a modest effect of homoeo-
pathy over placebo.
1
Because of the relatively small
number of patients studied, neither the positive nor
the negative result of the current study would shift this
estimate significantly. To move the scientific debate
forward, homoeopathic research needs trials with the
power to detect or effectively refute the moderate
effects suggested by the meta-analysis. Others have
shown that such trials are feasible in homoeopathy.
23
The new challenge for Reilly and colleagues is to do
the large trials that really could change thinking.
Competing interests: None declared.
1 Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV, Jonas
WB. Are the clinical effects of homeopathy placebo effects? A
meta-analysis of placebo-controlled trials. Lancet 1997;350:834-43.
2 Vickers AJ, Fisher P, Smith C, Wyllie SE,Rees R. Homeopathic arnica 30x
is ineffective for muscle soreness after long-distance running: a
randomized, double-blind, placebo-controlled trial. Clin J Pain
1998;14:227-31
3 Ferley JP, Zmirou D, D’Adhemar D, Balducci F. A controlled evaluation of
a homoeopathic preparation in the treatment of influenza-like
syndromes. Br J Clin Pharmacol 1989;27:329-35.
Papers
Department of
Primary Health
Care, Institute of
Health Sciences,
Oxford OX3 7LF
Tim Lancaster
clinical reader in
general practice
Integrative
Medicine Service,
Memorial
Sloan-Kettering
Cancer Center,
1275 York Avenue,
New York, NY
10021, USA
Andrew Vickers
assistant attending
research methodologist
Correspondence to:
T Lancaster
tim.Lancaster@
public-health.oxford.
ac.uk
476 BMJ VOLUME 321 19-26 AUGUST 2000 bmj.com
