ArticlePDF AvailableLiterature Review

Differences between experimental and placebo arms in manual therapy trials: a methodological review

  • Centre for Osteopathic MEdicine (COME) Collaboration
  • Soma Istituto Osteopatia Milano

Abstract and Figures

Background To measure the specific effectiveness of a given treatment in a randomised controlled trial, the intervention 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,, the Cochrane Library, chiloras/MANTIS, PubMed Europe, Allied and Complementary 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 summary 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, affecting, 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.
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BMC Medical Research Methodology (2022) 22:219
Dierences betweenexperimental
andplacebo arms inmanual therapy trials:
amethodological review
Giandomenico D’Alessandro1,2, Nuria Ruffini1,3, Alessandro Aquino1,4, Matteo Galli1,5, Mattia Innocenti2,
Marco Tramontano6 and Francesco Cerritelli1*
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,, 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
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Open Access
BMC Medical Research
Francesco Cerritelli
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’Alessandroetal. BMC Medical Research Methodology (2022) 22:219
‘Manual erapy’ (MT) is an umbrella term used and
variously defined by different professional groups
[14]. 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,
1113], 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 [1719]. 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 [242627].
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, 3034],
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
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 andevaluation ofstudies
Relevant studies were identified through a comprehensive
computerised bibliographic search on the following data-
ENCE, Scholar Google,, 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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D’Alessandroetal. 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
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
MTs classication inthepresent 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 etal. [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 withmore thanone 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
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 [4143] were considered
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D’Alessandroetal. 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 37.4years (Table1).
Fig. 1 Flow-chart of the study
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D’Alessandroetal. 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
73.3% (N = 228) of studies described the source of
enrolment, whereas 83 (26.7%) studies did not give any
information (Table1).
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 etal. 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
(26.1) 424
(83.8) 8
(2.8) 314
(26.3) 29
(27.6) 1712 (37.7) 1772
(42.0) 185 (61.1) 6053
- 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’Alessandroetal. 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
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 etal.,
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%) (Table2).
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’Alessandroetal. 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%) (Table3).
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
(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
3/6 0
(0%) 0
(0%) 0
(0%) 1
(5.0%) 0
(0%) 2
(1.8%) 6
(6.5%) 0
(0%) 9
4/6 1
(1.3%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 1
(0.9%) 0
(0%) 1 (25.0%) 3
5/6 2
(2.6%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 2
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D’Alessandroetal. 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
(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
5/10 2
(2.6%) 0
(0%) 0
(0%) 1
(5.0%) 0
(0%) 1
(0.9%) 3
(3.3%) 1
(25.0%) 8
6/10 2
(2.6%) 1
(12.5%) 0
(0%) 2
(10.0%) 0
(0%) 14
(12.8%) 9
(9.8%) 0
(0%) 28
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
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
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
10/10 7
(9.1%) 0
(0%) 0
(0%) 1
(5.0%) 1
(33.3%) 7
(6.4%) 3
(3.3%) 0
(0%) 19
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D’Alessandroetal. 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 (Table4).
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
(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
1/6 8
(10.4%) 2
(25.0%) 0
(0%) 5
(25.0%) 0
(0%) 12
(11.0%) 13
(14.1%) 0
(0%) 40
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
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
4/6 10
(13.0%) 1
(12.5%) 0
(0%) 0
(0%) 1
(33.3%) 6
(5.5%) 9
(9.8%) 0
(0%) 27
5/6 18
(23.4%) 0
(0%) 0
(0%) 0
(0%) 0
(0%) 1
(0.9%) 1
(1.1%) 0
(0%) 20
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D’Alessandroetal. 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”
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
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,
etal., 2012 [67]and Darragh, etal., 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
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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Page 11 of 14
D’Alessandroetal. 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 etal. [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.
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 etal. [16] was
followed, an a priori protocol for this methodological
review has not been published.
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’Alessandroetal. 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.
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 le1.
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.
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.
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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... Eight studies performed sham manual therapy, however, each one performed it differently, demonstrating how this topic is still in debate and needs to be addressed. The sham intervention is defined as an intervention that does not have the same specificity and effect as the intervention technique [33]. Therefore, regarding the specific effect, setup, and condition required for the experimental intervention, then one must exclude these variables to create the sham intervention and apply it in the same place as the experimental intervention. ...
... Therefore, regarding the specific effect, setup, and condition required for the experimental intervention, then one must exclude these variables to create the sham intervention and apply it in the same place as the experimental intervention. In a recent study by Giandomenico et al. 2022, they suggest describing the following items for both intervention and sham groups: (i) type of touch; (ii) amount of pressure; (iii) type of movement and patient positioning; (iv) areas of contact; (v) time of contact; and (vi) practitioner's characteristics [33]. In some of the included studies [21,[24][25][26]28] was performed the sham technique over the same places as the experimental techniques, but superficially without applying pressure over deep structures. ...
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Background Fascial Therapy is an ancient and widespread practice throughout the world. These approaches are very common in osteopathic practice and taught in workshops for professionals from different areas of health care, including Physiotherapy. This type of treatment is quite specialized and centered on the therapist. However, there is a lack of high-quality and low-risk bias studies that justify the use of this practice. Despite this, there is little scientific evidence about the effectiveness of Fascial Therapy to treat some visceral disorders. The purpose of this study was to critically appraise the scientific literature concerning the clinical efficacy of techniques used in Fascial Therapy targeting the visceral system. Methods This systematic review included randomized controlled trials in any language or date of publication. All primary outcomes reported were included. The methodological quality and statistical reporting of each eligible trial were evaluated using the version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). This systematic review provided a synthesis of current evidence on the effects of Fascial Therapy in patients with visceral disorders and/or pain. A total of 11 studies were included, with five of them covering gastrointestinal dysfunction, two covering cardiorespiratory dysfunction, two covering musculoskeletal dysfunction, and two covering urogenital dysfunction. Results Fascial Therapy targeting the visceral system has been shown to be effective in reducing pain over the long term in people with low back pain when combined with standard physical therapy and effective in reducing gastroesophageal reflux symptoms over the short term. Considering the overall bias, six studies were at high risk of bias, two studies had some concerns and only three studies were at low risk of bias. Of the three studies with a low risk of bias, only two showed positive results and were effective in improving the studied outcome. Conclusion This systematic review shows that currently, there is poor evidence for the efficacy of the techniques used in Fascial Therapy targeting the visceral system, and this information can help healthcare professionals in decision-making related to the use of Fascial Therapy targeting the visceral system in patients with visceral disorders and/or pain.
... Despite their usefulness, the result is a lack of direct studies examining the specific mechanisms underlying the manifestation of these effects, which poses the risk of not fully understanding whether these effects indeed stem from the touch itself or from other factors, such as a placebo [170]. ...
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(1) Background: Osteopathy in the cranial field (OCF) is a distinctive approach within osteopathy, focusing on the cranial region’s manual manipulation. Nevertheless, OCF fosters doubt in the scientific community because it refers to out-of-date models. This perspective paper critically analyzes the current knowledge in the fields of neurophysiology and mechanobiology to propose an evidence-informed rationale for OCF. (2) Methods: The reporting framework used in the current perspective article obeyed the guidelines for writing a commentary. (3) Results: The article’s main findings focus on the tactile stimulation of exocranial receptors and their implications in the management of craniofacial algic-dysfunctional syndromes implementing OCF. (4) Conclusions: By establishing an evidence-based rationale for OCF, this research aims to guide future directions in OCF and contribute to a more patient-centered and effective approach to health and wellbeing.
... Furthermore, biases and limitations, such as small sample size, inadequate study length, short-term follow-up, and inadequate controls (placebo or sham), undermine the internal and external validity of RCTs in manual therapy [17]. In addition, control groups have several areas to be improved, such as maintaining conditions comparable to experimental interventions or ensuring the inertness of the sham technique [18,19]. Furthermore, a non-manual comparator (e.g., modalities-detuned ultrasound or laser) is often applied in RCTs instead of using proper manual comparators (e.g., sham touch, shame joint mobilization), which lack the characteristics of indistinguishability necessary to define it as 'placebo' [20]. ...
... в методологическом обзоре отмечают, что применение «фиктивных вмешательств» в мануальной терапии ограничено, что влияет на силу доказательств. В обзоре были обсуждены методологические аспекты планирования будущих исследований и даны рекомендации по контролю за допущением равенства манипуляций [6]. ...
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The article presents the possibility of applying the principles of evidence-based medicine to manual therapy. The complementary medicine, which includes manual therapy, faces certain difficulties when carrying out randomized clinical trials. In our opinion, a new paradigm of the science-based clinical trials is needed for manual therapy.
... To reduce the impact of confounding factors and improve the quality of manual therapy research, researchers have previously conducted comparative studies of real manual therapy and sham manual therapy [32]. The objective of the study was as follows: to add Maitland mobilization to routine rehabilitation training for CAI patients to explore whether there was a more positive improvement than routine rehabilitation alone or routine rehabilitation combined with sham manual therapy, and to determine the effectiveness of Maitland mobilization for CAI patients. ...
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The study aims to determine whether routine rehabilitation training combined with the Maitland mobilization is more effective than routine rehabilitation training alone in patients with chronic ankle instability, intending to provide a novel rehabilitation strategy for chronic ankle instability. A total of 48 subjects were divided into three groups: EG (Maitland mobilization and routine rehabilitation), CG (routine rehabilitation), and SG (sham mobilization and routine rehabilitation). The intervention was performed three times each week for 4 weeks, for a total of 12 sessions. Before and after the intervention, the muscle strength, star excursion balance test (SEBT), weight-bearing dorsiflexion range of motion (WB-DFROM), ankle range of movement, Cumberland ankle instability tool (CAIT), self-comfort visual analog scale (SCS-VAS), and self-induced stability scale (SISS-VAS) were assessed. The results showed that the improvement of SEBT, WB-DFROM, and active ankle range of movement without the pain in EG was more obvious than CG and SG, but the improvement of the self-report of ankle severity and muscle strength was not. Compared with routine rehabilitation training alone, routine rehabilitation training combined with Maitland mobilization for patients with chronic ankle instability may provide more benefit in terms of balance and ankle range of movement than routine rehabilitation alone, but the improvement in muscle strength was not evident enough.
... In this unusual case, where the sham consists of applying pressure to wrong points, double-blinding is arguably preserved even when subjects are not naive to the intervention. In a recent systematic review of 311 trials, 86 trials reported using a double-blind design (17), referring to the blinding of participants and other key trial personnel (e.g., data collectors, outcome assessors, data analysts). However, these manual trials are wrongly described as double-blinded. ...
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Randomised placebo-controlled trials are implemented to determine whether a particular therapy is superior to placebo and can thus be considered, effective. However, adopting the standard RCT design in contexts other than pharmacological trials, such as manual therapy, may result in systematic biases. These biases may occur due to: the impossibility of traditional “double-blinding” in manual therapy trials; insufficient pre-training of operators delivering the treatment and/or sham therapy; biased recruitment of study participants; the problematic use of subjective and/or objective outcomes; and finally, the presence of phenomena mimicking placebo effects. From the perspective of placebo studies, the purpose of this paper is to discuss and make appropriate recommendations to address these five issues in manual therapy research.
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The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.
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The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.
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Previous research has indicated that the sex, status, and non-verbal behaviors of experimenters or clinicians can contribute to reported pain, and placebo and nocebo effects in patients or research participants. However, no systematic review has been published. Objective: To investigate the effects of experimenter/clinician characteristics and non-verbal behavior on pain, placebo, and nocebo effects. Methods: Using EmBase, Web of Knowledge, and PubMed databases, several literature searches were conducted to find studies that investigated the effects of the experimenter’s/clinician’s sex, status and non-verbal behaviors on pain, placebo, and nocebo effects. Results: Thirty-four studies were included, twenty on the effects of characteristics of the experimenter/clinician, eleven on the role of non-verbal behaviors, and three on the effects of both non-verbal behaviors and characteristics of experimenters/clinicians on pain and placebo/nocebo effects. Experimenters/clinicians induced lower pain report in participants of the opposite sex. Furthermore, higher confidence, competence, and professionalism of experimenters/clinicians resulted in lower pain report and higher placebo effects, whereas lower status of experimenters/clinicians such as lower confidence, competence, and professionalism generated higher reported pain and lower placebo effects. Positive non-verbal behaviors (e.g. smiling, strong tone of voice, more eye contact, more leaning toward the patient/participant, and more body gestures) contributed to lower reported pain and higher placebo effects, whereas negative non-verbal behaviors (i.e. no smile, monotonous tone of voice, no eye contact, leaning backward from the participant/patient, and no body gestures) contributed to higher reported pain and nocebo effects. Conclusion: Characteristics and non-verbal behaviors of experimenters/clinicians contribute to the elicitation and modulation of pain, placebo and nocebo effects.
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Background It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use.MethodsA review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form.Results11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0–10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results.Clinical implicationsThese estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor–patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy.
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Background context: Mobilization and manipulation therapies are widely used to benefit patients with chronic low back pain. However, questions remain about their efficacy, dosing, safety, as well as how these approaches compare to other therapies. Purpose: To determine the efficacy, effectiveness, and safety of various mobilization and manipulation therapies for treatment of chronic low back pain. Study design/setting: A systematic literature review and meta-analysis. Outcome measures: Self-reported pain, function, health-related quality of life, adverse events. Methods: We identified studies by searching multiple electronic databases from January 2000 to March 2017, examining reference lists, and communicating with experts. We selected randomized controlled trials comparing manipulation and/or mobilization therapies to sham, no treatment, other active therapies, and multimodal therapeutic approaches. We assessed risk of bias using Scottish Intercollegiate Guidelines Network criteria. Where possible, we pooled data using random-effects meta-analysis. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was applied to determine the confidence in effect estimates. This project is funded by the National Center for Complementary and Integrative Health under Award Number U19AT007912. Results: 51 trials were included in the systematic review. Nine trials (1176 patients) provided sufficient data and were judged similar enough to be pooled for meta-analysis. The standardized mean difference for a reduction of pain was SMD= -0.28, 95% CI, -0.47 to -0.09, P=0.004; I2=57% at post-treatment; within seven trials (923 patients) the reduction in disability was SMD= -0.33, 95% CI, -0.63 to -0.03, P=0.03; I2=78% for manipulation or mobilization as compared to other active therapies. Subgroup analyses showed that manipulation significantly reduced pain and disability, compared to other active comparators including exercise and physical therapy (SMD= -0.43, 95% CI, -0.86 to 0.00; P=0.05, I2=79%), (SMD= -0.86, 95% CI, -1.27 to -0.45; P<0.0001, I2=46%). Mobilization interventions, as compared to other active comparators including exercise regimens, significantly reduced pain (SMD= -0.20, 95% CI, -0.35 to -0.04; p=0.01; I2=0%) but not disability (SMD= -0.10, 95% CI, -0.28 to 0.07; p=0.25; I2=21%). Studies comparing manipulation or mobilization to sham or no treatment were too few or too heterogeneous to allow for pooling as were studies examining relationships between dose and outcomes. Few studies assessed health-related quality of life. Twenty-six of the 51 trials were multimodal studies and narratively described. Conclusions: There is moderate-quality evidence that manipulation and mobilization are likely to reduce pain and improve function for patients with chronic low back pain; manipulation appears to produce a larger effect than mobilization. Both therapies appear safe. Multimodal programs may be a promising option.
The logic underpinning randomized controlled trials depends on the assumption that any non-specific effects of treatment are equal and additive across trial arms. We label this the “assumption of specific efficacy”. There are a number of situations in which the assumption of specific efficacy does not hold. We describe the epistemic consequences that arise in these situations and discuss strategies for preserving the internal validity of randomized trials in such situations.
Objective: The aim of this review was to evaluate a selection of major reporting aspects in manual therapy (MT) trials, before and after the publication of the CONSORT extension for non-pharmacological trials (CONSORTnpt) STUDY DESIGN AND SETTING: We randomly selected 100 MT trials published between 2000 and 2015 and divided them into a pre-CONSORTnpt (n=50) and a post-CONSORTnpt (n=50) group. We extracted data about relevant issues of internal validity, reliability and description of interventions. Two authors extracted data independently. Percentages were used for descriptive analyses and Fisher's exact test and the chi-square test were used for group comparisons. Results: Six different types of MT interventions with up to 20 controls were analyzed. The most common populations/conditions studied were healthy subjects and subjects with lower back or neck pain. Over 70% of studies included multi-session interventions and 42% of studies reported long-term follow-up. The only significant differences between groups were the inclusion of a flowchart diagram, the estimated effect size, precision descriptions and the description of intervention procedures. Conclusion: Our findings suggest that trials in MT show poor reporting even after availability of standardized guidelines.
Background: Empathy plays a role in medical care. Studies have showed that higher empathy levels of physicians correlates with better patient outcomes. The role of empathy in osteopathic practice has been poorly investigated. Objective: To explore the feasibility of analysing the link between the empathy of osteopaths and the improvement in persistent musculoskeletal pain patients. Participants: 13 trainees attending the 5th year in a reference osteopathic teaching institution and 39 patients with chronic musculoskeletal pain. Methods: Trainees were tested for their empathy level by using the Jefferson Scale of Physician Empathy-Health Professional. Trainees with a score higher than the 80 th percentile and lower than the 20 th percentiles were identified as “highly” and “poorly” empathic therapists and were assigned respectively to the HET and LET group. Each trainee was assigned to patients. Pain intensity was monitored throughout the study by the validated Numerical Rating Scale (NRS). Results: Patients included into the HET and LET groups had comparable baseline characteristics. Both groups benefited from the treatment. The mean NRS improvement score in the HET group was 6.4 (95% CI 5.3 to 7.5; p < 0.0001). The LET mean NRS improvement score was 3.5 (95% CI 2.1 to 4.8; p < 0.0001). The intergroup difference indicated that the two patient groups differed in pain intensity starting from the third treatment (T3 p = 0.0032 and T4 p = 0.0021). Conclusions: Research on the link between empathy of therapists and the outcome of Osteopathic Manipulative Treatment for chronic musculoskeletal pain appears feasible. The reported findings might help to design further confirmatory studies.
Open-label placebos (OLP)-placebo pills honestly prescribed-have challenged the notion that placebos require either deception or concealment to evoke salubrious benefits. This essay describes how the author arrived at the counter-intuitive OLP hypothesis, discusses evidence for OLP effectiveness, and examines mechanistic explanations for OLP. Current dominant theories such as expectation and conditioning are found to be insufficient or inaccurate. The author proposes that emerging concepts of prediction and error processing (PEP), Bayesian brain, and embodied cognition are more appropriate models for understanding OLP. As a neural processing model, PEP argues that sensory predictions are embedded in and inseparable from perceptions; PEP circumvents mind-body dualism. The author discusses how OLP, mostly non-consciously, might perturb aberrant symptom amplifications and central sensitization resulting in perceptions of improvement in symptoms. Placebo effects are neurologically encoded predictions, less what patients think and more what they enact and perform.
Context: Although osteopathy is not yet certified as a health profession in Italy, many people choose osteopathic manipulative treatment (OMT) for pain relief. Nevertheless, no study evaluating patients' degree of satisfaction after OMT and the perceived quality of the treatment has occurred in Italy. Objectives: The study intended to assess outpatients' satisfaction with OMT carried out at a hospital. Design: The research team conducted a survey from January 2015 to January 2016 using 3 questionnaires. Setting: The study took place the Fondazione Santa Lucia Hospital (Rome, Italy), an institute for research and health care. Participants: Participants were 101 patients with musculoskeletal (MSK) disorders undergoing OMT at the hospital. Interventions: The OMT was performed by 3 osteopathic practitioners who had completed the 6-y, part-time training program recognized by the Italian Register of Osteopaths. Outcome measures: To measure the level of their satisfaction, the research team had patients complete the modified patient satisfaction questionnaire (mPSQ), the patient satisfaction with outpatient physical therapy (PSOPT) instrument, and the visual analog scale for satisfaction (VASS). Parametric and nonparametric analyses were performed to correlate the questionnaires and the demographic variables using the Pearson and Spearman tests. Results: Data were obtained from 97 patients, with mean age of 42.48 ± 16.1 y, 50 of whom were female. The data showed high, average general satisfaction after OMT: (1) VASS-9.36 ± 1.00 and (2) PSOPT-43.27 ± 3.65. A significant negative correlation was found between access to care (D1-TOT) on the mPSQ and at ages older than 65 y-r = -0.24 and P < .05. A significant positive correlation was found between the VASS and female gender-r = 0.23 and P < .05. A significant positive correlation was also found between continuity of care (D3-TOT) and continuity of care-family (D3-1) on the mPSQ and education level-r = .20 and P < .05 and r = 0.24, P < .05, respectively, and with other dimensions explored by the questionnaires. Conclusions: The data show a high level of general satisfaction in patients with MSK disorders who underwent OMT in an Italian hospital setting. The overall satisfaction rate was mainly influenced by the patient's perception of the practitioner's technical quality, the continuity of the treatment, and the cost of the service. Some differences emerged for age, gender, and educational level. The information from the current study may be useful for improving the therapeutic assistance provided with OMT and to promote alternative therapies in health and medicine.