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D’Alessandroetal.
BMC Medical Research Methodology (2022) 22:219
https://doi.org/10.1186/s12874-022-01704-8
RESEARCH
Dierences betweenexperimental
andplacebo arms inmanual therapy trials:
amethodological review
Giandomenico D’Alessandro1,2, Nuria Ruffini1,3, Alessandro Aquino1,4, Matteo Galli1,5, Mattia Innocenti2,
Marco Tramontano6 and Francesco Cerritelli1*
Abstract
Background To measure the specific effectiveness of a given treatment in a randomised controlled trial, the inter-
vention and control groups have to be similar in all factors not distinctive to the experimental treatment. The similarity
of these non-specific factors can be defined as an equality assumption. The purpose of this review was to evaluate the
equality assumptions in manual therapy trials.
Methods Relevant studies were identified through the following databases: EMBASE, MEDLINE, SCOPUS, WEB OF
SCIENCE, Scholar Google, clinicaltrial.gov, the Cochrane Library, chiloras/MANTIS, PubMed Europe, Allied and Comple-
mentary Medicine (AMED), Physiotherapy Evidence Database (PEDro) and Sciencedirect.
Studies investigating the effect of any manual intervention compared to at least one type of manual control were
included. Data extraction and qualitative assessment were carried out independently by four reviewers, and the sum-
mary of results was reported following the PRISMA statement.
Result Out of 108,903 retrieved studies, 311, enrolling a total of 17,308 patients, were included and divided into eight
manual therapy trials categories. Equality assumption elements were grouped in three macro areas: patient-related,
context-related and practitioner-related items. Results showed good quality in the reporting of context-related
equality assumption items, potentially because largely included in pre-existent guidelines. There was a general lack of
attention to the patient- and practitioner-related equality assumption items.
Conclusion Our results showed that the similarity between experimental and sham interventions is limited, affect-
ing, therefore, the strength of the evidence. Based on the results, methodological aspects for planning future trials
were discussed and recommendations to control for equality assumption were provided.
Keywords Manual therapies, Placebo, similarity, Sham therapy, Manual placebo, Systematic review
© The Author(s) 2022, corrected publication 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
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Open Access
BMC Medical Research
Methodology
*Correspondence:
Francesco Cerritelli
fcerritelli@comecollaboration.org
1 Clinical-Based Human Research Department, Foundation C.O.ME.
Collaboration, 65121 Pescara, Italy
2 Centre Pour L’Etude, La Recherche Et La Diffusion Ostéopathiques
“C.E.R.D.O”, 00199 Rome, Italy
3 Foundation C.O.ME. Collaboration, National Centre Germany,
10825 Berlin, Germany
4 Department of Health Sciences, University of Milan, 20142 Milan, Italy
5 Research Department, SOMA, Istituto Osteopatia Milano, Milan, Italy
6 Fondazione Santa Lucia IRCCS, 00179 Rome, Italy
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Page 2 of 14
D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
Background
‘Manual erapy’ (MT) is an umbrella term used and
variously defined by different professional groups
[1–4]. e definitions differ mainly for type of opera-
tor, presence of a hand-guided instrument, co-presence
of exercises, target tissue of the treatment [5], clinical
goals, and the active/passive role of the patient in the
process of care. Consequently, it is possible to consider
a more extensive sense of MT including manipulation,
mobilisation, massage [6], but also acupressure, nerve
manipulation [7] and gentle skin touch [8, 9] applied
with a therapeutic intent [7] on the patient’s body [10].
MT is one of the oldest known forms of medicine and
has been practised worldwide since ancient times [6,
11–13], and the interest in MT has grown in the last
years, with patients expressing a growing satisfaction
for the offered service [14] In analogy to other fields of
clinical research, the randomised control trial (RCT) is
also regarded as the gold standard [15] in manual ther-
apy research due to its robust methodology and ability
to conduct systematic reviews and meta-analyses. One
of the pillars of an RCT is the use of a control group
or placebo intervention, known in manual therapy RCT
(mtRCT) as ‘sham therapy [16]. e use of a placebo
arm is crucial to disentangle the specific effect of the
experimental treatment from the non-specific or not
distinctive effects of a given treatment [17–19]. ere
are currently no guidelines addressing how to conduct
appropriate sham therapy to ensure the robustness of
mtRCT’s methodology and results.
It is worth noting that the placebo effect is consid-
ered more relevant in non-pharmacological treatments
[20, 21] including complementary alternative medi-
cines (CAMs) [20, 22]. It depends on several conditions,
including the significant role of interpersonal touch [9],
the multiplicity of treatment sessions [23], and the opti-
misation of the patient-physician relationship [24–2627].
In light of the science of placebo [28] has been proposed
that one fundamental pillar of an RCT is the guaranteed
similarity between non-specific factors in both inter-
vention and sham arms. e entire paradigm has been
recently described by Annoni and Boniolo [29] and
can be defined as follows: “the specific efficacy (SE) of a
treatment (x) is equal to the overall improvement meas-
ured in the experimental group (Ix) minus the improve-
ment measured in the control group (Ic)”, thus SEx = Ix
– Ic [29]. One of the elements ensuring strength to the
equation is the robustness of the “equality assumption”
(EA), that is the overlap of non-specific aspects between
groups, e.g. the same patient-operator relationship in
the experimental and placebo groups. Although some
authors in MT research claim a similarity between the
experimental and sham arms of the trial [15, 27, 30–34],
there is not an organic perspective that takes into account
the science of placebo. A recent systematic review dem-
onstrated an incongruity among sham and experimental
treatment procedures in osteopathic trials, which hinders
the evaluation of the actual magnitude of the specific
effect of a therapy [16]. is might lead to skewed results
with potentially detrimental consequences for healthcare
decision making [35].
e purpose of this review is to systematically report
the similarity of non-specific factors between experimen-
tal and placebo arms in mtRCTs in other research fields,
outlying EA in 3 macro-areas—patients, operators and
context. Moreover, differences between manual thera-
pies and/or manual approaches were highlighted and
evaluated.
Methods
e present review followed the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-
Analyses) statement [36], and included multi-centre,
single-centre, quasi-randomised and randomised clinical
controlled trials, interrupted time series, and controlled
clinical trials. All included studies investigated the effect
of any manual intervention compared to at least one type
of manual control, sham and/or placebo intervention
with direct contact between practitioner and subjects.
Inclusion/exclusion criteria
No limit of population, study outcome, and language
restriction [37], was applied. Non-peer reviewed papers,
conference proceedings, editorials, letters, abstracts,
case reports, and case series, were excluded. Stud-
ies investigating the effect of osteopathic manipulative
treatment were also excluded as previously explored by
Cerritelli and colleagues [16]. Research utilising either
control without direct touch, i.e., interposing any mate-
rial between the operator’s hand and the patient, or non-
manual control interventions only were excluded.
Search methods, selection andevaluation ofstudies
Relevant studies were identified through a comprehensive
computerised bibliographic search on the following data-
bases: EMBASE, MEDLINE, SCOPUS, WEB OF SCI-
ENCE, Scholar Google, clinicaltrial.gov, the Cochrane
Library, chiloras/MANTIS, PubMed Europe, Allied and
Complementary Medicine (AMED), Physiotherapy Evi-
dence Database (PEDro) and Sciencedirect. e search
strategy used is detailed in Supplementary Information
S1, available online. All searches were carried out from
inception to 2021. Duplicate records were identified and
removed using the software EndNOTE.
GDA and NR developed and ran the search from
March to April 2019 with an update in February 2022,
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Page 3 of 14
D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
and included studies until 2021. e first screening
of titles and abstracts gathered through bibliographic
searches was independently carried out by two reviewers
(GDA and NR), based on the pertinence and relevance of
each study to inclusion and exclusion criteria. Discrep-
ancies were resolved by consensus with FC as an arbi-
ter. Full texts were subsequently assessed for inclusion.
Reviewers were able to translate to English from French,
Spanish, German, and Italian. For other languages, a
translation to English was required from the authors. In
case of unsuccessful contact, the study was excluded.
Data extraction and the qualitative assessment of
included studies were carried out independently by four
reviewers (GDA, MT, AA, NR). Extracted and summa-
rised data included: type of intervention, type of con-
trol, sample size, study outcomes, and other potentially
relevant characteristics. Authors were contacted twice,
separated by three weeks [34] when provided informa-
tion was insufficient, and, where possible, the reasons for
their omission were reported (details in Supplementary
Table S2, available online). All data were archived on a
shared fully encrypted server, accessible only to the four
reviewers. Disagreements were discussed and resolved by
consensus.
Data synthesis
Data were reported as means, point estimates, percent-
ages and ranges. X2 test was used to compare groups.
e distribution of Chi-square residuals was also used to
determine which categories leads the eventual significant
difference.
MTs classication inthepresent review
As pointed out by Farrel and Jessen, MT is not specific to
any profession [38]. Indeed, the same approach or tech-
nique could be used by different MTs [39]. erefore, the
included papers were grouped according to 3 criteria:
(1) Single category: when an MT uses techniques
that are unique to a discipline, it was considered as
a single category. It is the case of ‘acupressure’, ‘reiki’,
‘reflexology’ and ‘therapeutic touch’.
(2) Grouped by therapies: when different MTs
showed common features, a broader category has
been considered, as in the case of ‘massage’.
(3) Grouped by techniques: when authors used man-
ual techniques that are not distinctive for a specific
MT (e.g., thrust or high-velocity low-amplitude tech-
niques could be used in physiotherapy, chiropractic
and orthopaedics), the following categories were
used, based on Coulter etal. [40]: manipulation’ (or
‘thrust’) and ‘mobilisation’ (or ‘non-thrust’). e lat-
ter included neurodynamic techniques, Muscle
Energy Techniques, and tender/trigger point. Studies
encompassing both thrust and non-thrust techniques
were grouped into the ‘mixed-method’ category.
Studies withmore thanone sham group
When a study had two manual sham groups used to con-
trol for two interventions, it was considered as two differ-
ent studies.
EA score
To evaluate the EAs related to the three macro-areas, the
authors assigned one point per item investigated.
e patient-related EAs were described based on the
following characteristics: patients’ expectations, deblind-
ing questionnaire or interview, credibility questionnaire
or interview, patients’ previous experiences with the
given therapy, psychological traits and reimbursement to
patients (score range 0 to 6).
e context-related EAs was based on the following
characteristics: frequency of sessions, treatment period,
description of the pre-treatment phase, detailed descrip-
tion of the sham therapy protocol, overlap of body areas
treated between intervention and sham therapy, duration
of experimental and sham intervention, description of
the post-treatment phase, setting for interventions, time-
points assessment, and side effect (score range 0 to 10).
Regarding the practitioners-related EAs, the follow-
ing characteristics were considered: the number of prac-
titioners, type of practitioners, years of practitioners’
experience, pre-trial training for practitioners, mean age
of practitioners, and gender of the practitioner (score
range 0 to 6). e determination of EA was performed
by two reviewers (GDA, NR), and the discrepancies were
resolved by consensus with a third reviewer (FC) as an
arbiter.
Results
A total of 108,903 records were identified through data-
base searching and other sources. After the removal of
duplicates, 81,494 titles and abstracts were screened.
1101 full-text articles were consequently assessed for eli-
gibility. 790 articles were excluded for not respecting the
inclusion criteria, or because full-texts were unavailable.
Data and publications from the same study were consid-
ered as duplicates and therefore excluded from the sys-
tematic review. e final sample included 311 studies,
enrolling a total of 17,308 patients, of which 6053 were
males (35.0%) (Fig.1). irteen studies did not report the
gender of their participants.
e first analysis showed that four studies included
two sham groups. ree studies [41–43] were considered
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D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
as double because they used two different sham groups
to control for two different intervention groups: in
Geisser et al. 2015 [41] the two interventions (manual
therapy + adjuvant physical exercises; manual ther-
apy + non-specific exercises) were compared to two
sham groups (sham manual therapy + adjuvant physi-
cal exercises; sham manual therapy + non-specific exer-
cises). Haik and colleagues [42] investigated the effect
of thoracic spine thrust manipulation on symptomatic
and asymptomatic subjects, compared to sham thoracic
spine thrust manipulation on respectively symptomatic
and asymptomatic subjects. In Nansel and colleagues
[43] two different techniques (upper cervical and lower
cervical adjustment) were respectively compared to two
different sham therapies (sham upper cervical and sham
lower cervical manipulation).
In Bialosky and colleagues [44] basic and enhanced
sham therapy were used as a control for only one inter-
vention on the same kind of population, it was consid-
ered as double because of the number of sham arms.
Based on the number of sham therapy arms, the total
number (N) of the studies included in the review was,
therefore, 315. e latter was used as N for the analy-
sis of the EAs, whereas 311 studies were considered for
describing the general characteristics of the studies.
All the results are reported in the tables, and only sta-
tistically significant results have been highlighted in the
main text.
e included sample comprehended a number of dif-
ferent therapeutic approaches, descriptively: 77 stud-
ies investigated the effect of acupressure (24.8%); 8 were
relative to massage (2.6%); 2 to reiki (0.6%), 20 to reflexol-
ogy (6.4%), 3 considered therapeutic touch (0.96%), 108
mobilisation (34.7%), 89 manipulation (28.6%) and 4 used
a mixed-method approach (1.3%).
206 studies (66.2%) investigated symptomatic subjects,
104 studies (33.4%) included asymptomatic participants
and 1 study (0.3%) included both symptomatic and non-
symptomatic patients.
e global mean age for the participants in the studies
was 37.4years (Table1).
Fig. 1 Flow-chart of the study
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D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
As per methodological design, 264 (84.9%) trials used
a parallel design and 47 (15.1%) used a crossover-design.
e Chi-squared analysis showed a significant differ-
ence among therapies, with acupressure and mobilisation
choosing a parallel design more than the other therapies
(X2 = 24.034.62, p = 0.001). Additional details regard-
ing the intervention and control arms are summarised in
Supplementary Table S3, available online.
Of the 311 included trials, 86 (27.7%) declared to use
a double-blind design, 112 studies (36.0%) were defined
as single-blinded, and 113 studies (36.3%) did not define
the type of blinding. e Chi-square analysis showed that
significantly more mobilisation studies reported a double
blind design, and manipulation not reporting the kind of
blinding (X2 = 26.19, p = 0.02).
109 (35.1%) studies utilised patient-reported out-
comes (PROMs), 135 (43.4%) used exclusively outcomes
measured using devices, 67 (21.5%) used both PROMs
and instruments. 68 studies (21.9%) considered opera-
tor-dependent outcome measurements. In 218 studies
(70.1%), the outcome was not operator dependent. In
25 studies (8.0%), both types of outcomes were assessed.
e Chi-square analysis showed a significant difference
among therapies (X2 = 37.578, p = 0.006), with thera-
peutic touch using mostly both types of outcome meas-
urement, and reflexology choosing operator-dependent
outcomes.
73.3% (N = 228) of studies described the source of
enrolment, whereas 83 (26.7%) studies did not give any
information (Table1).
Patients’ EA
A total of 26 studies (8.3%) investigated patients’ expec-
tations about the treatment. e chi-squared analysis
showed that massage and reiki investigated patients’
expectations significantly more than the other catego-
ries (X2 = 46.296, p < 0.0001). In all 26 studies, patients’
expectations between treatment and sham arms were
homogeneous at the baseline.
e majority of studies (272/315, 86.4%) did not per-
form any deblinding procedures. e Chi-Squared
analysis showed a prevalence of acupressure not investi-
gating the deblinding and of manipulation performing a
deblinding procedure (X2 = 18.022, p = 0.01). Among the
43 studies that fulfilled the deblinding process, 40 showed
homogeneity between study arms, whereas the remain-
ing 3 trials demonstrated heterogeneity (X2 = 31.837,
p < 0.001).
e credibility of the provided treatment, according
to patients, was not investigated in the majority of stud-
ies (291/315, 93.6%). In 23 studies, the credibility of the
provided treatment according to patients, between treat-
ment and sham arms was homogeneous, except for Bia-
losky etal. 2014 [45].
Patients’ previous experiences with the investigated
intervention were not reported by 76.8% of studies
Table 1 General characteristics of the population and methodological characteristics of the studies included in the review
N Number, Acu Acupressure Mas Massage, Rei Reiki, TT T herapeutic Touch, Mob Mobilisation, Man Manipulation, Mix Mixed-Method, NR Not reported
Acu Mas Rei Ref TT Mob Man Mix Total
N studies 77 8 2 20 3 108 89 4 311
sample size 6155 506 289 1192 105 4537 4221 303 17,308
mean age (years) 35.6 30.9 61.5 41.3 50.5 32.5 29.8 17 37.4
Male
(%)
1609
(26.1) 424
(83.8) 8
(2.8) 314
(26.3) 29
(27.6) 1712 (37.7) 1772
(42.0) 185 (61.1) 6053
(35.0)
- Parallel 74 8 2 19 2 79 76 4 264
- Crossover 3 0 0 1 1 29 13 0 47
PROM (yes) 29 1 2 11 0 39 24 3 109
PROM (no) 35 4 0 7 1 40 47 1 135
PROM (both) 13 3 0 2 2 29 18 0 67
Operator dependent measurements ( yes) 10 1 0 9 0 26 21 1 68
Operator dependent measurements (no) 65 6 2 7 1 71 63 3 218
Operator dependent measurements (both) 2 1 0 4 2 11 5 0 25
Blinding (double) 15 2 1 7 1 43 15 2 86
Blinding (single) 35 3 0 6 2 36 29 1 112
Blinding (not declared) 27 3 1 7 0 29 45 1 113
Source of enrolment (yes) 56 7 2 15 3 77 65 3 228
Source of enrolment (NR) 21 1 0 5 0 31 24 1 83
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D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
(242/315). Among the remaining 73, 68 studies (93.2%)
included only patients who were naive to the investigated
intervention, being therefore homogeneous at base-
line. In the remaining 5 studies, participants had previ-
ous experiences with the given therapy. 4 of them were
manipulation studies, hence determining a statistically
significant difference among treatments (X2 = 11.012
p = 0.05). Furthermore, two out of five papers did not
report whether the groups were homogeneous about this
characteristic.
Regarding psychological features, 282/315 studies
(89.5%) did not investigate the psychological features of
patients. e Chi-squared analysis showed that massage,
reflexology and therapeutic touch considered the psycho-
logical features of subjects significantly more than other
categories (X2 = 31.916, p < 0.0001). In all remaining 33
studies, patients’ psychological features between treat-
ment and sham arms were homogeneous at the baseline.
Regarding the reimbursement to patients, the quasi-
totality of trials (306/315, 97.1%) did not declare
whether reimbursement was issued. erapeutic touch
reported this information more than the other thera-
pies (X2 = 48.136, p < 0.0001). e issued reimburse-
ment was homogeneous among groups in all the studies
that reported the information but Zeidabadinejad etal.,
where only the sham group was offered the real interven-
tion after the trial’s ending (Fig.2).
e patient-related EAs score was 0/6 in 195 stud-
ies (61.9%), 1/6 in 83 studies (26.3%), 2/6 in 23 studies
(7.3%), 3/6 in 9 studies (2.9%), 4/6 in 3 studies (0.9%), 5/6
in 2 studies (0.6%) (Table2).
Context related EA
302/315studies (95.9%) reported the same frequency of
session for different intervention groups. e quasi-total-
ity of studies (300/315, 95.2%) reported a similar treat-
ment period among groups.
e pre-treatment phase, intended as the protocolled
process preceding the treatment (e.g., baseline meas-
urements, preparation of the patient), was described as
the same for both experimental and sham interventions
in 255/315 studies (81.0%), 1 study (0.3%) used different
pre-treatment phases, and 59 studies (18.7%) did not
report sufficient information to evaluate this specific
EA, especially in reflexology (X2 = 26.19, p = 0.02).
308/315 studies (97.8%) reported adequate details
to establish the similarity of the applied technique
between experimental and sham arms. ere is, how-
ever, a significant difference among therapies, with
therapeutic touch describing the sham technique less
than the other categories (X2 = 24.142, p < 0.001).
Fig. 2 Equality assumption for patient-related characteristics of the included studies
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D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
Concerning the areas of intervention, in 280/315
studies (88.9%) intervention and sham techniques tar-
geted the same bodily regions and/or tissue; in 25/315
studies (7.9%) experimental and sham therapy were
applied to different areas, and 10/315 studies (3.2%)
did not report sufficient or clear information. e
Chi-squared analysis showed that reiki and thera-
peutic touch gave less information than other MTs
(X2 = 30.445, p0.007).
In 212/315studies (67.39%) experimental and sham
intervention had the same duration. 98/315 studies
(31.1%) reported insufficient or unclear data, especially
in manipulation studies (X2 = 108.43, p < 0.0001).
e post-treatment phase, intended as the process
following the intervention (e.g., post-treatment meas-
urements), was described as the same for both experi-
mental and sham interventions in 196/315 studies
(62.2%), 119/315 studies (37.8%) did not report suf-
ficient information, mostly in reflexology (X2 = 17.61,
p = 0.01).
e setting for intervention was reported as the same
among groups in 214/315 studies (67.9%).
e number of time points assessments was reported
as the same among intervention and sham groups in all
included trials.
In a total of 315 included studies, 242(76.8%) did not
collect or report data on side effects after either sham or
experimental intervention (Fig.3).
e context-related EAs score was 4/10 in 6 stud-
ies (1.9%), 5/10 in 8 studies (2.5%), 6/10 in 28 studies
(8.93%), 7/10 in 62 studies (19.7%), 8/10 in 109 studies
(34.6%), 9/10 in 83 studies (26.3%), 10/10 in 19 studies
(6.0%) (Table3).
Practitioner related EA
As expected, the majority of the studies (242/315, 76.8%),
declared how many practitioners delivered the different
interventions, although 23.2% (73/315) underreported
the numbers of operators involved.
Overlapping results were shown for the type of practi-
tioner, where 78.4% (247/315) declared to have enrolled
the same type of practitioner for experimental and sham
interventions. e Chi-squared showed a significance for
reiki, in which both studies used different types of practi-
tioners for intervention and control groups (X2 = 249.23,
p < 0.0001).
Regarding the experience of practitioners 66.0% stud-
ies (208/315) reported unclear or no information; the 2
studies investigating the effect of reiki used practitioners
with a different experience for intervention and control
groups, thus determining a statistical significance imbal-
ance (X2 = 290.975, p < 0.0001).
208/315 (66.0%) of the research included did not report
whether or not practitioners were trained before the
study, with a higher prevalence for mobilisation; whereas
acupressure reported the practitioner training more than
other catergories (X2 = 74.084, p < 0.0001).
e mean age of practitioners was not reported in
294/315 (93.3%) studies and the only 21 studies (6.7%)
that reported the age of the person who intervened were
the acupressure trials in which the patients performed a
self-treatment, thus determining a statistical significance
(X2 = 69.55, p < 0.001).
Where the practitioners’ gender is considered, 283/315
studies did not report it (89.8%). e remaining 32 trials
reported the gender of the operator, with a prevalence of
acupressure (X2 = 35.294 p < 0.001). e 20 acupressure
Table 2 Patient-related equality assumption score
Numbers in table are referred to the actual number of studies reporting the respective item
N Number, Acu Acupressure, Mas Massage, Rei Reiki, TT Therapeutic Touch, Mob Mobilisation, Man Manipulation, Mix Mixed-Method
No studies scored 6/6
Acu
(n = 77) Mas
(n = 8) Rei
(n = 2) Ref
(n = 20) TT
(n = 3) Mob
(n = 109) Man
(n = 92) Mix
(n = 4) Total
(n = 315)
0/6 54
(70.1%) 5
(62.5%) 0
(0%) 10
(50.0%) 0
(0%) 65
(56.6%) 58
(63.0%) 3
(75.0%) 195 (61.9%)
1/6 19 (24.7%) 2
(25.0%) 1
(50.0%) 7 (35.0%) 3
(100.0%) 34
(31.2%) 17
(18.5%) 0
(0%) 83 (26.4%)
2/6 1
(1.3%) 1
(12.5%) 1
(50.0%) 2
(10.0%) 0
(0%) 7
(6.4%) 11
(12.0%) 0
(0%) 23
(7.3%)
3/6 0
(0%) 0
(0%) 0
(0%) 1
(5.0%) 0
(0%) 2
(1.8%) 6
(6.5%) 0
(0%) 9
(2.9%)
4/6 1
(1.3%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 1
(0.9%) 0
(0%) 1 (25.0%) 3
(0.9%)
5/6 2
(2.6%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 2
(0.6%)
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D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
studies that reported the practitioners’ gender performed
a self-administered intervention (Fig.4). e practitioner-related EAs score was 0/6 in 28 stud-
ies (8.9%), 1/6 in 40 studies (12.7%), 2/6 in 88 stud-
ies (27.9%), 3/6 in 112 studies (35.6%), 4/6 in 27 studies
Fig. 3 Equality assumption for context-related characteristics of the included studies. Acu Acupressure, Mas Massage, Rei Reiki, TT Therapeutic
Touch, Mob Mobilisation, Man Manipulation, Mix Mixed-Method
Table 3 Context-related equality assumption score
No studies scored 0/10 to 3/10
Acu Acupressure, Mas Massage, Rei Reiki, TT Therapeutic Touch, Mob Mobilisation, Man Manipulation, Mix Mixed-Method
Acu
(n = 77) Mas
(n = 8) Rei
(n = 2) Ref
(n = 20) TT
(n = 3) Mob
(n = 109) Man
(n = 92) Mix
(n = 4) Total
(n = 315)
4/10 1
(1.3%) 0
(0%) 0
(0%) 1
(5.0%) 0
(0%) 1
(0.9%) 3
(3.3%) 0
(0%) 6
(1.9%)
5/10 2
(2.6%) 0
(0%) 0
(0%) 1
(5.0%) 0
(0%) 1
(0.9%) 3
(3.3%) 1
(25.0%) 8
(2.5%)
6/10 2
(2.6%) 1
(12.5%) 0
(0%) 2
(10.0%) 0
(0%) 14
(12.8%) 9
(9.8%) 0
(0%) 28
(8.9%)
7/10 16
(20.8%) 1
(12.5%) 0
(0%) 4
(20.0%) 1
(33.3%) 20
(18.3%) 20
(21.7%) 0
(0%) 62
(19.7%)
8/10 24
(31.2%) 4
(50.0%) 1
(50.0%) 6
(30.0%) 1
(33.3%) 40
(36.7%) 32
(34.8%) 1
(25.0%) 109
(34.6%)
9/10 25
(32.5%) 2
(25.0%) 1
(50.0%) 5
(25.0%) 0
(0%) 26
(22.0%) 22
(23.9%) 2
(50.0%) 83
(26.3%)
10/10 7
(9.1%) 0
(0%) 0
(0%) 1
(5.0%) 1
(33.3%) 7
(6.4%) 3
(3.3%) 0
(0%) 19
(6.0%)
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D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
(8.6%), 5/6 in 20 studies (6.3%), all of them were acupres-
sure studies. No studies score 6/6 (Table4).
Discussion
e present review aimed to systematically report the
similarity of non-specific factors between experimental
and placebo arms in mtRCTs. Our results showed that
there is a general lack of patient- and practitioner- related
EA reporting. In contrast, the context-related EA items
are well described. Among the patients’ characteristics
analysed under the macro-area of patient-related EAs,
patients’ expectations are the most decisive element [46,
47], Indeed, it has been demonstrated in physical ther-
apy that expectation could influence clinical outcomes
Fig. 4 Equality assumption for practitioner-related characteristics of the included studies. Acu Acupressure, Mas Massage, Rei Reiki, TT Therapeutic
Touch, Mob Mobilisation, Man Manipulation, Mix Mixed-Method
Table 4 Practitioner-related equality assumption score
Acu Acupressure, Mas Massage, Rei Reiki, TT Therapeutic Touch, Mob Mobilisation, Man Manipulation, Mix Mixed-Method
No studies scored 6/6
Acu
(n = 77) Mas
(n = 8) Rei
(n = 2) Ref
(n = 20) TT
(n = 3) Mob
(n = 109) Man
(n = 92) Mix
(n = 4) Total
(n = 315)
0/6 10
(12.3%) 1
(12.5%) 0
(0%) 0
(0%) 0
(0%) 11
(10.2%) 6
(6.5%) 0
(0%) 28
(8.9%)
1/6 8
(10.4%) 2
(25.0%) 0
(0%) 5
(25.0%) 0
(0%) 12
(11.0%) 13
(14.1%) 0
(0%) 40
(12.7%)
2/6 12
(15.6%) 2
(25.0%) 1
(50.0%) 4
(30.0% 0
(0%) 32
(29.4%) 35
(38.0%) 2
(50.0%) 88
(27.9%)
3/6 19
(24.7%) 2
(25.0%) 1
(50.0%) 11
(55.0%) 2
(66.7%) 47
(43.1%) 28
(30.4%) 2
(50.0%) 112
(35.6%)
4/6 10
(13.0%) 1
(12.5%) 0
(0%) 0
(0%) 1
(33.3%) 6
(5.5%) 9
(9.8%) 0
(0%) 27
(8.6%)
5/6 18
(23.4%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 1
(0.9%) 1
(1.1%) 0
(0%) 20
(6.3%)
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D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
in patients suffering from musculoskeletal pain, in par-
ticular neck pain [48], low back pain [45] and cumulative
trauma disorders [49]. Despite the availability of expec-
tancy questionnaires [50], the present findings showed
that expectancy effects had been considered in only 8.3%
of the studies.
Previous experiences highly mediate expectancy
in various ways: previous effective active treatments
showed a higher likelihood to elicit placebo response
[51, 52], whereas ineffective results attenuate them [53,
54], patients with more prolonged treatment exposure
showed more significant placebo or nocebo effect [53,
55]. Our results showed that 23% of the included stud-
ies investigated patients’ previous experiences, but
the quasi-totality enrolled naive participants. Naivety
was often related to the investigated technique and/or
therapy, but this could be insufficient to ensure similar-
ity between groups. For example, a positive experience
with one form of manual therapy can trigger a placebo
response when the subject is receiving another manual
approach. Notably, generalisation seems to be a funda-
mental characteristic of conditioning where learning
about a specific treatment cue can generalise to other
similars [53]. Although there are no validated tools accu-
rately assessing patients’ previous experiences, the lat-
ter could be appraised through precise questions (e.g.,
“have you ever been treated with manual therapy?”; “if so,
which one and what kind of experience did you have?”).
However, some authors are currently challenging the
importance of expectation and previous experiences in
exerting the placebo effect, using the models of predic-
tion and error processing and Bayesian brain: placebo
effects appear to be strongly influenced by “what you do,
and only secondarily, or not at all, by what you think”
[56].
Although interesting, this new conceptual proposal
is, as of today, only marginally relevant to the present
review. Future developments of the theories and more
consistent evidence could lead to an update of the sug-
gestions for planning strategies to control for EAs.
According to the literature, treatment credibility is
the measure by which patients believe the interven-
tion to be able to modify illness [26, 57]. is, in turn,
would affect their expectation [20] producing a definite
functional improvement [58]. It has been found that the
placebo response could depend more on patients’ per-
ception than on treatment effect [54, 59, 60]. e pre-
sent review found that only 7.9% of the studies took this
aspect into account. It is possible to control for treatment
credibility through deblinding procedures, already struc-
tured to control for the success of the blinding process
[61]. Deblinding procedures were used only by 13.6% of
studies.
Another key feature of placebo response is represented
by the patients’ personality traits [62], both in pain [19,
54, 63, 64], and in non-pain paradigms [65, 66] (see Jaksis,
etal., 2012 [67]and Darragh, etal., 2014 [65] for a com-
prehensive review on personality and placebo response).
Our results showed that only 10.5% of studies accounted
for the personality and psychological traits and state of
participants, specifically massage, reflexology and thera-
peutic touch studies. is significant trend could be
explained with a holistic mind–body perspective inher-
ent in the respective disciplines, but also with a second
consideration. ese CAMs, being relatively new to the
evidence-based paradigm, need to increase the level of
clinical-based research to prove their effectiveness. We
could speculate that researchers are more prone to con-
trol for factors that could impact the overall response to
the therapy, to enhance the quality of trials. Given their
importance in affecting the placebo response, psycho-
logical traits should be investigated in all therapies. ere
are, indeed, several questionnaires regarding traits [68,
69] and mood [70, 71] that could be used at baseline to
ensure a homogeneous distribution of patients.
e second macro-area regards the context-related
EAs and includes all characteristics of the intervention
surrounding patient and operator, going from where the
intervention took place to how often, how long, when the
outcomes were assessed, which body areas were targeted,
and the possible side-effects following the intervention,.
Literature suggests that contextual stimuli [54, 72], asso-
ciated environmental cues [73] and the context in gen-
eral [74] are critical elements for the placebo response.
Environment, architecture, and interior design could also
modulate patients’ outcome (see Testa and Rossettini,
2016 for details [74]). Treatments are therefore required
to be administered in the same setting [5], also consid-
ering the influence of the conditions of the room (i.e.
temperature, humidity) on several biological outcome
measures.
In addition to the physical context, the operative con-
text can be relevant in determining the effect of a given
therapy. e operative context could be described as a
ritual, that is a series of formal, repetitive acts or behav-
iours [32] occurring in association with the therapeutic
act. Rituals are essential in eliciting the placebo effect
[17, 75, 76] both before, during and after the session. It
is worth noting that the simple measurement (i.e. blood
pressure readings) can act as treatment [77, 78] and,
therefore, a ritual can induce clinical effects.
Strong evidence supports these assumptions about
context-related EAs; they are indeed included in the
most common RCT guidelines (i.e., CONSORT), mak-
ing them an already essential part of the study design.
Our results showed in fact that the context-related EAs
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D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
were generally considered more than EAs items relating
to the patient and the practitioner. An exception is rep-
resented by the reporting of side effects, present only
in 23.2% of studies. is prevents, in part, the ability to
evaluate the similarity between groups. We could specu-
late that the presence of side effects could modify the pla-
cebo response in patients. For example, side effects could
be interpreted as a signal to be part of the experimental
treatment group (regardless if it is true or not), and so
affect the outcomes.
e better reporting of context-related items seems
in contrast with the results of a methodological review
by Alvarez and colleagues, [23], that showed a lack of
improvements in the methodology of MT trials com-
paring before and after the publication of CONSORT.
With respect to the systematic review of Alvarez and col-
leagues [23], we analysed studies based on a conceptual
paradigm (equality assumption), and we only included
studies with at least one sham manual control. Further-
more, there is a distinction between the type of review
applied as per methodological vs systematic. e third
and last macro-area concerns the role of the practitioner,
which is essential for both specific and non-specific
effects of therapy. e doctor has been called “a powerful
therapeutic agent” and both a “practitioner effect” [79]
and a “physiotherapist’s effect” have been estimated in
patients with musculoskeletal disorders [74]. It has been
argued that a placebo effect is a form of the therapeutic
alliance [80], e therapeutic alliance, defined as a work-
ing relationship or a positive social connection between
the patient and the therapist [81], is particularly relevant
in manual therapies. erapists could shape the placebo
response in several ways. For example, the physician’s
enthusiasm would result in a significantly higher effect
on the patient response [77, 81], communication seems
to have a crucial role in eliciting placebo response [72],
patients’ perception of the operator’s expertise, profes-
sionalism and reputation is of significance in modify-
ing clinical outcomes [74, 82, 83]. It is unclear whether
age and gender of the treating practitioner can influence
the placebo response [84]. It may, therefore, represent a
confounding factor for the treatment effectiveness, when
treatments are delivered by different therapists [85].
Our results showed that approximately 80% of the
included studies reported the type and the number of
operators; whereas their experience, training, gender
and age were underreported. To ensure the practitioner-
related EAs, it should be recommended that each opera-
tor performs the same number of treatments in both
experimental and sham intervention; it is advisable to
provide training for the practitioners, aimed not only
at a homogeneous execution of experimental and sham
techniques but also at defining verbal and nonverbal
communication with the patient. A useful and valid tool
to control for these variables in MT could be the TIDieR
checklist [86], as suggested by Alvarez etal. [23].
Training in performing the sham technique is funda-
mental. e operator should pay attention to avoid any
specificity in sham treatments. Sham procedures should
be tailored to the therapeutic approach or technique it
mimics, as some researchers have already done [30, 61].
86 studies declared to have a double-blind design, bor-
rowing the expression from pharmacological research,
in which “both sides” of treatment administration (i.e.,
patient and clinician) do not know whether the active
principle is present in a given drug. On the contrary, in
MT scenario, it is impossible to blind who administers
the treatment. So, if a second person is blinded (e.g., data
analyst, data collector, or outcome assessor) the expres-
sion “dual blind” should be preferred [87]).
ere are many factors to consider when planning an
mtRCT and a large number of tools available to do so.
e evidence-based panorama is vast and can be disper-
sive, even more so in the absence of clear guidelines. It
would be useful and efficient to unify the existing tools
in a comprehensive, shared and specific checklist for MT.
is would offer a structured step-by-step guide giv-
ing researchers the possibility to improve the areas that
need adjustments, and thus increasing the likelihood of
obtaining valid, generalisable and robust results.
Limitations
We acknowledge some limitations. Firstly, despite the
effort to identify all relevant literature, the search strat-
egy may have left out some studies. Secondly, we did not
take into account some EA items that may influence the
placebo response and should be taken into consideration
when planning a sham therapy. Particularly the opera-
tors’ empathy [88], the characteristics of the interaction
between operators and participants (both verbal [51])
and nonverbal [31]) that can modify the patient percep-
tion of the therapy believability [44], including the even-
tual training of operator aimed at the style of rapport
with the patient, and quality of patient-operator interac-
tion [20, 26] through a satisfaction questionnaire. Finally,
although a protocol similar to Cerritelli etal. [16] was
followed, an a priori protocol for this methodological
review has not been published.
Conclusions
is review showed a moderate quality in the reporting
of context-related EA items, potentially because they are
primarily included in pre-existent guidelines. In con-
trast, there is a general lack of attention to the patient-
and practitioner- related EAs, that could be controlled
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Page 12 of 14
D’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
through already existing tools. Poor planning and report-
ing might limit the robustness of the EA, and the validity
of the evidence.
Abbreviations
EA Equality assumption
MT Manual therapy
RCT Randomised controlled trials
mtRCT Randomised controlled trials of manual therapy
CAMs Complementary alternative medicines
PROMs Patient-reported outcome measures
Acu Acupressure
Mas Massage
Rei Reiki
TT Therapeutic touch
Mob Mobilisation
Man Manipulation
Mix Mixed-method
N Number
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s12874- 022- 01704-8.
Additional le1.
Acknowledgements
No funds were received for the study. The authors thank Prof. Jorge E. Esteves
for his help in reviewing the manuscript.
Authors’ contributions
G.DA., F.C. conceived the design and coordinated the study. G.DA., N.R, M.T.,
A.A., F.C. participated in the study, and drafted the manuscript. G.DA., N.R, M.T.,
A.A., G.M., I.M. searched for the studies, collected and analyzed the data. F.C.
was in charge of data management and analyzed the data. All authors read
and approved the final manuscript.
Funding
This research received no specific grant from any funding agency in the pub-
lic, commercial or not-for-profit sectors.
Availability of data and materials
The datasets used and/or analysed during the current study are available from
the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 21 April 2021 Accepted: 4 August 2022
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