[ viewpoint ]

JOEL E. BIALOSKY, PT, PhD1,2 MARK D. BISHOP, PT, PhD1 CHARLES W. PENZA, DC, PhD1

Placebo Mechanisms of
ManualTherapy: A Sheep
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inWolfs Clothing?
J Orthop Sports Phys Ther 2017;47(5):301-304. doi:10.2519/jospt.2017.0604

W
Copyright 2017 Journal of Orthopaedic & Sports Physical Therapy. All rights reserved.

hen a physical therapist provides a manual therapy (MT) participants are aware from the consent
intervention for a patient presenting with pain and the process of the chance of receiving a pla-
patient experiences a positive clinical outcome, we cannot cebo treatment.27 Placebo analgesia is
much larger when the placebo treatment
answer as to why this occurs. Still, the Commission on
is provided with an instructional set en-
Accreditation in Physical Therapy Education mandates that MT be hancing expectation (eg, the agent you
taught in entry-level physical therapy programs and that practicing have just received is known to powerfully
clinicians seek continuing education and fellowship opportunities. reduce pain in some patients).28 Placebo
Would we continue to devote valuable tervention without a treatment effect. In analgesia is further augmented when
Journal of Orthopaedic & Sports Physical Therapy

time and financial resources to learning contrast, placebo treatments are associ- participants are conditioned to expect
and improving our skills in providing MT ated with marked analgesia.27 Further- analgesia through researchers surrepti-
interventions if the related clinical out- more, the placebo response is an active tiously lessening a painful stimulus after
comes were placebo responses? In this neurophysiological process associated the treatment21 or surreptitiously replac-
Viewpoint, we conceptualize placebo as with consistent responses in both the spi- ing a medication with a placebo.1 Fur-
an active and important mechanism of nal cord10 and supraspinal regions.9 Col- thermore, increased placebo analgesia
MT. We are not suggesting that placebo lectively, these findings support multiple is observed following a previous positive
is the only pathway through which MT endogenous pain modulatory processes response18 and after watching another
inhibits pain; however, we argue that pla- in response to the expectation of receiv- person experience pain relief in response
cebo mechanisms deserve consideration ing care. to a treatment.6 Subsequently, placebo
as an important component of the treat- analgesia is increased when participants
ment effect. For the sake of brevity, we The Placebo Treatment-Effect (1) believe they have received an effective
will focus on placebo as a mechanism of Mechanism analgesic agent, (2) are conditioned to
MT-related pain relief, and from here on Placebo effects result from the psycho- expect a placebo intervention to be effec-
will refer to pain relief corresponding to social context surrounding the clinical tive, (3) are conditioned with an effective
a placebo treatment as placebo analgesia. encounter and are reliably produced treatment and then given a placebo treat-
in laboratory settings by manipulating ment, and (4) have had prior successful
Not Your Fathers Placebo expectations and through conditioning experiences and/or when the environ-
Traditionally, placebo has had a nega- and learning. Placebo analgesia is small ment includes other persons benefiting
tive connotation, implying an inert in- in placebo-controlled studies, in which from the treatment.
1
Department of Physical Therapy, University of Florida, Gainesville, FL. 2Brooks RehabilitationCollege of Public Health and Health Professions (University of Florida) Research
Collaboration, University of Florida, Gainesville, FL. No funding support was received. Institutional Review Board approval was not required for this study. The authors certify that
they have no affiliations with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the article. Address
correspondence to Dr Joel E. Bialosky, Department of Physical Therapy, University of Florida, PO Box 100154, Gainesville, FL 32610. E-mail: bialosky@phhp.ufl.edu t Copyright
2017 Journal of Orthopaedic & Sports Physical Therapy

journal of orthopaedic & sports physical therapy|volume 47|number 5|may 2017|301


Placebo Mechanism Considerations of MT
In a famous scene from Raiders of the
Lost Ark, Indiana Jones is confronted
by a skilled swordsman. The swords-
man pulls out his weapon and undergoes
elaborate swordplay as he prepares for
the battle. Indiana Jones calmly pulls
out a gun and shoots the swordsman.
The humor in this scene results from the
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contrast between the theatrical, choreo-
graphed approach of the swordsman and
the apathetic approach of Indiana Jones.
Manual therapy, at face value, resembles
Indiana Jones, that is, an intervention
without fanfare; however, in clinical
practice MT is accompanied by an elabo-
rate ritual involving the evaluative and
application process and more closely
resembles the swordsman. Though the
Copyright 2017 Journal of Orthopaedic & Sports Physical Therapy. All rights reserved.
choreographed dance of the swords-
man does not serve him well, the ritual
surrounding MT may play a major role
in the corresponding outcomes. In the
following sections, we present findings
from the placebo literature with implica-
tions for interpreting patient responses
to MT.
Journal of Orthopaedic & Sports Physical Therapy
MT Is an Experience
Placebo analgesia is influenced by con-
textual factors. Physical placebo treat-
ments, such as placebo injections,
acupuncture, or surgery, result in greater
analgesic responses than oral placebos.2
Additionally, the magnitude of placebo
analgesia is dependent on the corre-
sponding meaning. For example, greater
analgesia is observed when placebos are
presented as more expensive,29 as well as
when they are labeled with a recognizable
brand name.4 Manual therapy is a physi-
cal intervention provided by enthusiastic
practitioners who readily inform their
patients of its likely benefits. The physi-
cal nature of MT along with the positive
framing so often provided by practitio-
ners may effectively alter or reinforce the
patients beliefs and perceptions of the
intervention influencing the related out-
comes. Subsequently, the MT and provid-
er brand should be considered for their
role in clinical outcomes.
302|may 2017|volume 47|number 5|journal of orthopaedic & sports physical therapy
[ viewpoint ]
Variability in Response to MT
Attempts to identify individuals who are
likely to respond positively to MT13 have
been unsuccessful. The placebo response
is a complex, individualized experience
influenced by multiple factors, and all
individuals are likely placebo responders;
however, the magnitude of the placebo
response and conditions under which
each person responds are highly vari-
able.15 Placebo responses are mislabeled
as nonspecific, implying a general effect
across interventions. Instead, placebo
responses are highly specific and depen-
dent on the individual intervention. For
example, placebo analgesia conditioned
through opioid agents is abolished by
opioid antagonists, whereas placebo an-
algesia conditioned through nonsteroidal
anti-inflammatory agents is not.1 Placebo
analgesia varies within individuals, sug-
gesting a state-dependent event rather
than an individual characteristic,30 and
analgesia to one form of placebo does not
predict analgesia to another form of pla-
cebo.20 Subsequently, placebo analgesia
is a specific and individualized response
to the context of a provided intervention.
Similarly, identifying MT responders
may be insensitive to the mean findings
of larger studies and dependent on indi-
vidual patient beliefs, experiences, and
relationship with the provider.
The Manual Therapists Role in Contextual
Enhancement
Placebo analgesia is enhanced by a posi-
tive and empathetic provider.17 Similarly,
the interaction between the provider and
patient is influential in interventions for
pain such as medication7 and electrical
stimulation.11 In addition, provider ex-
pectations influence placebo analgesia.12
Specific to MT, provider expectations in-
fluence the manner of interacting with
the patient,24 and provider preferences
are associated with clinical outcomes.8
Collectively, these findings suggest that
the provider communication style, as well
as beliefs, may influence placebo analge-
sia and clinical outcomes in response to
interventions for pain. Subsequently, the
mannerisms and beliefs of the provider
are likely to play a key role in the clinical
effectiveness of MT.
Therapeutic Benefits From the Act of
Treatment
Treatment response is dependent on
many factors, including those related to
simply seeking and receiving care. Recent
studies have observed analgesia exceed-
ing natural history of the disorder when
individuals are aware of having received a
placebo (open-label placebo).16 Such find-
ings suggest that patients benefit from
the act of receiving treatment, and part of
the treatment response to MT may be at-
tributed to the process of receiving care.
Next Steps for Research: Determining the
Contribution of the Placebo Mechanisms
to MT
Placebo-Controlled Trials of MT: Have
We Been Comparing Good Apples to
Bad Apples? A placebo comparator for
a medication is seemingly simple, as the
active ingredient and biological mecha-
nism are generally well established. Man-
ual therapies are complex interventions,
and the active mechanisms behind their
clinical effectiveness are not established.
Consequently, a suitable placebo compar-
ator lacking the specific key ingredients
of an MT intervention is elusive.
Blinding of both the patient and pro-
vider is an important consideration in
placebo-controlled trials. Blinding may
be compromised due to poorly designed
placebos that are not believable. Further-
more, blinding may be lost due to sensa-
tions unique to the studied intervention22
or side effects in the active arm.26 Similar
loss of blinding may occur in MT trials
if the active arm is more elaborate (ie,
a skilled hands-on MT intervention) or
prone to side effects such as transient
soreness. Expectation is an important
consideration, as an MT placebo compar-
ator may successfully blind participants;
however, it may also be associated with
low expectations for its effectiveness.
For example, a skillfully applied MT in-
tervention for which participants have
 high expectations may result in superior
outcomes to a light-touch comparator for
which participants have lower expecta-
tions. Furthermore, the same MT inter-
vention may lack efficacy when compared
to a sham MT that is similar in context
to the studied MT and for which par-
ticipants have higher expectations. Sub-
sequently, the superiority, or failure to
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demonstrate superiority, of the studied
MT intervention to a placebo treatment
may be related to the expectations attrib-
uted to each.
Potentially, even more challenging
and problematic is blinding the provid-
er to whether he or she is providing the
real or the placebo intervention. Pro-
vider blinding has implications for out-
comes due to the known effect of provider
Copyright 2017 Journal of Orthopaedic & Sports Physical Therapy. All rights reserved.
preferences,8 as well as unconscious bias
in interacting with patients.24
Placebo may be a primary mechanism
through which MT interventions exert
their effect on pain. As such, placebo-con-
trolled trials of MT may not be optimally
designed to determine clinical effective-
ness, and carefully designed studies with
appropriate placebo comparators and
Journal of Orthopaedic & Sports Physical Therapy
rigorous blinding may result in repeated
null findings or clinically meaningless ef-
fect sizes. Manual therapy efficacy studies
that include placebo comparators should
account for blinding, as well as partici-
pant and provider expectation, in each
study arm.
Determining the Placebo Effect Size of
MT A placebo treatment corresponds to
a placebo response caused by the placebo
mechanism, along with other factors,
such as natural history of the disorder and
regression to the mean. The placebo effect
is the difference between the placebo re-
sponse and changes occurring in response
to no treatment (ie, the natural history of
the disorder), within an experimental de-
sign that can account for influences such
as natural history of the disorder and re-
gression to the mean.3 Imagine the scene
from Raiders of the Lost Ark as a random-
ized controlled trial, with the swordsman,
in this example, considered as the pla-
cebo. Half the participants are assigned
journal
journal
to be shot by Indiana Jones (active arm),
while half are assigned to be impaled by
the swordsman (placebo arm). We would
likely conclude that Indiana Jones was
ineffective due to his inability to outper-
form the swordsman. Equivocal findings
between Indiana Jones and the swords-
man (placebo) do not necessarily imply
the ineffectiveness of Indiana Jones but,
instead, may suggest 2 equally effective
interventions. A third, no-treatment arm
would allow us to determine whether In-
diana Jones and the swordsman resulted
in larger and more meaningful outcomes
than natural history and could argue for
the effectiveness of both. Studies of the
mechanisms of MT should account for the
magnitude of placebo mechanisms, with
additional mechanisms beyond placebo
considered to account for the remaining
treatment effect.
Placebo as a Mechanism of MT Rather
Than a Control for MT Participants in a
clinical trial may differ from those seek-
ing care in terms of their expectations for
treatment (patients do not enter treat-
ment expecting to receive a placebo)
and preferences (individuals with strong
preferences for MT may not participate
in clinical trials knowing that they could
be assigned to a different treatment
arm). Participants in placebo-mecha-
nism studies receive a placebo treatment
with instructions suggesting an effective
intervention. This study design is more
consistent with clinical care, in which
interventions are provided by enthusias-
tic practitioners instructing the patient
of the likely effectiveness. Placebo anal-
gesia is greater in placebo-mechanism
studies than in placebo-control studies,27
and similar approaches may result in a
more accurate representation of the mag-
nitude of the placebo effect size of MT in
clinical practice. Furthermore, placebo-
controlled studies may underestimate the
effect size of MT as well.23 Collectively,
these findings suggest that randomized
controlled trials underestimate both the
placebo and treatment effect sizes due
to differences in participant preferences
and expectations from those observed
of orthopaedic
of orthopaedic
& sports
& sports
physical
physical
therapy|volume
therapy|volume
in clinical care. Carefully designed stud-
ies are necessary to account for the true
magnitude of these factors on outcomes
and may provide a more valid indication
both of the effectiveness of MT as well as
of the extent of placebo mechanisms in
the observed clinical outcomes.
Is There an Additive Effect Between Pla-
cebo and MT? Randomized controlled
trials assume an additive effect, implying
that the treatment effect is the difference
between the response to the studied in-
tervention and the response to the pla-
cebo treatment. The assumption of an
additive effect is not established for MT,
and placebo treatments may represent
separate but at times equally effective
interventions. Furthermore, the total
treatment effect of MT may represent
interacting (MT and placebo) mecha-
nisms.19 For Indiana Jones, a gun without
fanfare was effective. In the case of MT,
however, the ritual may be the active in-
gredient or may be necessary for the in-
tervention to maximally influence pain.
The strictly additive solution should not
be assumed, and determining whether
the sword and the gun are separate but
equally effective interventions of differ-
ing underlying mechanisms, as well as
the degree to which the dance interacts
with the sword to enhance its effective-
ness, is imperative to our understanding
of the mechanisms of MT.
Reframing the Placebo Mechanism
Manual therapy is diverse, encapsulat-
ing differing approaches with markedly
different theoretical mechanisms. Head-
to-head comparisons consistently ob-
serve that one type of MT is as effective
as another for pain, despite the differing
theories and approaches, suggesting a
common, shared mechanism. Manual
therapists, having invested large amounts
of time perfecting their craft, may be
troubled by the prospect of placebo as
a primary mechanism. Rather, placebo
mechanisms are active neurophysiologi-
cal effects generated and influenced by
the expectations and experience of receiv-
ing skilled treatment from a rigorously
40|number
47|number
8|august 2017|303
5|may 2010|

trained professional. Approaches such
as transcranial direct-current stimula-
tion and repetitive transcranial magnetic
stimulation,25 intermittent hypoxia,14
and ischemic conditioning5 may prime
the nervous system to enhance the effec-
tiveness of rehabilitation interventions.
Similarly, placebo mechanisms may
prime the nervous system to augment
Downloaded from www.jospt.org at Univ of New England on May 1, 2017. For personal use only. No other uses without permission.
the effectiveness of MT or may serve as
the primary mechanism of MT. Manual
therapists should continue to pursue
clinical excellence, while understanding
that the hours spent perfecting individual
approaches may result in better outcomes
not strictly from precise application but
rather from improved contextual factors
related to reputation, confidence, and
therapeutic alliance. To best serve our pa-
Copyright 2017 Journal of Orthopaedic & Sports Physical Therapy. All rights reserved.
tients, we must stop considering placebo
as the benchmark of an ineffective inter-
vention and accept placebo mechanisms
as part of any treatment for pain. Would
we more readily embrace priming neu-
rophysiological capacity for endogenous
pain modulation or active central ner-
vous system effects as an explanation for
why our patients get better? t
Journal of Orthopaedic & Sports Physical Therapy
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