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Alastair
Forbes, Sue Jackson, Clare Walter, Shafi Quraishi, Meron Jacyna, Max
Pitcher, St Mark's
Hospital, Watford Road, Harrow
HA1 3UJ, United Kingdom
Supported by the a donation gratefully received from the T-R
Golden Charitable Trust
Correspondence to: Dr. Alastair Forbes, St Mark's
Hospital, Watford Road, Harrow
HA1 3UJ, United Kingdom. lastair.forbes@ic.ac.uk
Telephone: +44-20-8235-4046
Fax: +44-20-8235-4039
Received: 2002-12-22
Accepted: 2003-11-12
Abstract
Aim: Irritable
bowel syndrome (IBS) is a common disorder and many patients fail to
find adequate relief from conventional therapies for their symptoms.
This study tests the claim that acupuncture is effective for a
majority of these patients.
Methods: A
prospective, blinded, sham acupuncture-controlled trial of
traditional Chinese acupuncture was performed at a single
postgraduate teaching hospital in Europe. Sixty patients with
well-established IBS were recruited. The blinded comparator was sham
acupuncture administered by the second of two acupuncturists who
alone was aware of the randomization, and who otherwise followed the
prescription of the first. The primary end-point was a defined fall
in the symptom score at 13 wk (by intention to treat). The prior
expectation was a 30% placebo response, and a response rate of 70%
from acupuncture, for which the study was adequately powered.
Results:
Patients in treated and sham groups improved significantly during
the study-mean improvement in scores being equal (minus 1.9) and
significant for both (P<0.05; one-tailed t test).
There was a small numeric but non-significant difference between the
response rate in patients receiving acupuncture (40.7%) and sham
treatment (31.2%). Several secondary end-points marginally favored
active treatment, but an improved symptom score of any degree of
magnitude occurred more often with sham therapy (65.6% vs
59.2%). For no criterion was statistical significance approached.
Conclusion:
Traditional Chinese acupuncture is relatively ineffective in IBS in
the European hospital setting, and the magnitude of any effect
appears insufficient to warrant investment in acupuncture services.
� 2005
The WJG Press and Elsevier Inc. All rights reserved.
Key words: Acupuncture; Complementary therapy; Irritable
bowel syndrome; Traditional medicine
Forbes A, Jackson S, Walter C, Quraishi S, Jacyna M, Pitcher M.
Acupuncture for irritable bowel syndrome: A blinded
placebo-controlled trial. World J Gastroenterol
2005; 11(26): 4040-4044
http://www.wjgnet.com/1007-9327/11/4040.asp
INTRODUCTION
Acupuncture has been utilized for a variety of conditions, by up to
19% of the European population, and with as many as 12 million
treatments per year in the USA[1].
Gastrointestinal problems are addressed[2],
and in addition to publications in the traditional Chinese medicine
(TCM) literature there has been support in more mainstream journals[3,4].
Not all reviewers have been so positive however[5].
Irritable bowel syndrome (IBS) is common, and many patients fail to
find adequate relief from conventional therapies. It is claimed that
acupuncture is effective for a majority of patients with IBS, but
there are few data to support this. Case reports do not adequately
address the large placebo response in this condition, the often
substantial inter-subject variability in response, nor the differing
systems of nomenclature in acupuncture. The US NIH consensus did not
include IBS amongst 12 conditions for which it found evidence
favoring acupuncture[4].
The only paper specific to acupuncture in IBS that we have found is
a pilot study of seven patients, which recorded improvements in
bloating and general well-being[6].
A complex Austrian study in which acupuncture or sham acupuncture
(inter alia) was used for irritable colon demonstrated benefit at 1
mo (43.7% vs 26.7% relief; P<0.01)[7].
However, the definition of response, the nature of the
randomization, and the mechanism of blinding are unclear. Evidence
in favor of acupuncture for IBS cannot be considered definite.
Previous attempts to assess the placebo response
in acupuncture therapy have been criticized. Orthodox
clinician-scientists object to poor blinding, while acupuncturists
argue that attempts to blind therapy negate the diagnostic and
therapeutic process, and confound the individualization of the
chosen regime necessary for the TCM paradigm. The present study
addresses a single hypothesis and tackles the issues of methodology
in a novel and creative fashion.
MATERIALS AND METHODS
Patients and consent
Patients were selected by personal approach in the St Mark's
Hospital clinics. Eligibility
required a confident clinical diagnosis of IBS and age of over 16
years. Patients were to satisfy the Rome criteria[8]
and the Manning criteria[9].
The Rome II criteria[10]
became available during the study; their fulfillment was noted but
not required. Patients were to have had symptoms for at least 3 mo
and to have failed to respond to standard therapies including:
increased dietary fiber, reduction of lactose-containing foods,
antispasmodics, simple laxatives (in those with predominant
constipation), and opioids (in those with predominant diarrhea).
Other physical disease was required to be absent or inactive. Formal
psychiatric disease was an exclusion criterion. Patients were not
permitted to use psychotropic drugs during the study period unless
these had been commenced at least 3 mo before recruitment and were
maintained at static dose throughout. Potentially fertile women were
required to use effective contraception.
Normality of routine hematology, renal, hepatic
and thyroid biochemistry, and of inflammatory markers was required.
All subjects had a normal sigmoidoscopic examination within 3 mo of
entry. Those over 40 years of age were required to have had
colonoscopy, or flexible sigmoidoscopy and barium enema within 2
years of entry. All were given an information leaflet and were
required to provide written informed consent.
Study methodology
The study was a double blind, sham-controlled trial of TCM
acupuncture therapy. Two acupuncturists, fully trained in
traditional Chinese acupuncture and accredited to the British
Acupuncture Council, were responsible for the active and sham
interventions. Recruited patients were allocated according to
computer-generated random numbers concealed in sealed envelopes. Ten
treatments were administered, at approximately 1-wk intervals.
Technical aspects of active and sham acupuncture
The first acupuncturist was the "diagnosing
acupuncturist" (DA), whom the patient saw for the initial
consultation, and before and after each treatment. A full case
history was taken by the DA, together with tongue and pulse
examination, to arrive at an individual diagnosis in accordance with
the principles of TCM, with an additional lesser emphasis on Five
Element Acupuncture[11-14].
Although all patients in the study had IBS, this corresponded to a
wide range of TCM patterns, making individual diagnosis essential.
Dietary and lifestyle advice (important in treatment according to
TCM principles) was given to all patients by the DA, who then
selected acupuncture points.
The second "treating
acupuncturist" (TA) opened the randomization envelope, and for
the duration of the study remained the only individual aware of
treatment allocation. The TA carried out the treatment-either
according to instructions issued by the DA or using sham points,
depending on the randomization.
In TCM meridian-based acupuncture the aim is to
manipulate or remove blocking of the "Oi".
A variety of needling techniques is necessary, both to achieve
requisite "deqi"
or "needling
sensation", and, subsequently, a range of therapeutic effects.
Eight to sixteen needles were inserted at 4-8 specified acupuncture
sites, bilaterally, in each session. Needles were left in place
momentarily, or for up to 25 min, depending on the desired effect.
For active patients the TA implemented the instructions of the DA,
including the needle technique, and the length of time of their
retention.
'Sham'
acupuncture points were chosen from three different areas on the
body (the anterior thigh distally, the posterior thigh, and the
lateral aspect of the lower back), which do not correspond to
recognized acupuncture points and are deemed to have no therapeutic
value. These were varied to some degree each week as in genuine
treatment, including variation in needle technique and length of
time of retention. No deqi needling sensation was sought or obtained
at sham points.
Sterile single-use 'Carbo'
brand needles were used (mostly 0.22 mm25 mm, some 0.25 mm40 mm).
Insertion may be uncomfortable but is not normally painful (less
discomfort than venepuncture). Needles were generally well
tolerated, and were gently stimulated, as required, by the
acupuncturist during treatment.
Moxibustion (therapeutic burning of the herb Artemisia
vulgaris) is integral to the practice of traditional Chinese
acupuncture, but was not used during the study, although there were
a number of patients for whom it was considered indicated. This
reflected hospital fire regulations and added difficulties with
blinding.
The DA re-examined the patients pulses at the end
of every session, as pulse changes during treatment are considered
important indicators of efficacy. On the basis of these, and the
verbal, pulse and tongue feedback at the start of the next session,
the DA varied the emphasis on different treatment principles and the
choice of acupuncture points prescribed for the next treatment.
Outcome measures and data analysis
Patients completed weekly symptom diaries, supplemented by
psychological and quality of life scales at entry and at 12th
wk (or prior exit). Therapeutic effects were judged from the diaries
and questionnaires, and by physician assessment.
The symptom diary is based on the Bristol scale[15]
and has been previously validated[16].
It employs eight Likert scales relating to abdominal symptomatology
and their interference with activities (Appendix), and permits the
compilation of a numerical (non-linear) global "symptom
score" between 0 and 30. Patients also completed the Hospital
Anxiety and Depression (HAD) scale[17],
and the EuroQol[18]
quality of life questionnaire.
The principal outcome measure was a change in the
symptom score. A reduction of four is considered indicative of a
clinically useful response, and was expected from sham or placebo
therapy in approximately 30% of eligible patients. Acupuncturists
expect to obtain a useful response in around 70% of patients with
IBS (informal enquiries of several practitioners), with the proviso
that limitations imposed by the experimental protocol might reduce
this a little.
Secondary outcome measures included assessment by
one of the blinded investigators at the end of the study period,
which made a simple categorization of patient status as "improved",
"unchanged"
or "worse".
Secondary outcomes also included changes on the HAD and EuroQol
instruments. As the principal objective is to reduce symptomatology
and to improve quality of life, the patients perceptions of these
are the outcomes of critical interest to them. The end-points
recorded are comparable to those utilized in respected studies of
this condition.
Statistical calculations for 60 subjects provided
for a study with 60% power to demonstrate a 30% numerical (not
relative) difference between the two groups, if a placebo response
of 30% is assumed. Results were analyzed by intention to treat.
Apart from the hospital notes all data were retained anonymously.
The study complied with the requirements of the Declaration of
Helsinki (1996 modification), the British Data Protection Act
(1984), the International Conference on Harmonization Tripartite
Guideline for Good Clinical Practice, and had approval from the
Harrow Research Ethics Committee.
Patients
Sixty patients (40 female) were recruited; one female withdrew after
recruitment but before randomization. Results are therefore recorded
for 59 individuals (Table 1). Twenty-eight patients were allocated
to acupuncturist A as the DA and to acupuncturist B as the TA, with
the converse in the other 31. There was a good balancing of the two
groups: for no parameter was there a statistically significant
difference at study entry (Table 1).
Role of sponsors: None in either design of the
study or in the writing of the report.
Table 1 Patient
characteristics at study entry
| |
Acupuncture
group |
Sham
group |
| Number |
27 |
32 |
| Number
female |
16 |
23 |
| Mean
age (yr) |
43.0 |
44.4 |
| Age
range (yr) |
19-67 |
17-79 |
| Predominant
symptom |
|
|
| Pain |
11 |
10 |
| Bloating |
7 |
11 |
| Diarrhea |
7 |
9 |
| Constipation |
2 |
2 |
| Mean
symptom score |
13.5 |
13.1 |
| Mean
anxiety score (HAD) |
10.2 |
11.2 |
| Mean
depression score (HAD) |
5.8 |
6.8 |
| Mean
EuroQol LAS score (%) |
59 |
64 |
HAD = hospital
anxiety and depression scale. LAS = linear analog scale.
RESULTS
The mean global symptom score in the acupuncture-treated patients
fell from 13.5�4.51 to 11.6�5.13, and in
the sham group from 13.1�4.30 to 11.2�4.17 (P<0.05
for one-tailed t test for the improvements in both study
groups) (Figure 1). A reduction in symptom score was observed in 16
acupuncture subjects (59.2%), and by at least four points in 11
(40.7%). The equivalent figures for the sham group were 21 (65.6%)
and 10 (31.2%). The differences between sham and actively treated
groups did not approach statistical significance.
Figure
1
(PDF) Change in the global symptom score from entry to 13 wk.
The upper panel shows the individual values for the actively treated
patients and the lower panel those for sham-treated patients.
The blinded clinician considered 13 of the
acupuncture group (48.1%) improved, compared to 10 of the sham group
(31.2%) (NS). These were predominantly the same patients who
considered themselves improved (reduction in symptom score of four
or more). Similar proportions in the two groups were considered to
have deteriorated or had withdrawn (18.5% vs 21.9%; NS).
For those with pain predominance at enrollment
the median score of 13 remained at 13 in the actively treated group,
and fell from 15 to 10 in the sham group; for bloating the
equivalent figures were 14 to 9, and 14 to 11; for diarrhea 11 to 8
compared to 11 to 10.5; and for constipation 16 to 15 vs 11
to 8.
There were no significant differences between the
HAD scores for the sham and active groups, but a slightly higher
proportion of the sham-treated group had anxiety scores in the "probable"
(≥12)
range (47% vs 41%). The response rate (drop of ≥4
symptom points) was 27% in the subset of anxious patients receiving
sham treatment and 54% in those on active therapy (NS).
The EuroQol score rose slightly (improvement) in
the actively treated (59.4-64.6%) and the sham treated (64.6-65.6%);
neither change was significant. There was no correlation between
initial EuroQol score and the likelihood of a response.
Acupuncturist A (as TA) treated 31 patients, of
whom 19 were allocated to sham therapy. Their mean score of 13.6�4.84 fell to
12.3�4.56; the
score fell by ≥4
in 7 (36.8%). In the 12 patients who received active acupuncture the
mean score fell from 14.3�4.68 to 11.6�6.69, with a
fall of ≥4
in 6 (50%). Acupuncturist B (as TA) treated 28 patients of whom 13
were allocated to sham; the score fell by ≥4
in 3 (23.1%) of these. In the 15 patients randomized to active
acupuncture a "qualifying"
fall in score occurred in 5 (33.3%). Overall 41.9% of patients "diagnosed"
by acupuncturist B and "treated"
by acupuncturist A responded with a qualifying fall in score,
compared to 28.6% of those with the acupuncturists filling the
alternative roles (NS).
Adverse events and non-completing patients
No direct adverse events were elicited. One patient was commenced on
antidepressants after psychiatric consultation, and another on
beta-blockers for anxiety. Six other patients failed to complete the
study period. Of these eight withdrawals, five belonged to the
acupuncture group and three to sham. These patients have been
included in the above analyses by intention to treat. If the
principal outcome measure is applied only to those completing the
intended therapy the results are unchanged: the mean symptom score
at completion of the acupuncture course was 11.4 compared to 10.9 in
the sham group (NS).
DISCUSSION
As expected there was a response to TCM acupuncture and to sham
treatment. The number of responding patients in the sham group and
the magnitude of the responses were in line with our prior
expectations (31.2% good responders compared to an anticipated 30%
placebo response). The study group is therefore likely to be
generally representative. Formal acupuncture failed to elicit
significant advantage (40.7% responders). There were several areas
in which numeric advantage lay with acupuncture, including the
clinician's
assessment and the proportion
achieving at least a four point reduction in symptom score, but sham
therapy had the numeric advantage if responses of any degree of
magnitude are included (65.6% vs 59.2%). There was no obvious
trend according to predominant symptom at study entry, but initial
anxiety possibly predicts a better response.
The inference that TCM acupuncture is of very
limited value in IBS is supported by the absence of positive data in
the literature, its absence from the conclusions of the NIH
consensus[4],
and from a small study which showed no effect on colonic motility in
constipation[19].
We are confident that our sham technique was performed with
retention of complete blinding of the DA, the gastroenterologist and
the patient. This necessarily unblinded nature of the treating
acupuncturist clearly had important effects on the two practitioners
concerned, who felt uncomfortable "deliberately
denying" the patient, a therapy in which they had confidence.
It is possible that this proved a confounding factor. The close
similarity of the outcome from sham therapy to that expected from
placebo suggests that neither positive nor negative effects
predominate. In consequence, it is not clear that anything would
have been gained by the use of sham needles, as has been advocated[20],
since while this strategy has the potential to conceal sham
administration from the TA it may unblind the patient. It is
acknowledged that the use of sham needling probably elicits
important physiological effects (such as increased endorphin
activation), but the absence of an obvious difference in response
rate in our sham group from that anticipated from "other"
placebos indicates that the effect is not one of lasting clinical
consequence.
The combination of acupuncturist B as
diagnostician with acupuncturist A as acupuncturist appeared "better"
than the converse. This was probably a direct consequence of the
individualization of therapy (by the TA as well as that planned by
the DA), but represents a post hoc and non-significant observation.
We deliberately chose to permit both acupuncturists to engage in
therapy so as to increase the generalizability of the study, hence
avoiding results dependent on the consequences of a unique pairing
of practitioners.
The outcome may have included systematic bias
against acupuncture. The specific dietary and lifestyle advice
considered important to TCM was given to all patients regardless of
randomization. It is unlikely that this was a major influence as the
sham response was closely similar to that expected for placebo. The
proscription of moxibustion would be expected to have placed the
actively treated group at a disadvantage compared to those treated
outside the study context. However, this technique cannot easily be
a practical proposition in health service premises in which fire
regulations and the presence of smoke detectors are ubiquitous. The
third factor potentially disadvantageous to acupuncture therapy was
the impossibility of completely individualized therapy in a formal
trial, and perhaps adverse influences from other constraints of the
hospital environment. This drawback was considered carefully during
the devising of the study and felt to be an acceptable compromise
between Western scientific method and traditional Chinese practice.
The possibility that simplified acupuncture as delivered by
Western-medicine-trained acupuncturists might have given a different
result is intriguing and may warrant further study.
The study was underpowered to demonstrate a small
benefit, but it was of sufficient size to confirm the large
difference that was anticipated. If such an effect has been missed
by the present study it is our opinion that it is of insufficient
clinical relevance to justify de novo investment in provision of
acupuncture services to hospital patients with IBS.
ACKNOWLEDGMENTS
We are also grateful for the support of our research nurses, to the
clinicians who referred patients to us, and to the patients
themselves. We greatly appreciate the very useful comments of Dr.
Andrew Thillainayagam, MD, FRCP (medically trained acupuncturist),
on an earlier draft of the manuscript.
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