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To what extent are surgery and invasive
procedures effective beyond a placebo
response? A systematic review with
meta-analysis of randomised, sham
controlled trials
Wayne B Jonas,
1
Cindy Crawford,
1
Luana Colloca,
2,3
Ted J Kaptchuk,
4
Bruce Moseley,
5
Franklin G Miller,
6
Levente Kriston,
7
Klaus Linde,
8
Karin Meissner
9
To cite: Jonas WB,
Crawford C, Colloca L, et al.
To what extent are surgery
and invasive procedures
effective beyond a placebo
response? A systematic
review with meta-analysis of
randomised, sham controlled
trials. BMJ Open 2015;5:
e009655. doi:10.1136/
bmjopen-2015-009655
▸
Prepublication history
and additional material is
available. To view please visit
the journal (http://dx.doi.org/
10.1136/bmjopen-2015-
009655).
Received 10 August 2015
Revised 28 October 2015
Accepted 5 November 2015
For numbered affiliations see
end of article.
Correspondence to
Dr Wayne B Jonas;
wjonas@siib.org
ABSTRACT
Objectives:
To assess the quantity and quality of
randomised, sham-controlled studies of surgery and
invasive procedures and estimate the treatment-specific
and non-specific effects of those procedures.
Design: Systematic review and meta-analysis.
Data sources: We searched PubMed, EMBASE,
CINAHL, CENTRAL (Cochrane Library), PILOTS,
PsycInfo, DoD Biomedical Research, clinicaltrials.gov,
NLM catalog and NIH Grantee Publications Database
from their inception through January 2015.
Study selection: We included randomised controlled
trials of surgery and invasive procedures that
penetrated the skin or an orifice and had a parallel
sham procedure for comparison.
Data extraction and analysis: Three authors
independently extracted data and assessed risk of bias.
Studies reporting continuous outcomes were pooled
and the standardised mean difference (SMD) with 95%
CIs was calculated using a random effects model for
difference between true and sham groups.
Results: 55 studies (3574 patients) were identified
meeting inclusion criteria; 39 provided sufficient data
for inclusion in the main analysis (2902 patients). The
overall SMD of the continuous primary outcome
between treatment/sham-control groups was 0.34
(95% CI 0.20 to 0.49; p<0.00001; I
2
=67%). The SMD
for surgery versus sham surgery was non-significant
for pain-related conditions (n=15, SMD=0.13, p=0.08),
marginally significant for studies on weight loss (n=10,
SMD=0.52, p=0.05) and significant for
gastroesophageal reflux disorder (GERD) studies (n=5,
SMD=0.65, p<0.001) and for other conditions (n=8,
SMD=0.44, p=0.004). Mean improvement in sham
groups relative to active treatment was larger in pain-
related conditions (78%) and obesity (71%) than in
GERD (57%) and other conditions (57%), and was
smaller in classical-surgery trials (21%) than in
endoscopic trials (73%) and those using percutaneous
procedures (64%).
Conclusions: The non-specific effects of surgery and
other invasive procedures are generally large.
Particularly in the field of pain-related conditions,
more evidence from randomised placebo-controlled
trials is needed to avoid continuation of ineffective
treatments.
INTRODUCTION
Surgery and other invasive procedures such
as endoscopy and percutaneous procedures
are widely used in medicine but their specific
efficacy and risk-benefitprofile are rarely
assessed in rigorous and systematic ways. The
development of minimally invasive proce-
dures has expanded the use of such interven-
tions for treating a variety of conditions such
as low-back pain,
1
arthritis,
2
endometriosis,
3
Parkinson’s disease,
4
gastro-oesophageal
reflux
5
and obesity.
6
Strengths and limitations of this study
▪ This is the first systematic review using a
meta-analysis approach to estimate both specific
and non-specific components in sham-controlled
surgical trials, and to what extent those effects
differ among conditions and procedures.
▪ All sensitivity analyses showed similar results as
the main analysis, except one, namely the sensi-
tivity analysis for large studies (≥100 patients),
which showed a smaller non-significant effect
size.
▪ Our results have implications for clinical research
and practice by arguing against the continued
use of ineffective invasive treatments, especially
in the field of chronic pain.
▪ One limitation might be that the conclusions
from our meta-analysis are restricted to available
published data on surgical interventions that
have been tested in sham-controlled clinical
trials.
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Rarely are these procedures evaluated using rigorous
research designs involving randomisation, allocation
concealment and blinding or placebo controls, which
are considered gold standards for medical interventions.
In the absence of controls for common sources of bias,
studies on these procedures may give a false impression
of their true efficacy. Is it possible to test invasive proce-
dures using rigorous methods? Blinding of outcome
assessment is challenging since mimicking a complex,
invasive procedure such as surgery, or insertion of a
scope or a needle, requires an elaborate sham proced-
ure. Moreover, there is signi ficant controversy over the
ethics of using sham procedures, even with carefully
informed patients, further restricting the number of
such studies being carried out.
78
However, can we justify
widespread use of these procedures wit hout rigorous
testing?
The use of blinded, sham procedures permits rigorous
assessment of treatment efficacy by comparing the
outcome in the treatment and sham groups. Specifically,
sham procedures control for a variety of observed out-
comes in the sham group that are distinct from the spe-
cificefficacy of the surgery or invasive procedure under
investigation. These ‘non-specific’ outcomes include
placebo responses (also sometimes called placebo
effects), which we define here as the observed outcome
changes in the sham groups. These changes are due to
the natural history of the patient’s condition or regres-
sion to the mean and a response to the ritual of medical
treatments. Such rituals include the type of procedure
(pill, needle, knife or touch), the status, authority and
communication style of the provider, the setting and
context of the treatment and the patient’s and practi-
tioners expectation about the outcome.
9
Yet, invasive procedures are thought to incorporate
many factors that may contribute to the placebo
responses including use of a hospital-like setting; mul-
tiple, authoritative providers; frequent and repeated sug-
gestions about expected outcomes; a physical invasion of
the body; and an elaborate ritual of treatment delivery
and recovery.
10
Thus, one would expect a significant
contribution from surgical ritual and other non-specific
factors to the observed outcomes during invasive proce-
dures in clinical practice and in randomised trials
without sham control groups. Several high profile
studies support this hypothesis in which sham proce-
dures involving only superficial anaesthesia were com-
pared to the more invasive true procedure.
11–13
For
example, Moseley et al
11
reported no greater pain
improvement in patients with osteoarth ritis of the knee
that underwent arthroscopic knee surgery compared to
a sham procedure in which a cut was made over the
knee without introducing the arthroscope. Two more
recent controlled studies of vertebroplasty for painful
osteoporotic vertebral fractures reported similar degrees
of pain relief from sham procedures involving only
superficial anaesthesia compared to the more invasive
active procedures.
12 13
In contrast, a systematic review
comparing surgical with non-surgical treatments for
painful osteoporotic vertebral fractures came to the con-
clusion that vertebropla sty and kyphoplasty are superior
to non-surgical treatments.
14
Since invasive interventions
frequently go along with larger non-specific effects than
non-invasive treatments
15 16
surgical trials that do not
include a sham surgery arm may give biased results.
Thus, the efficacy of invasive procedures, for example,
for chronic pain conditions, remains controversial.
17
In
addition, many invasive procedures involve the risk of
anaesthesia and high cost.
17
Therefore, it is important to
estimate to what degree the observed outcomes from
invasive procedures are due to specificefficacy of the
treatments or to other factors.
To better understand these issues we conducted a sys-
tematic review and meta-analysis of studies on surgery
and invasive procedures in which a parallel sham pro-
cedure was included for comparison. Our study aims
were to: (1) assess the quantity and quality of such
studies; (2) estimate the magnitude of specific effects
over sham procedures; and, (3) estimate the contribu-
tion of the surgical ritual and other non-specific factors
to outcomes from these procedures.
METHODS
Identification of studies
The following online databases were searched from their
inception through January 2015: PubMed, EMBASE,
CINAHL, CENTRAL (Cochrane Library), PILOTS,
PsycInfo, DoD Biomedical Research, clinicaltrials.gov,
NLM catalog, as well as NIH Grantee Publications
Database. We used as our initial search terms:
‘Diagnostic Techniques, Surgical’ OR ‘Orthopedic
Procedures’ OR ‘Specialties, Surgical’ OR ‘Surgical
Procedures, Operative’ OR ‘surgery’ (Subheading) or
surgery) AND (‘Placebos’ OR ‘Placebo Effect’ or sham
surg* or placebo surg* or mock surg* or simulated
surg* or placebo proc* or sham proc* or mock proc* or
simulated proc*). We restricted our search to humans
and randomised controlled trials. Variations of these
search terms were made for MESH terms, where neces-
sary, and are available on request from the first author.
The ‘Grey literature’ was searched by looking for rele-
vant dissertations, conference proceedings, Google
Scholar and searching the internet using the keyword
scheme as well as searching all relevant reference lists of
identified articles and related reviews. We also contacted
and consulted with leading experts in the fields of
surgery and placebo, and shared databases that these
experts have collected over the years relating to placebo
to make sure we captured all the relevant literature.
Eligibility criteria
Studies were included in the systematic review if they:
(1) were randomised controlled trials; (2) involved a
population for which there was a symptom-driven
medical condition for which an invasive procedure or
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classical surgery as defi ned below was being performed;
and (3) had a comparison group that used a sham pro-
cedure to mimic the real procedure.
Classical surgery was defined as a procedure that fol-
lowed the typical surgical experience that uses preopera-
tive preparation, anaesthesia, an incisional trauma
(usually through muscle and fascia and into the periton-
eum) and a postoperative recovery process. Invasive pro-
cedures were defined as when an instrument was
inserted into the body (either endoscopically or percu-
taneously) for the purpose of manipulating tissue or
changing anatomy. In all cases we selected studies where
when these procedures were compared to a sham pro-
cedure that used the same surgical or invasive proced-
ure, instrument and ritual, but eliminated the
hypothesised active component of tissue manipulation.
We excluded studies in which the procedure was used
simply as a delivery mechanism for another ongoing
active treatment such as a pacemaker, brain or cardiac
stimulation, or delivery of a drug or biological product.
Studies where an invasive procedure was implemented
for prevention of a medical condition or there was no
symptom-driven condition were also excluded.
Four investigators (CC, LC, KL and KM) screened
titles and abstracts for relevance in two phases based on
the inclusion criteria : phase one eliminated all clearly
irrelevant studies, phase two applied all inclusion/exclu-
sion criteria listed above for the remaining studies. Any
disagreements about including a study were resolved
through discussion and consensus, and approved by the
first author (WJ). All reviewers were fully trained in sys-
tematic review methodology. At least two reviewers had
to review each citation in order for it to progress to the
next phase of the review. A Cohen’s κ on agreement was
attained for both phases above 88%.
Quality assessment and data extraction
The methodological quality of the individual studies
(sequence generation, allocation concealment, was
assessed independently by three reviewers using the
Cochrane Risk of Bias (ROB) tool.
18
Descriptive data
was independently extracted on the following items:
population; condition for which surgery was performed;
sample (population) entered; dropout rate; informed
consent details; whether a power calculation was per-
formed and achieved; intervention and sham procedure
used; primary and secondary outcomes and the statistical
data associated with these; whether expectation was
reported; author conclusions; adverse events reported;
funding source, and reviewer comments. We also
extracted from each study, if available, a continuous and
a dichotomous main outcome at two time points (inter-
mediate and late), and a continuous and a dichotomous
pain outcome (when applicab le). The most important
outcome measure (miOM) was defined as either: (1)
the primar y main outcome measure (pMOM) at a time
point as predefined in the trial; or (if not 1), (2) the
only major outcome of a trial at the latest available time
point; or (if neither 1 nor 2), (3) the clearly most rele-
vant outcome determined by two independent reviewers
at the latest available time point. Secondary outcomes
were intermediate time points of the most important
outcome measure; pain outcomes at the latest available
time point; or, pain outcomes at the intermediate time
point. All discrepancies were tracked by the review
manager and were resolved by consensus and discussions
during team meetings. Data were entered into a web-
based, secure, systematic review management pro-
gramme called Mobius Analytics SRS (Mobius Analytics
Inc, Ottawa, Ontario, Canada).
Data synthesis and analysis
According to our analysis plan, the meta-analyses
focused on continuous outcomes. The primary analysis
was based on trials reporting a most important continu-
ous outcome measure in sufficient detail to be included
in the meta-analysis. Secondary analyses were based on
trials reporting (1) a continuous outcome measure at an
intermediate time point, (2) a pain measure at a late
time point, (3) a pain measure at an intermediate time
point. Trials reporting only a dichotomous outcome
measure (responder data) are noted in online supple-
mentary table 1, and a sensitivity analysis was computed
for these outcomes (see below).
Within-group and between-group effect sizes were
based on Cohen’s
19
d for change within one group, and
Cohen’s d for between-group effect measures, respect-
ively, correcting for small-sample bias.
20
In order to keep
the effect size framework coherent for within-group and
between-group designs, change from baseline was used
throughout. When SD was not reported, it was calcu-
lated from pre-SD and post-SD,
21
using r=0.5 for the
product-moment correlation between pre and post
measures.
Analyses of continuous data were performed with the
generic inverse variance module of the Cochrane
Collaboration’s Review Manager software (V.5.1), using
standardised mean difference (SMD) as the effect size
measure. As we expected heterogeneity, a random
effects model was used. Within-group effect sizes were
pooled in such a way that positive values indicate
improvement, while positive values of between-group
effect sizes indicate superiority (more pronounced
improvement) of the intervention group over the
control (sham) group. To estimate the relative contribu-
tion of non-specific outcomes to treatment effects, the
per cent ratio of the pooled within-group treatment
effects in the sham and the treatment groups was calcu-
lated. We used Cochrane’s Q test and calculated I
2
to
examine statistical heterogeneity, with low, moderate
and high I
2
values of 25%, 50%, and 75%.
22
Egger’s
test was used to assess funnel plot asymmetry.
23
A p value of less than 0.05 was set as the level
of significance.
24 25
Subgroup analyses were performed according to pre-
defined categories of target diseases and types of
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surgery. To check the robustness of results, we per-
formed sensitivity analyses with four criteria: (1) studies
specifying a primary main outcome measure (pMOM);
(2) imputing 0.3 and 0.7 for pre–post correlation coeffi-
cient r, when missing; (3) studies with total sample sizes
≥100; and, (4) studies with low risk of allocation con-
cealment. An additional sensitivity analysis was per-
formed for dichotomous outcomes of 12 studies that
provided no continuous outcome (see online supple-
mentary figure 1).
RESULTS
Eligible studies
Our search identified a total of 7360 citations. After
excluding clearly irrelevant references the full text of
113 publications were obtained. Of these, 46 were
excluded, mainly for not including an instrumental or
surgical intervention or a sham procedure as defined
above. A total of 55 studies (in 67 publications) involving
a total of 3574 enrolled patients met our inclusion cri-
teria for systematic review (figure 1).
26
Characteristics and quality of included studies
Characteristics of the included studies are summarised in
online supplementary table 1. About half (25) of the
studies were carried out on pain-related conditions with
back pain (7) being the most frequent
11 12 27–31
followed
by arthritis (4),
13 32–34
angina from coronary artery
disease (4),
35–39
) abdominal pain (3),
40–42
endometriosis
(3),
43–47
cholia (2)
48 49
and migraine (2).
50 51
) The most
frequently studied non-pain condition was obesity,
especially when using balloon insertion (11).
52–62
) Other
conditions that had more than one study included gastro-
esophageal reflux disease (GERD) (5),
63–67
Parkinson’s
Disease (2),
68–74
sleep apnoea (2),
75 76
dry eye (2)
77 78
and asthma (2).
79–81
Some other conditions were also
studied (see online supplementary table 1).
80–90
Many
(22) of the studies involved endoscopic or percutaneous
procedures in which tissue was removed or altered or a
material (eg, dye, cement, balloon) was inserted.
11–13
28 31 34 38 40–43 52 54 56 61 63 65 67 77–79 90
Some of these
procedures used a catheter to reach an internal organ
(such as the heart or gall bladder) or a needle to inject a
material or cell (often into the lumbar spine or
Figure 1 Flow chart of included
studies. RCT, randomised
controlled trial.
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brain).
27 29 30 32 53 55 57 59 60 62 64 66 85 89
Five studies evalu-
ated more classi cal surgical procedures in which the body
was opened with a scalpel or drill.
50 51 74–76
In most studies, blinding was achieved using elaborate
sham procedures. Those mimicking classical surgical
procedures usually cut the body, leaving a scar but
causing less damage than the real surgery. Sham percu-
taneous and endoscopic procedures often involved
superficial insertion of a needle or a scope. For
example, in the Parkinson’s studies on surgical interven-
tions on the brain, sham procedures involved placing
burr holes without penetration of the skull.
68–74
Sham
surgery for endometriosis would often involve ‘diagnos-
tic laparoscopy’ with no internal tissue destruction.
Sham balloon insertion for obesity treatment usually
involved inserting the balloon but not inflating it.
52–62
Overall, the risk of bias was low in these studies, with
some exceptions. Of the 55 studies (67 publications)
included in the systematic review, 34 studies (62%)
reported an adequate method for generating the alloca-
tion sequence, however only 23 (42%) had adequate
concealment of allocation. Blinding of the patients and
outcome assessors was adequate in 48 (87%) studies and
incomplete data was adequately addressed in 52 (95%).
Fifty-two (95%) of the studies were free from suggestion
of selective outcome reporting and 53 studies were
judged to be free of other sources of bias.
Overall analyses
Thirty-nine studies (2902 patients) with continuous data
were included in the main analysis. The overall effect of
surgery compared to sham surgery was highly significant
(SMD 0.34, 95% CI 0.20 to 0.49; p<0.00001), while het-
erogeneity was large (I
2
=67%, p<0.00001). Excluding
one outlier
52
reduced I
2
to 57% (SMD, 0.30, 95% CI
0.17 to 0.43; p<0.00001), indicating moderate heterogen-
eity. Sensitivity analyses provided comparable effect sizes
(figure 2), except for studies with overall sample sizes of
100 participants or more, for which the SMD was non-
significant at 0.15 (n=10; 95% CI −0.02 to 0.32; p=0.09;
I
2
=66%). Inspection of the funnel plot suggests the pres-
ence of biases in the meta-analysis, such as small study
bias or publication bias (figure 3). Asymmetry in the
funnel plot was confirmed by the Egger’s test (asym-
metry coefficient 1.7, p=0.017).
Non-significant SMD were found when combining
available data for the most important continuous
outcome measure at an intermediate time point (n=14;
SMD 0.12, 95% CI − 0.05 to 0.29; p=0.17; I
2
=54%) as
well as for specific pain outcomes at a late (n=14; SMD
0.12, 95% CI −0.03 to 0.27; p=0.11; I
2
=29%;) or an inter-
mediate time point (n=8; SMD 0.07, 95% CI −0.06 to
0.20; p=0.31; I
2
=0%).
Subgroup analyses of most important outcome measures
Subgroups by condition
Figure 4 summarises the SMD and subgroup means for
between-group changes and the 95% CIs for each
condition. The overall test for subgroup differences was
significant (χ
2
=10.26, p=0.04), indicating significant het-
erogeneity of SMD between subgroups. Fifteen studies
(analysing 1584 patients) included in the meta-analysis
investigated pain-related conditions, the overall SMD was
non-significant at 0.13 (95% CI −0.01 to 0.28; p=0.08;
I
2
=46%). Ten studies (287 patients) reported on weight
loss, the SMD was marginally significant at 0.52 (95% CI
0.01 to 1.03; p=0.05; I
2
=76%). Excluding one outlier
52
reduced I
2
to 14% (SMD 0.27, 95% CI 0.00 to 0.55;
p=0.05). Most (nine) of these studies involved balloon
and sham balloon ins ertion. Five studies (342 patients)
involved GERD. They showed a significant SMD of 0.65
(95% CI 0.31 to 1.00; p=0.0002; I
2
=55%). One study on
Parkinson’s (34 patients) showed an SMD of 0.36 (95%
CI −0.37 to 1.09). Eight studies (655 patients) on other
diseases yielded a pooled SMD of 0.44 (95% CI 0.14 to
0.74, p=0.004; I
2
=57%).
Subgroups by type of procedure
Between-group SMD did not differ significantly between
classical surgery, endoscopic surgery and percutaneous
procedures (χ
2
=1.10, p=0.58; results not shown).
Dichotomous outcomes
Twelve studies provided only a dichotomous outcome
measure (see online supplementary table 1). Sensitivity
analyses showed an overall effect of surgery compared to
sham surgery (risk ratio 1.54, 95% CI 1.11 to 2.15;
p=0.01), while heterogeneity was large (I
2
=59%,
p=0.005). Subgroup analyses according to condition
revealed a significant effect of surger y versus sham
surgery for pain studies (n=9; risk ratio 1.60, 95% CI 1.11
to 2.30; p=0.01; I
2
=59%, p=0.01) but not for other studies
(n=3; risk ratio 2.19, 95% CI 0.44 to 10.84; p=0.33;
I
2
=60%, p=0.08; see online supplementary figure 1).
Changes from baseline within sham and active groups
The pooled SMD for changes from baseline was 0.61 in
the sham groups (95% CI 0.47 to 0.75, p<0.00001, n=39,
I
2
=76%) and 0.92 (95% CI 0.74 to 1.09, p<0.00001,
n=39, I
2
=86%) in the treatment groups. Thus, on
average, the changes in the sham groups accounted for
65% of the overall improvement from the treatments.
This proportion of specific to non-specific treatment
effects was larger in pain-related conditions (78%) and
obesity (71%) than in GERD (57%) and other condi-
tions (57%), and was considerably smaller in classical
surgery trials (21%) than in endoscopic trials (73%) and
those using percutaneous procedures (64%; figure 4).
Changes in the sham groups accounted for 89% and
82% of overall improvement in intermediate and late
pain outcomes.
DISCUSSION
This is the first comprehensive systematic review with
meta-analysis estimating the magnitude of the specific
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effects of surgery and invasive procedures for various
conditions. While some high profile studies have
reported no difference between treatment and sham
procedures, we found a positive though modest overall
effect size (Cohen’s d) from the invasive procedures
included in the analysis. When only larger studies (≥100
participants) are taken, the specific effects invasive pro-
cedures disappears, indicating the current evidence is
Figure 2 The specific effect of
invasive procedures and surgery.
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not strong and could be changed with more and better
research. In addition, the contribution of non-specific
effects is even more substantial for certain conditions
and procedures. While non-specific effects accounted
for approximately 65% of the effects from all invasive
procedures, they made up to 78% of the active treat-
ment effects in chronic pain conditions and 71% of the
active treatment effects in obesity. These percentages are
substantially higher than those observed in non-surgical
trials, namely 40% for chronic pain conditions and 33%
for obesity.
91
The higher contribution of non-specific
effects in surgical trials could well be the result of
higher placebo effects. However, the lack of
no-treatment groups in our data set (and other data
set)
92
allows no fi rm conclusion.
91
Our subgroup ana-
lyses indicate that the current evidence does not support
the specificefficacy of invasive procedures for chronic
pain conditions (p=0.08) and was borderline for obesity
(p=0.05), but does support these procedures for GERD
(p=0.0002). However, please note that the analysis of
dichotomous outcomes showed a somewhat larger spe-
cific effect for pain studies (see online supplementary
figure 1). There is ins ufficient data to make recommen-
dations about the other conditions examined.
Strengths and weakness of this study
This study has several limitations. First, both the central
strength and limitation of our study is that we pooled
effect estimates of the included studies. We consider this
a strength at is allows us to: (1) make an estimate of the
overall effects of invasive procedures in sham-controlled
surgical studies, (2) estimate the strength of confidence
in the currently available data as to the specificefficacy
of those procedures; and, (3) empirically investigate to
what extent results differ between conditions and proce-
dures. Obviously, it is not reasonable to expect that
surgery has similar specific effects across conditions and
outcomes so our subgroup estimates should not be inter-
preted clinically without considering how the interven-
tions and outcomes varied. This is also indicated by the
moderate-to-large heterogeneity in our meta-analyses,
indicating more variation of effect sizes than would be
expected by chance. Second, it is difficult to fully
double-blind invasive procedures. While most studies
successfully blinded patients and outcome assessors, phy-
sicians doing these procedures could not be blinded.
Thus, it is possible that they communicated information
to patients that biased the studies. Price and others have
shown that physician expectations can influence pain
outcomes even when restrictions are placed on verbal
communication.
93 94
Third, public ation bias may play a
role in the accuracy of our estimates. It is known that
negative studies (in this case, studies showing no differ-
ence between real and sham procedures) are not pub-
lished as frequently as positive studies. However, our
search strategy was comprehensive and the study selec-
tion process was reliable. We also conducted a thorough
search of the grey literature, as described above, and
had input by experts in placebo research, increasing the
likelihood of capturing all studies in this area. This activ-
ity allowed for a cross-check in the end to ensure we cap-
tured most of the relevant published randomised
controlled trials for this review. We did not find any
unpublished reports that met our inclusion criteria
appropriate for this review, however there were some
publications that were not readily accessible through the
search engines commonly accessed that we were able to
Figure 3 Funnel plot using continuous outcomes (effects of
active vs sham treatment) of the 39 studies included in the
main meta-analysis.
Figure 4 Relative contribution to
improvement in the placebo and
active treatment groups.
Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655 7
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capture through these methods. Our sensitivity analyses
on study quality factors did not change our primary find-
ings, except restricting the analyses to large studies with
100 participants and above, revealed a considerably
smaller, non-significant SMD at 0.15 (95% CI −0.02 to
0.32; p=0.09). Egger’s test for funnel plot asymmetry,
however, suggested a small study bias in our data set.
While our combined estimates of effect size must be
considered crude for the overall meta-analysis, they are
reasonable estimates for the pain, GERD and obesity
subgroups. Meta-analyses of placebo-controlled drug
studies in pain, depression, hypertension, ulcer treat-
ment and other areas often report a similar magnitude
of specific treatment effects compared to non -specific
effects.
95–98
Those studies, however, usually have much
larger sample sizes, increasing confidence in their esti-
mates. Finally, we found only one three-armed study that
included no treatment, active and sham groups.
67
Therefore, it is not possible to estimate the contribution
that the ritual and context make to outcomes in invasive
procedures compared to no treatment. Especially in the
field of pain and obesity such three-armed studies would
seem to be essential for making good evidence-based
decisions.
Our findings are consistent with a systematic review
published in the BMJ in 2014.
92
That study, however,
used vote count and reported that 74% of 55 trials
showed improvement in the placebo arm with 51%
reporting no difference between surgery and placebo
and 49% reporting surgery was superior to placebo. We
have built on that study by doing a more comprehensive
literature search and meta-analysis which allowed us to
estimate the magnitude of surgical effects, the confi-
dence in the current findings and to examine that mag-
nitude across various quality parameters, conditions,
procedures and outcomes. We can now conclude that at
least chronic pain conditions lack clear evidence for the
efficacy of the explored surgical interventions (eg,
classic surgery and endoscopic procedures. Since these
conditions represent a high public health burden world-
wide we need to obtain better evidence for the use of
these procedures. In addition, it is clear that the evi-
dence from placebo controlled trials in the field as a
whole is poor.
Implications for practice, research and policy
These results have a number of implications for practice,
research and policy. The evidence from available sham-
controlled trials indicates that invasive procedures are
not clearly more effective than sham procedures for
various chronic pain conditions including endometri-
osis, back pain, arthritis, angina and migraine. There is
evidence to support surgical interventions for GERD
and limited evidence to support the use of balloon inser-
tion for obesity.
Given the large number of invasive and surgical proce-
dures being performed, it is noteworthy that we could
identify only 55 sham-controlled studies in the literature.
Certainly, not all invasive procedures warrant sham-
controlled comparisons; for example, when results dem-
onstrate indisputable changes in objective parameters
the risks of sham procedures would be excessive.
However, given that non-specific factors make a large
contribution to the effects from invasive procedures for
conditions like pain, more rigorous evaluation is needed
before their widespread use is recommended for these
conditions. A recent survey of surgeon’s attitudes about
sham surgery may provide an opportunity to conduct
more such research. Surgeons generally agreed that a
placebo component to surgical intervention might
exist.
99
Furthermore, results of a recent systematic review
indicate that the risks of adverse effects associated with
sham surgical procedures are small.
92
Thus, more well-
designed sham-controlled surgical trials are warranted to
avoid the continued use of ineffective invasive
treatments.
Author affiliations
1
Samueli Institute, Alexandria, Virginia, USA
2
Department of Pain and Translational Symptom Science, School of Nursing,
University of Maryland, Baltimore, Maryland, USA
3
Department of Anesthesiology, School of Medicine, University of Maryland,
Baltimore, Maryland, USA
4
Program in Placebo Studies, Beth Israel Deaconess Medical Center, Harvard
Medical School Boston, Massachusetts, USA
5
The Methodist Hospital, Houston, Texas, USA
6
Department of Bioethics, Clinical Center, National Institutes of Health,
Bethesda, Maryland, USA
7
Department of Medical Psychology, University Medical Center Hamburg-
Eppendorf, Hamburg-Eppendorf, Hamburg, Germany
8
Institute of General Practice, Technische Universitat Munchen, Munich,
Germany
9
Institute of Medical Psychology, Ludwig-Maximilians-University Munich,
Munich, Germany
Acknowledgements The authors would like to thank Ms LaDonna Johnson,
Research Assistant at Samueli Institute for assistance with article retrieval
and tracking, and Ms Viviane Enslein for assistance with manuscript
preparation.
Contributors WBJ served as the PI on this project and was responsible for
the conception and design of the project, obtaining funding, acquisition of
data and interpretation of the data, drafting and final revision of the article,
and final approval of the version submitted. CC served as the project
manager and reviewer, and contributed to the conception and design of the
systematic review, acquisition of data and analysis and interpretation of
data, drafting the article, and approval of the version to be submitted. LC
and KM served as study quality reviewers and contributed to the
conception and design, acquisition of data, analysis and interpretation of
data, drafting the manuscript and approval of the version to be submitted.
In addition, KM led the meta-analysis section of the project. TJK and FGM
served as subject matter experts, and were involved in the conception and
design and interpretation of the data, revising the manuscript critically for
important intellectual content and approval of the version to be submitted.
LK served as the statistical expert on the project and was involved in the
design and conduct of the meta-analysis, acquisition of data, analysis and
interpretation of the data, contributing to the manuscript in statistics,
meta-analysis techniques, the results section of the manuscript and
approval of the version submitted. KL served in the conception and design,
acquisition of the data, analysis and interpretation of the data, design of the
meta-analysis technique for extracting data, assisted in drafting and revising
the article for important intellectual content, and approval of the version to
be submitted.
8 Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655
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group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
Funding This work is supported by the US Army Medical Research and
Materiel Command under Award number W81XWH-08-1-0615. The views,
opinions and/or findings contained in this report are those of the author(s)
and should not be construed as an official Department of the Army position,
policy or decision unless so designated by other documentation. The funding
source had no role in the design and conduct of the study, in the collection,
analysis and interpretation of the data, or in the preparation, review, or
approval of the manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/4.0/
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Wayne B Jonas, Cindy Crawford, Luana Colloca, Ted J Kaptchuk, Bruce
doi: 10.1136/bmjopen-2015-009655
2015 5: BMJ Open
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