ArticlePDF Available

To what extent are surgery and invasive procedures effective beyond a placebo response? A systematic review with meta-analysis of randomised, sham controlled trials

Article

To what extent are surgery and invasive procedures effective beyond a placebo response? A systematic review with meta-analysis of randomised, sham controlled trials

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; I2=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.
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 specic
efcacy and risk-benetprole 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
Parkinsons disease,
4
gastro-oesophageal
reux
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.
Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655 1
Open Access Research
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
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 efcacy. 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 cant 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 efcacy by comparing the
outcome in the treatment and sham groups. Specically,
sham procedures control for a variety of observed out-
comes in the sham group that are distinct from the spe-
cicefcacy of the surgery or invasive procedure under
investigation. These non-specic outcomes include
placebo responses (also sometimes called placebo
effects), which we dene here as the observed outcome
changes in the sham groups. These changes are due to
the natural history of the patients 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 patients 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 signicant
contribution from surgical ritual and other non-specic
factors to the observed outcomes during invasive proce-
dures in clinical practice and in randomised trials
without sham control groups. Several high prole
studies support this hypothesis in which sham proce-
dures involving only supercial anaesthesia were com-
pared to the more invasive true procedure.
1113
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
supercial 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-specic effects than
non-invasive treatments
15 16
surgical trials that do not
include a sham surgery arm may give biased results.
Thus, the efcacy 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 specicefcacy 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 specic effects
over sham procedures; and, (3) estimate the contribu-
tion of the surgical ritual and other non-specic 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 rst 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
identied articles and related reviews. We also contacted
and consulted with leading experts in the elds 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
2 Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
classical surgery as dened below was being performed;
and (3) had a comparison group that used a sham pro-
cedure to mimic the real procedure.
Classical surgery was dened 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 dened 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
rst 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 Cohens 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 dened as either: (1)
the primar y main outcome measure (pMOM) at a time
point as predened 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 sufcient 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 Cohens
19
d for change within one group, and
Cohens 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
Collaborations 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-specic 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 Cochranes Q test and calculated I
2
to
examine statistical heterogeneity, with low, moderate
and high I
2
values of 25%, 50%, and 75%.
22
Eggers
test was used to assess funnel plot asymmetry.
23
A p value of less than 0.05 was set as the level
of signicance.
24 25
Subgroup analyses were performed according to pre-
dened categories of target diseases and types of
Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655 3
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
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 prepost correlation coef-
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 gure 1).
RESULTS
Eligible studies
Our search identied 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 dened
above. A total of 55 studies (in 67 publications) involving
a total of 3574 enrolled patients met our inclusion cri-
teria for systematic review (gure 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 2731
followed
by arthritis (4),
13 3234
angina from coronary artery
disease (4),
3539
) abdominal pain (3),
4042
endometriosis
(3),
4347
cholia (2)
48 49
and migraine (2).
50 51
) The most
frequently studied non-pain condition was obesity,
especially when using balloon insertion (11).
5262
) Other
conditions that had more than one study included gastro-
esophageal reux disease (GERD) (5),
6367
Parkinsons
Disease (2),
6874
sleep apnoea (2),
75 76
dry eye (2)
77 78
and asthma (2).
7981
Some other conditions were also
studied (see online supplementary table 1).
8090
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.
1113
28 31 34 38 4043 52 54 56 61 63 65 67 7779 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.
4 Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
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 7476
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
supercial insertion of a needle or a scope. For
example, in the Parkinsons studies on surgical interven-
tions on the brain, sham procedures involved placing
burr holes without penetration of the skull.
6874
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 inating it.
5262
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 signicant
(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
(gure 2), except for studies with overall sample sizes of
100 participants or more, for which the SMD was non-
signicant 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 (gure 3). Asymmetry in the
funnel plot was conrmed by the Eggers test (asym-
metry coefcient 1.7, p=0.017).
Non-signicant 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 specic 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
signicant (χ
2
=10.26, p=0.04), indicating signicant 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-signicant 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 signicant 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 signicant SMD of 0.65
(95% CI 0.31 to 1.00; p=0.0002; I
2
=55%). One study on
Parkinsons (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 signicantly 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 signicant 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 gure 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 specic to non-specic 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%; gure 4).
Changes in the sham groups accounted for 89% and
82% of overall improvement in intermediate and late
pain outcomes.
DISCUSSION
This is the rst comprehensive systematic review with
meta-analysis estimating the magnitude of the specic
Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655 5
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
effects of surgery and invasive procedures for various
conditions. While some high prole studies have
reported no difference between treatment and sham
procedures, we found a positive though modest overall
effect size (Cohens d) from the invasive procedures
included in the analysis. When only larger studies (100
participants) are taken, the specic effects invasive pro-
cedures disappears, indicating the current evidence is
Figure 2 The specific effect of
invasive procedures and surgery.
6 Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
not strong and could be changed with more and better
research. In addition, the contribution of non-specic
effects is even more substantial for certain conditions
and procedures. While non-specic 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-specic
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 rm conclusion.
91
Our subgroup ana-
lyses indicate that the current evidence does not support
the specicefcacy 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-
cic effect for pain studies (see online supplementary
gure 1). There is ins ufcient 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 condence
in the currently available data as to the specicefcacy
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 specic 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 difcult 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 inuence 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 nd 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
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
capture through these methods. Our sensitivity analyses
on study quality factors did not change our primary nd-
ings, except restricting the analyses to large studies with
100 participants and above, revealed a considerably
smaller, non-signicant SMD at 0.15 (95% CI 0.02 to
0.32; p=0.09). Eggers 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 specic treatment effects compared to non -specic
effects.
9598
Those studies, however, usually have much
larger sample sizes, increasing condence 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
eld of pain and obesity such three-armed studies would
seem to be essential for making good evidence-based
decisions.
Our ndings 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 con-
dence in the current ndings 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
efcacy 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 eld 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-specic 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 surgeons 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
Open Access
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/
REFERENCES
1. Friedly J, Standaert C, Chan L. Epidemiology of spine care:
the back pain dilemma. Phys Med Rehabil Clin N Am 2010;21:
65977.
2. Khanna A, Gougoulias N, Longo UG, et al. Minimally invasive total
knee arthroplasty: a systematic review. Orthop Clin North Am
2009;40:47989, viii.
3. Donnez J, Squifflet J, Donnez O. Minimally invasive gynecologic
procedures. Curr Opin Obstet Gynecol 2011;23:28995.
4. Politis M, Lindvall O. Clinical application of stem cell therapy in
Parkinsons disease. BMC Med 2012;10:1.
5. Rosemurgy AS, Donn N, Paul H, et al. Gastroesophageal reflux
disease. Surg Clin North Am 2011;91:101529.
6. Encinosa W, Bernard D, Steiner C, et al. Use and costs of bariatric
surgery and prescription weight-loss medications. Health Aff
2005;24:103946.
7. Miller FG, Kaptchuk TJ. Sham procedures and the ethics of clinical
trials. J R Soc Med 2004;97:5768.
8. Miller FG, Wendler D. The ethics of sham invasive intervention trials.
Clin Trials 2009;6:4012.
9. Meissner K, Bingel U, Colloca L, et al. The placebo effect: advances
from different methodological approaches. J Neurosci
2011;31:1611724.
10. Johnson A. Surgery as placebo. Lancet 1994;344:11402.
11. Moseley JB Jr., OMalley K, Petersen NJ, et al. A controlled trial of
arthroscopic surgery for osteoarthritis of the knee. New Engl J Med
2002;347:818.
12. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of
vertebroplasty for painful osteoporotic vertebral fractures. N Engl J
Med 2009;361:55768.
13. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of
vertebroplasty for osteoporotic spinal fractures. N Engl J Med
2009;361:56979.
14. Papanastassiou ID, Phillips M, Van Meirhaeghe J, et al. Comparing
effects of kyphoplasty, vertebroplasty, and non-surgical management
in a systematic review of randomized and non-randomized controlled
studies. Eur Spine J 2012;21:1826
43.
15. Meissner K, Fässler M, Rücker G, et al. Differential effectiveness of
placebo treatments: a systematic review of migraine prophylaxis.
JAMA Intern Med 2013;173:194151.
16. Bannuru RR, McAlindon TE, Sullivan MC, et al. Effectiveness and
implications of alternative placebo treatments: a systematic review
and network meta-analysis of osteoarthritis trials. Ann Intern Med
2015;163:36572.
17. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus
intensive medical therapy in obese patients with diabetes. N Engl J
Med 2012;366:156776.
18. Higgins J. Chapter 8: assessing risk of bias of included studies. In:
Higgins J, Green S, eds. Cochrane handbook of systematic reviews
of interventions. Wiley Online Library, 2008. http://handbook.
cochrane.org/chapter_8/8_assessing_risk_of_bias_in_included_
studies.htm
19. Cohen J. Statistical power analysis for the behavioral sciences. 2nd
edn. Hillsdale, NJ: Erlbaum, 1988.
20. Hedges L. Estimation of effect size from a series of independent
experiments. Psychol Bull 1982;92:4909.
21. Follmann D, Elliott P, Suh I, et al. Variance imputation for overviews
of clinical trials with continuous response. J Clin Epidemiol
1992;45:76973.
22. Higgins J, Thompson S, Deeks J, et al. Measuring inconsistency in
meta-analyses. BMJ 2003;327:55760.
23. Egger M, Smith GD, Schneider M, et al. Bias in meta-analysis
detected by a simple, graphical test. BMJ 1997;315:62934.
24. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials 1986; 7:17788.
25. Higgins J, Green S, eds. Cochrane handbook for systematic reviews
of interventions. Chichester: Wiley-Blackwell, 2008.
26. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for
reporting systematic reviews and meta-analyses of studies that
evaluate health care interventions: explanation and elaboration.
Ann Intern Med 2009;151:W6594.
27. Freeman BJ, Fraser RD, Cain CM, et al. A randomized,
double-blind, controlled trial: intradiscal electrothermal therapy
versus placebo for the treatment of chronic discogenic low back
pain. Spine (Phila Pa 1976) 2005;30:236977; discussion 78.
28. Leclaire R, Fortin L, Lambert R, et al. Radiofrequency facet joint
denervation in the treatment of low back pain: a placebo-controlled
clinical trial to assess efficacy. Spine 2001;26:141116;
discussion 17.
29. Nath S, Nath CA, Pettersson K. Percutaneous lumbar zygapophysial
(facet) joint neurotomy using radiofrequency current, in the
management of chronic low back pain: a randomized double-blind
trial. Spine 2008;33:12917.
30. van Kleef M, Barendse GA, Kessels A, et al. Randomized trial of
radiofrequency lumbar facet denervation for chronic low back pain.
Spine (Phila Pa 1976) 1999;24:193742.
31. Patel N, G ross A, Brown L, et al. A randomized, placebo-controlled
study to assess the efficacy of lateral branch neurotomy for chronic
sacroiliac joint pain. Pain Med 2012;13:38398.
32. Bradley JD, Heilman DK, Katz BP, et al . Tidal irrigation as treatment
for knee osteoarthritis: a sham-controlled, randomized,
double-blinded evaluation. Arthritis Rheum 2002;46:1008.
33. Moseley JB Jr., Wray NP, Kuykendall D, et al. Arthroscopic
treatment of osteoarthritis of the knee: a prospective, randomized,
placebo-controlled trial. Results of a pilot study. Am J Sports Med
1996;24:2834.
34. Sihvonen R, Paavola M, Malmivaara A, et al. Arthroscopic partial
meniscectomy versus sham surgery for a degenerative meniscal
tear. N Engl J Med 2013;369:251524.
35. Cobb LA, Thomas GI, Dillard DH, et al. An evaluation of
internal-mammary-artery ligation by a double-blind technic. N Engl J
Med 1959;260:111518.
36. Dimond EG, Kittle CF, Crockett JE. Comparison of internal
mammary artery ligation and sham operation for angina pectoris.
Am J Cardiol 1960;5:4836.
37. Leon MB, Kornowski R, Downey WE, et al. A blinded, randomized,
placebo-controlled trial of percutaneous laser myocardial
revascularization to improve angina symptoms in patients
with severe coronary disease. J Am Coll Cardiol 2005;46:
181219.
38. Salem M, Rotevatn S, Stavnes S, et al. Release of cardiac
biochemical markers after percutaneous myocardial laser or sham
procedures. Int J Cardiol 2005;104:14451.
39. Salem M, Rotevatn S, Stavnes S, et al. Usefulness and safety of
percutaneous myocardial laser revascularization for refractory
angina pectoris. Am J Cardiol 2004;93:108691.
40. Cote G, Imperiale T, Schmidt S, et al. Similar efficacies of biliary,
with or without pancreatic, sphincterotomy in treatment of idiopathic
recurrent acute pancreatitis. Gastroenterology 2012;143:150209
e01.
41. Boelens O, Assen TV, Houterman S,
et al. A double-blind,
randomized, controlled trial on surgery for chronic abdominal pain
due to anterior cutaneous nerve entrapment syndrome. Ann Surg
2013;257:845
9.
42. Swank D, Swank-Bordewijk S, Hop W, et al. Laparoscopic
adhesiolysis in patients with chronic abdominal pain: a blinded
randomised controlled multi-centre trial. Lancet 2003;361:
124751.
43. Abbott J, Hawe J, Hunter D, et al. Laparoscopic excision of
endometriosis: a randomized, placebo-controlled trial. Fertil Steril
2004;82:87884.
44. Jarrell J, Brant R, Leung W, et al. Womens pain experience predicts
future surgery for pain associated with endometriosis. J Obstet
Gynaecol Can 2007;29:988 91.
45. Jarrell J, Mohindra R, Ross S, et al. Laparoscopy and reported pain
among patients with endometriosis. J Obstet Gynaecol Can
2005;27:47785.
Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655 9
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
46. Sutton CJ, Pooley AS, Ewen SP, et al. Follow-up report on a
randomized controlled trial of laser laparoscopy in the treatment of
pelvic pain associated with minimal to moderate endometriosis. Fertil
Steril 1997;68:10704.
47. Sutton CJ, Ewen SP, Whitelaw N, et al. Prospective, randomized,
double-blind, controlled trial of laser laparoscopy in the treatment of
pelvic pain associated with minimal, mild, and moderate
endometriosis. Fertil Steril 1994;62:696700.
48. Geenen JE, Hogan WJ, Dodds WJ, et al. The efficacy of endoscopic
sphincterotomy after cholecystectomy in patients with
sphincter-of-Oddi dysfunction. N Engl J Med 1989;320:827.
49. Toouli J, Roberts-Thomson IC, Kellow J, et al. Manometry based
randomised trial of endoscopic sphincterotomy for sphincter of Oddi
dysfunction. Gut 2000;46:98102.
50. Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With
STARFlex Technology (MIST) trial: a prospective, multicenter,
double-blind, sham-controlled trial to evaluate the effectiveness of
patent foramen ovale closure with STARFlex septal repair implant to
resolve refractory migraine headache. Circulation
2008;117:1397404.
51. Guyuron B, Reed D, Kriegler JS, et al. A placebo-controlled surgical
trial of the treatment of migraine headaches. Plast Reconstr Surg
2009;124:4618.
52. Genco A, Cipriano M, Bacci V, et al. BioEnterics Intragastric Balloon
(BIB): a short-term, double-blind, randomised, controlled, crossover
study on weight reduction in morbidly obese patients. Int J Obes
(Lond) 2006;30:12933.
53. Gersin KS, Rothstein RI, Rosenthal RJ, et al. Open-label,
sham-controlled trial of an endoscopic duodenojejunal bypass liner
for preoperative weight loss in bariatric surgery candidates.
Gastrointest Endosc 2010;71:97682.
54. Lindor KD, Hughes RW Jr., Ilstrup DM, et al. Intragastric balloons in
comparison with standard therapy for obesitya randomized,
double-blind trial. Mayo Clin Proc 1987;62:9926.
55. Martinez-Brocca MA, Belda O, Parejo J, et al. Intragastric
balloon-induced satiety is not mediated by modification in fasting or
postprandial plasma ghrelin levels in morbid obesity. Obes Surg
2007;17:64957.
56. Mathus-Vliegen EM, Tytgat GN, Veldhuyzen-Offermans EA.
Intragastric balloon in the treatment of super-morbid obesity.
Double-blind, sham-controlled, crossover evaluation of 500-milliliter
balloon. Gastroenterology 1990;99:3629.
57. Mathus-Vliegen EMH, Tytgat GNJ. Gastro-oesophageal reflux in
obese subjects: influence of overweight, weight loss and chronic
gastric ball oon distension. Scand J Gastroenterol 2002;37:
124652.
58. Mathus-Vliegen EMH, Tytgat GNJ. Intragastric balloon for
treatment-resistant obesity: safety, tolerance, and efficacy of 1-year
balloon treatment followed by a 1-year balloon-free follow-up.
Gastrointest Endosc 2005;61:1927.
59. Mathus-Vliegen EMH, Van Weeren M, Van Eerten PV. LOS function
and obesity: the impact of untreated obesity, weight loss, and
chronic gastric balloon distension. Digestion 2003;68:1618.
60. Mathus-Vliegen LMH, Tytgat GNJ. Twenty-four-hour pH
measurements in morbid obesity: effects of massive overweight,
weight loss and gastric distension. Eur J Gastroenterol Hepatol
1996;8:63540.
61. Meshkinpour H, Hsu D, Farivar S. Effect of gastric bubble as a
weight reduction device: a controlled, crossover study.
Gastroenterology 1988;95:58992.
62. Rigaud D, Trostler N, Rozen R, et al. Gastric distension, hunger and
energy intake after ballo on implantation in severe obesity. Int J Obes
Relat Metab Disord 1995;19:48995.
63. Corley DA, Katz P, Wo JM, et al. Improvement of gastroesophageal
reflux symptoms after radiofrequency energy: a randomized,
sham-controlled trial. Gastroenterology 2003;125:66876.
64. Deviere J, Costamagna G, Neuhaus H, et al. Nonresorbable
copolymer implantation for gastroesophageal reflux disease:
a randomized sham-controlled multicenter trial. Gastroenterology
2005;128:53240.
65. Montgomery M, Hakanson B, Ljungqvist O, et al. Twelve months
follow-up after treatment with the EndoCinch endoscopic
technique for gastro-oesophageal reflux disease: a randomized,
placebo-controlled study. Scand J Gastroenterol 2006;41:
13829.
66. Rothstein R, Filipi C, Caca K, et al. Endoscopic full-thickness plication
for the treatment of gastroesophageal reflux disease: a randomized,
sham-controlled trial. Gastroenterology 2006;131:7 0412.
67. Schwartz MP, Wellink H, Gooszen HG, et al. Endoscopic
gastroplication for the treatment of gastro-oesophageal reflux
disease: a randomised, sham-controlled trial. Gut 2007;56:208.
68. Freed CR, Greene PE, Breeze RE, et al. Transplantation of
embryonic dopamine neurons for severe Parkinsons disease.
N Engl J Med 2001;344:71019.
69. Gordon PH, Yu Q, Qualls C, et al. Reaction time and movement
time after embryonic cell implantation in Parkinson disease. Arch
Neurol 2004;61:858 61.
70. Greene PE, Fahn S. Status of fetal tissue transplantation for the
treatment of advanced Parkinson disease. Neurosurg 2002;13:e3.
71. McRae C, Cherin E, Diem G, et al
. Does personality change as a
result of fetal tissue transplantation in the brain? J Neurol
2003;250:2826.
72.
McRae C, Cherin E, Yamazaki TG, et al. Effects of perceived
treatment on quality of life and medical outcomes in a double-blind
placebo surgery trial. Arch Gen Psychiatry 2004;61:41220.
73. Nakamura T, Dhawan V, Chaly T, et al. Blinded positron emission
tomography study of dopamine cell implantation for Parkinsons
disease. Ann Neurol 2001;50:1817.
74. Olanow CW, Goetz CG, Kordower JH, et al. A double-blind
controlled trial of bilateral fetal nigral transplantation in Parkinsons
disease. Ann Neurol 2003;54:40314.
75. Friedman M, Schalch P, Lin HC, et al. Palatal implants for the
treatment of snoring and obstructive sleep apnea/hypopnea
syndrome. Otolaryngol Head Neck Surg 2008;138:20916.
76. Koutsourelakis I, Georgoulopoulos G, Perraki E, et al. Randomised
trial of nasal surgery for fixed nasal obstruction in obstructive sleep
apnoea. Eur Respir J 2008;31:11017.
77. Geldis JR, Nichols JJ. The impact of punctal occlusion on soft
contact lens wearing comfort and the tear film. Eye Contact Lens
2008;34:2615.
78. Slusser TG, Lowther GE. Effects of lacrimal drainage occlusion with
nondissolvable intracanalicular plugs on hydrogel contact lens wear.
Optom Vis Sci 1998;75:3308.
79. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of
bronchial thermoplasty in the treatment of severe asthma:
a multicenter, randomized, double-blind, sham-controlled clinical
trial. Am J Respir Crit Care Med 2010;181:11624.
80. Curran WS, Graham WG. Long term effects of glomectomy. Follow-
up of a double-blind study. Am Rev Respir Dis 1971;103:5668.
81. Curran WS, Oser JF, Longfield AN, et al. Glomectomy for severe
bronchial asthma. A double-blind study. Am Rev Respir Dis
1966;93:849.
82. Bajbouj M, Becker V, Eckel F, et al. Argon plasma coagulation of
cervical heterotopic gastric mucosa as an alternative treatment for
globus sensations. Gastroenterology 2009;137:4404.
83. Bretlau P, Tho msen J, Tos M, et al. Placebo effect in surgery for
Meniere
s disease: a three-year follow-up study of patients in a
double blind placebo controlled study on endolymphatic sac shunt
surgery. Am J Otol 1984;5:558
61.
84. Davys HJ, Turner DE, Helliwell PS, et al. Debridement of plantar
callosities in rheumatoid arthritis: a randomized controlled trial.
Rheumatology (Oxford) 2005;44:20710.
85. Larson TR, Blute ML, Bruskewitz RC, et al. A high-efficiency
microwave thermoablation system for the treatment of benign
prostatic hyperplasia: results of a randomized, sham-controlled,
prospective, double-blind, multicenter clinical trial. Urology
1998;51:73142.
86. Thomsen J. Placebo effect in surgery for Menieres disease. Arch
Otolaryngol 1981;107:2717.
87. Thomsen J, Bretlau P, Tos M, et al. Placebo effect in surgery for
Menieres disease: three-year follow-up. OtolaryngologyHead &
Neck Surgery 1983;91:1836.
88. Thomsen J, Bretlau P, Tos M, et al. Endolymphatic sac-mastoid
shunt surgery. A nonspecific treatment modality? Ann Otol Rhinol
Laryngol 1986;95:325.
89. Winters C, Artnak EJ, Benjamin SB, et al. Esophageal bougienage
in symptomatic patients with the nutcracker esophagus. A primary
esophageal motility disorder. JAMA 1984;252:3636.
90. Rodriguez L, Reyes E, Fagalde P, et al. Pilot clinical study of an
endoscopic, removable duodenal-jejunal bypass liner for the
treatment of type 2 diabetes. Diabetes Technol Ther 2009;11:
72532.
91. Krogsboll LT, Hrobjartsson A, Gotzsche PC. Spontaneous
improvement in randomised clinical trials: meta-analysis of
three-armed trials comparing no treatment, placebo and active
intervention. BMC Med Res Methodol 2009;9:1.
92. Wartolowska K, Judge A, Hopewell S, et al. Use of placebo controls
in the evaluation of surgery: systematic review. BMJ 2014;348:
g3253.
93. Robinson ME, Gagnon CM, Riley JL III, et al. Altering gender role
expectations: effects on pain tolerance, pain threshold, and pain
ratings. J Pain 2003;4:2848.
10 Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
94. Vase L, Robinson ME, Verne GN, et al. The contributions of
suggestion, desire, and expectation to placebo effects in irritable bowel
syndrome patients. An empirical investigation. Pain 2003;105:1725.
95. Meissner K, Distel H, Mitzdorf U. Evidence for placebo effects on
physical but not on biochemical outcome parameters: a review of
clinical trials. BMC Med 2007;5:3.
96. Mora M, Nestoriuc Y, Rief W. Lessons learned from placebo groups
in antidepressant trials. Philos Trans R Soc Lond B Biol Sci
2011;366:187988.
97. Enck P, Klosterhalfen S. The placebo response in functional bowel
disorders: perspectives and putative mechanisms.
Neurogastroenterol Motil 2005;17:32531.
98. Leucht S, Hierl S, Kissling W, et al. Putting the efficacy of psychiatric
and general medicine medication into perspective: review of
meta-analyses. Br J Psychiatry 2012;200:97106.
99. Wartolowska K, Beard D, Carr A. Attitudes and beliefs about
placebo surgery among orthopedic shoulder surgeons in the United
Kingdom. PLoS ONE 2014;9:e91699.
Jonas WB, et al. BMJ Open 2015;5:e009655. doi:10.1136/bmjopen-2015-009655 11
Open Access
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
controlled trials
meta-analysis of randomised, sham
response? A systematic review with
procedures effective beyond a placebo
To what extent are surgery and invasive
Meissner
Moseley, Franklin G Miller, Levente Kriston, Klaus Linde and Karin
Wayne B Jonas, Cindy Crawford, Luana Colloca, Ted J Kaptchuk, Bruce
doi: 10.1136/bmjopen-2015-009655
2015 5: BMJ Open
http://bmjopen.bmj.com/content/5/12/e009655
Updated information and services can be found at:
These include:
Material
Supplementary
655.DC1.html
http://bmjopen.bmj.com/content/suppl/2015/12/11/bmjopen-2015-009
Supplementary material can be found at:
References
#BIBLhttp://bmjopen.bmj.com/content/5/12/e009655
This article cites 96 articles, 18 of which you can access for free at:
Open Access
http://creativecommons.org/licenses/by-nc/4.0/non-commercial. See:
provided the original work is properly cited and the use is
non-commercially, and license their derivative works on different terms,
permits others to distribute, remix, adapt, build upon this work
Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
This is an Open Access article distributed in accordance with the Creative
service
Email alerting
box at the top right corner of the online article.
Receive free email alerts when new articles cite this article. Sign up in the
Collections
Topic
Articles on similar topics can be found in the following collections
(207)Surgery
(406)Evidence based practice
(94)Complementary medicine
Notes
http://group.bmj.com/group/rights-licensing/permissions
To request permissions go to:
http://journals.bmj.com/cgi/reprintform
To order reprints go to:
http://group.bmj.com/subscribe/
To subscribe to BMJ go to:
group.bmj.com on December 14, 2015 - Published by http://bmjopen.bmj.com/Downloaded from
... Research has shown that positive outcome expectations about medical and psychological treatments are critical mechanisms driving the placebo effect and can be employed to augment an intervention's positive effect (18,19). In contrast to a surgical procedure or a drug's pharmacological ingredient, which are considered specific factors, expectations are understood as nonspecific factors of medical treatments (15,20). Medical treatments always combine specific and nonspecific factors. ...
... Notably, they can also impact objective outcomes such as immunological markers, cardiovascular parameters, or neurotransmitters (15). Even for invasive procedures such as CABG, treatment outcomes do not solely depend on medical factors and surgical skills (20); the nonspecific (placebo) effects of surgery and invasive procedures are generally large (20). In cardiac surgery, patients' expectations predict disability and quality of life (21), physical health status (22), and rehospitalization (23) post-surgery. ...
... Notably, they can also impact objective outcomes such as immunological markers, cardiovascular parameters, or neurotransmitters (15). Even for invasive procedures such as CABG, treatment outcomes do not solely depend on medical factors and surgical skills (20); the nonspecific (placebo) effects of surgery and invasive procedures are generally large (20). In cardiac surgery, patients' expectations predict disability and quality of life (21), physical health status (22), and rehospitalization (23) post-surgery. ...
Article
Full-text available
The PSY-HEART-I trial indicated that a brief expectation-focused intervention prior to heart surgery improves disability and quality of life 6 months after coronary artery bypass graft surgery (CABG). However, to investigate the clinical utility of such an intervention, a large multi-center trial is needed to generalize the results and their implications for the health care system. The PSY-HEART-II study aims to examine whether a preoperative psychological intervention targeting patients' expectations (EXPECT) can improve outcomes 6 months after CABG (with or without heart valve replacement). EXPECT will be compared to Standard of Care (SOC) and an intervention providing emotional support without targeting expectations (SUPPORT). In a 3-arm multi-center randomized, controlled, prospective trial (RCT), N=567 patients scheduled for CABG surgery will be randomized to either SOC alone or SOC and EXPECT or SOC and SUPPORT. Patients will be randomized with a fixed unbalanced ratio of 3:3:1 (EXPECT: SUPPORT: SOC) to compare EXPECT to SOC and EXPECT to SUPPORT. Both psychological interventions consist of 2 in-person sessions (à 50 min), two phone consultations (à 20 min) during the week prior to surgery, and one booster phone consultation post-surgery 6 weeks later. Assessment will occur at baseline approx. 3-10 days before surgery, preoperatively the day before surgery, 4-6 days later, and 6 months after surgery. The study's primary endpoint will be patients’ illness-related disability 6 months after surgery. Secondary outcomes will be patients’ expectations, subjective illness beliefs, quality of life, length of hospital stay and blood sample parameters (e.g., inflammatory parameters such as IL-6, IL-8, CRP). This large multi-center trial has the potential to corroborate and generalize the promising results of the PSY-HEART-I trial for routine care of cardiac surgery patients, and to stimulate revisions of treatment guidelines in heart surgery.
... In a meta-analysis of 39 publications with randomised sample versus placebo (sham surgery), covering traditional surgery (n = 5) and invasive procedures (n = 34) such as endoscopy and percutaneous technique, in cases of back pain, abdominal pain (endometriosis; colic; gastro-oesophageal reflux) and introduction of a gastric balloon in obesity, the results showed that surgery had a non-significant greater therapeutic benefit versus the placebo group (sham surgery) with a higher percentage of adverse events (34-42%). Among the invasive procedures, only endoscopy for gastro-oesophageal reflux showed a significant benefit over placebo; for the other procedures, there were inconclusive results (Jonas et al. 2015). Further trials in traditional and invasive surgery with randomised, placebo group sampling are required to reach conclusive results (Cousins et al. 2020). ...
... The participation of a placebo group in the clinical trial (phase III) is necessary today, not only in pharmacotherapy but also in surgery and invasive procedures. In the case of surgery, the small number of trials with a placebo group and randomisation of the sample raises the question of whether certain surgical procedures whose efficacy is unknown and which subject patients to unnecessary surgical risk (Jonas et al. 2015;Vase and Wartolowska 2019) should continue to be performed as they have been up to now. ...
Article
Full-text available
Our aims were to provide updated information on placebo/nocebo effect and the potential use of placebo in clinical practice. This article can only provide a rough overview on the placebo and nocebo effect and is intended to serve as a starting point for the reader to go deeper into the corresponding literature. The placebo effect has been observed in multiple medical conditions, after oral administration, with manual therapies as well as with surgery and invasive procedures. The use of placebo in clinical trials is fundamental, although the ethics of its use is under discussion. The placebo may behave like a drug from the pharmacokinetic and pharmacodynamic point of view and can also be associated with adverse events (nocebo effect). Placebo can modify treatment by increasing or decreasing the effects of drugs. The factors associated with the occurrence of placebo effect are multiple, but in addition to those that depend on the placebo itself, the doctor-patient relationship would be the most important. As a result of findings that were published in the last two decades, the psycho-neurobiological basis of placebo is becoming better understood, although further studies are needed. In conclusion, the placebo effect in the clinic exhibits weak to moderate intensity. Placebo, in addition to its use in the clinical trial, should be considered another therapeutic remedy either as stand alone or in association with treatment, and could be useful in certain circumstances. The use of placebo should be regulated by the European health authorities through a guide in clinical practice that will improve patient care.
... [4][5][6] However, there is no systematic evidence to support this hypothesisprevious studies suggesting a large placebo effect measured improvement after receiving placebo intervention that includes both placebo and other nonspecific effects combined. [7][8][9][10][11][12] The aims of this a Assumes that surgical group also receives nonoperative regimen. study were to estimate (1) the mean proportion of the observed effect of surgery that can be attributed to total nonspecific factors; (2) the magnitude of the surgical placebo effect; and (3) the difference in the treatment effect between placebo-and nonoperative-controlled surgical trials testing the same surgical intervention. ...
... Like previous studies, we found large improvements after placebo surgery. 7,8,12,23 However, this observed improvement should not be considered the placebo effect because it includes all ...
Article
Full-text available
Importance: Nonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials. Objective: To estimate the proportion of the observed effect of surgical treatment that is due to nonspecific effects (including the placebo effect). Data sources: Published Cochrane reviews and updated, extended search of MEDLINE, Embase, and CENTRAL until March 2019. Study selection: Published randomized placebo-controlled surgical trials and trials comparing the effect of the same surgical interventions with nonoperative controls (ie, no treatment, usual care, or exercise program). Data extraction and synthesis: Pairs of authors independently screened the search results, assessed full texts to identify eligible studies and the risk of bias of included studies, and extracted data. The proportion of all nonspecific effects was calculated as the change in the placebo control divided by the change in the active surgery and pooled in a random-effect meta-analysis. To estimate the magnitude of the placebo effect, we pooled the difference in outcome between placebo and nonoperative controls and used metaregression to estimate the association between the type of control group and the treatment effect (difference between the groups), adjusting for risk of bias, sample size, and type of outcome. Main outcomes and measures: Between- and within-group effect sizes expressed as Hedges g. Results: In this review, 100 trials were included comprising data from 62 trials with placebo controls (3 also included nonoperative controls), and 38 trials with nonoperative controls (32 interventions; 10 699 participants). Risk of bias across trials was comparable except for performance and detection bias, which was high in trials with nonoperative controls. The mean nonspecific effects accounted for 67% (95% CI, 61% to 73%) of the observed change after surgery; however, this varied widely between different procedures. The estimated surgical placebo effect had a standardized mean difference (SMD) of 0.13 (95% CI, -0.26 to 0.51). Trials with placebo and nonoperative controls found comparable treatment effects (SMD, -0.09 [95% CI, -0.35 to 0.18]; 15 interventions; 73 between-group effects; adjusted analysis: SMD, -0.11 [95% CI, -0.37 to 0.15]). Conclusions and relevance: In this review, the change in health state after surgery was composed largely of nonspecific effects, but no evidence supported a large placebo effect. Placebo-controlled surgical trials may be redundant when trials with nonoperative controls consistently report no substantial association from surgery compared with nonoperative treatment.
... Given the large and enduring nonspecific responses observed after pedicle access alone in the sham group of the SMART trial [17], it is possible this same effect is partially represented in patient reported pain relief after BVN RFA [48]. This would be consistent with findings from systematic reviews describing large placebo effects associated with invasive treatments, where the effects of noxious stimuli are influenced by psychological and social pain processing in the central nervous system [49]. However, in the field of Pain Medicine, it is generally accepted that legitimate treatments will have both specific and nonspecific effects, as is likely the case with BVN RFA. ...
Article
Full-text available
Objective Investigate associations between endplate and motion segment magnetic resonance imaging (MRI) characteristics and treatment outcomes following basivertebral nerve radiofrequency ablation (BVN RFA) in patients with clinically suspected vertebral endplate pain (VEP). Design Aggregated cohort study of 296 participants treated with BVN RFA from three prospective clinical trials. Methods Baseline MRI characteristics were analyzed using stepwise logistic regression to identify factors associated with treatment success. Predictive models used three definitions of treatment success: (1) ≥50% low back pain (LBP) visual analog scale (VAS), (2) ≥15-point Oswestry Disability Index (ODI), and (3) ≥50% VAS or ≥15-point ODI improvements at 3-months post-BVN RFA. Results The presence of lumbar facet joint fluid (odds ratio [OR] 0.586) reduced the odds of BVN RFA treatment success in individuals with clinically suspected VEP. In patients with a less advanced degenerative disc disease (DDD) profile, a > 50% area of the endplate with bone marrow intensity changes (BMIC) was predictive of treatment success (OR 4.689). Both regressions areas under the curve (AUCs) were under 70%, indicating low predictive value. All other vertebral endplate, intervertebral disc, nerve roots facet joint, spinal segmental alignment, neuroforamina, lateral recesses, and central canal MRI characteristics were not associated with BVN RFA success. Conclusions In patients with vertebrogenic low back pain with Modic changes, the presence of degenerative findings of the anterior and posterior column was not associated with a clinically important impact on BVN RFA treatment success. None of the models demonstrated strong predictive value, indicating that the use of objective imaging biomarkers (Type 1 and/or 2 Modic changes) and a correlating presentation of pain remain the most useful patient selection factors for BVN RFA.
... Finally, no SHAM operation was performed in the control group for ethical reasons. Surgery is known to have a considerable placebo effect, which most certainly explains part of the effect seen in both studies [71]. ...
Article
Objectives Our objectives were to examine the magnitude of the proportion attributable to contextual effects (PCE), which shows what proportion of the treatment arm response can be achieved by the placebo arm across various interventions, and to examine PCE variability by outcome type and condition. Design We conducted a meta-epidemiological study. Setting We searched the Cochrane Database of Systematic Reviews with the keyword ‘placebo’ in titles, abstracts and keywords on 1 January 2020. Participants We included reviews that showed statistically significant beneficial effects of the intervention over placebo for the first primary outcome. Main outcome measures We performed a random-effects meta-analysis to calculate PCEs based on the pooled result of each included review, grouped by outcome type and condition. The PCE quantifies how much of the observed treatment response can be achieved by the contextual effects. Public and patient involvement statement No patient or member of the public was involved in conducting this research. Results We included 328 out of 3175 Cochrane systematic reviews. The results of meta-analyses showed that PCEs varied greatly depending on outcome type (I ² =98%) or condition (I ² =98%), but mostly lie between 0.40 and 0.95. Overall, the PCEs were 0.65 (95% CI 0.59 to 0.72) on average. Subjective outcomes were 0.50 (95% CI 0.41 to 0.59), which was significantly smaller than those of semiobjective (PCE 0.78; 95% CI 0.72 to 0.85) or objective outcomes (PCE 0.94; 95% CI 0.91 to 0.97). Conclusions The results suggest that much of the observed benefit is not just due to the specific effect of the interventions. The specific effects of interventions may be larger for subjective outcomes than for objective or semiobjective outcomes. However, PCEs were exceptionally variable. When we evaluate the magnitude of PCEs, we should consider each PCE individually, for each condition, intervention and outcome in its context, to assess the importance of an intervention for each specific clinical setting.
Article
The topic of this article is the biopsychosocial model. My main contention is that – notwithstanding doubts as to what exactly it is, or indeed whether it is anything – there is a coherent account of it, in terms of both applications to particular health conditions and mechanisms with wide application. There is accumulating evidence from recent decades that psychosocial as well as biological factors are implicated in the aetiology and treatment of a large range of physical as well as mental health conditions. The original proposer of the biopsychosocial model, George Engel, back in 1977, was substantially correct about what he saw was on its way.
Article
Introduction Robot-assisted cholecystectomies are often criticized as expensive with uncertain benefit to patients. Characterization of robotic surgery benefits, as well as specific factors that drive cost, has the potential to shape the current debate. Methods The surgical cost and outcomes among patients who underwent robotic (n = 283) or non-robotic (n = 1438) laparoscopic cholecystectomies between 2012 and 2018 at a single academic institution were examined retrospectively. All cholecystectomies were primary surgical procedures with no secondary procedures. We also examined the subset of robotic (n = 277) and non-robotic (n = 1108) outpatient procedures. Results Robotic cholecystectomies were associated with higher median total cost compared to conventional procedures, largely attributable to variable costs and surgical costs. Patients who underwent conventional cholecystectomy had longer mean lengths of stays (1.7 versus 1.1 days) compared to robotic procedures–with over 10 times as many requiring hospital admission. Conclusions At present, robotic cholecystectomies have a little value to patients and institutions outside of surgical training. Prior to narrowing the analysis to outpatient cases, difference in total cost between procedures was less pronounced due to more frequent inpatient management following conventional procedures. Future optimization of robotic consumables and free market competition among system manufacturers may increase financial feasibility by decreasing variable costs associated with robotic surgery.
Article
This prospective, double-blind, randomized, sham-controlled trial was designed to control for patient and investigator bias in assessing symptomatic improvement after percutaneous myocardial laser revascularization (PMLR) therapy. Eighty-two patients with stable angina pectoris (class III or IV) not amenable to conventional revascularization and with evidence of reversible ischemia, ejection fraction >25%, and myocardial wall thickness >8 mm were randomized to either PMLR with optimal medical therapy (n � 40) or to a sham procedure with optimal medical therapy (n � 42). With the exception of 1 laser technician, all patients, investigators, and assessors were blinded to treatment through the 12-month follow-up. The primary end point was restricted to Canadian Cardiovascular Society angina class improvement to limit the number of patients exposed to a sham procedure. Secondary assessments included medication usage, quality of life, exercise testing, ejection fraction, and hospitalizations. The incidence of serious adverse events, as determined by cardiac event-free survival at 12 months, was similar between groups. At 12 months, Canadian Cardiovascular Society angina scores improved by >2 classes in significantly more PMLR-treated patients than sham control patients (35% vs 14%, p � 0.04). Angina-specific quality-of-life measures were significantly higher in the PMLR group at each follow-up (p <0.05). Exercise and medication usage was similar between groups at 12 months. We conclude that PMLR therapy is reasonably safe and effective as symptomatic improvement in patients refractory to medical therapy, and that the clinical benefit is not attributable to placebo effect or investigator bias.
Article
This prospective, double-blind, randomized, sham-controlled trial was designed to control for patient and investigator bias in assessing symptomatic improvement after percutaneous myocardial laser revascularization (PMLR) therapy. Eighty-two patients with stable angina pectoris (class III or IV) not amenable to conventional revascularization and with evidence of reversible isch-emia, ejection fraction >25%, and myocardial wall thickness >8 mm were randomized to either PMLR with optimal medical therapy (n 40) or to a sham procedure with optimal medical therapy (n 42). With the exception of 1 laser technician, all patients, investigators , and assessors were blinded to treatment through the 12-month follow-up. The primary end point was restricted to Canadian Cardiovascular Society angina class improvement to limit the number of patients exposed to a sham procedure. Secondary assessments included medication usage, quality of life, exercise testing , ejection fraction, and hospitalizations. The incidence of serious adverse events, as determined by cardiac event-free survival at 12 months, was similar between groups. At 12 months, Canadian Cardiovascular Society angina scores improved by >2 classes in significantly more PMLR-treated patients than sham control patients (35% vs 14%, p 0.04). Angina-specific quality-of-life measures were significantly higher in the PMLR group at each follow-up (p <0.05). Exercise and medication usage was similar between groups at 12 months. We conclude that PMLR therapy is reasonably safe and effective as symptomatic improvement in patients refrac-tory to medical therapy, and that the clinical benefit is not attributable to placebo effect or investigator bias.