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Journal of Orthopaedic & Sports Physical Therapy®
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JOEL E. BIALOSKY, PT, PhD1,2 • MARK D. BISHOP, PT, PhD1 • CHARLES W. PENZA, DC, PhD1
Placebo Mechanisms of
Manual Therapy: A Sheep
in Wolf’s Clothing?
J Orthop Sports Phys Ther 2017;47(5):301-304. doi:10.2519/jospt.2017.0604
W
hen a physical therapist provides a manual therapy (MT)
intervention for a patient presenting with pain and the
patient experiences a positive clinical outcome, we cannot
answer as to why this occurs. Still, the Commission on
Accreditation in Physical Therapy Education mandates that MT be
taught in entry-level physical therapy programs and that practicing
clinicians seek continuing education and fellowship opportunities.
Would we continue to devote valuable
time and financial resources to learning
and improving our skills in providing MT
interventions if the related clinical outcomes were placebo responses? In this
Viewpoint, we conceptualize placebo as
an active and important mechanism of
MT. We are not suggesting that placebo
is the only pathway through which MT
inhibits pain; however, we argue that placebo mechanisms deserve consideration
as an important component of the treatment effect. For the sake of brevity, we
will focus on placebo as a mechanism of
MT-related pain relief, and from here on
will refer to pain relief corresponding to
a placebo treatment as placebo analgesia.
Not Your Father’s Placebo
Traditionally, “placebo” has had a negative connotation, implying an inert in-
tervention without a treatment effect. In
contrast, placebo treatments are associated with marked analgesia.27 Furthermore, the placebo response is an active
neurophysiological process associated
with consistent responses in both the spinal cord10 and supraspinal regions.9 Collectively, these findings support multiple
endogenous pain modulatory processes
in response to the expectation of receiving care.
The Placebo Treatment-Effect
Mechanism
Placebo effects result from the psychosocial context surrounding the clinical
encounter and are reliably produced
in laboratory settings by manipulating
expectations and through conditioning
and learning. Placebo analgesia is small
in placebo-controlled studies, in which
participants are aware from the consent
process of the chance of receiving a placebo treatment.27 Placebo analgesia is
much larger when the placebo treatment
is provided with an instructional set enhancing expectation (eg, “the agent you
have just received is known to powerfully
reduce pain in some patients”).28 Placebo
analgesia is further augmented when
participants are conditioned to expect
analgesia through researchers surreptitiously lessening a painful stimulus after
the treatment21 or surreptitiously replacing a medication with a placebo.1 Furthermore, increased placebo analgesia
is observed following a previous positive
response18 and after watching another
person experience pain relief in response
to a treatment.6 Subsequently, placebo
analgesia is increased when participants
(1) believe they have received an effective
analgesic agent, (2) are conditioned to
expect a placebo intervention to be effective, (3) are conditioned with an effective
treatment and then given a placebo treatment, and (4) have had prior successful
experiences and/or when the environment includes other persons benefiting
from the treatment.
Department of Physical Therapy, University of Florida, Gainesville, FL. 2Brooks Rehabilitation–College 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®
1
journal of orthopaedic & sports physical therapy | volume 47 | number 5 | may 2017 | 301
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Placebo Mechanism Considerations of MT
Variability in Response to MT
In a famous scene from Raiders of the
Lost Ark, Indiana Jones is confronted
by a skilled swordsman. The swordsman 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
contrast between the theatrical, choreographed 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 elaborate ritual involving the evaluative and
application process and more closely
resembles the swordsman. Though the
choreographed dance of the swordsman 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 implications for interpreting patient responses
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 variable.15 Placebo responses are mislabeled
as “nonspecific,” implying a general effect
across interventions. Instead, placebo
responses are highly specific and dependent on the individual intervention. For
example, placebo analgesia conditioned
through opioid agents is abolished by
opioid antagonists, whereas placebo analgesia conditioned through nonsteroidal
anti-inflammatory agents is not.1 Placebo
analgesia varies within individuals, suggesting 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 placebo.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 individual patient beliefs, experiences, and
relationship with the provider.
MT Is an Experience
Placebo analgesia is influenced by contextual factors. Physical placebo treatments, 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 corresponding 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 physical intervention provided by enthusiastic
practitioners who readily inform their
patients of its likely benefits. The physical nature of MT along with the positive
framing so often provided by practitioners may effectively alter or reinforce the
patient’s beliefs and perceptions of the
intervention influencing the related outcomes. Subsequently, the MT and provider “brand” should be considered for their
role in clinical outcomes.
The Manual Therapist’s Role in Contextual
Enhancement
Placebo analgesia is enhanced by a positive 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 expectations influence placebo analgesia.12
Specific to MT, provider expectations influence 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 analgesia and clinical outcomes in response to
interventions for pain. Subsequently, the
302 | may 2017 | volume 47 | number 5 | journal of orthopaedic & sports physical therapy
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 exceeding natural history of the disorder when
individuals are aware of having received a
placebo (open-label placebo).16 Such findings suggest that patients benefit from
the act of receiving treatment, and part of
the treatment response to MT may be attributed 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 mechanism are generally well established. Manual therapies are complex interventions,
and the active mechanisms behind their
clinical effectiveness are not established.
Consequently, a suitable placebo comparator lacking the specific key ingredients
of an MT intervention is elusive.
Blinding of both the patient and provider is an important consideration in
placebo-controlled trials. Blinding may
be compromised due to poorly designed
placebos that are not believable. Furthermore, blinding may be lost due to sensations 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 comparator may successfully blind participants;
however, it may also be associated with
low expectations for its effectiveness.
For example, a skillfully applied MT intervention for which participants have
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high expectations may result in superior
outcomes to a light-touch comparator for
which participants have lower expectations. Furthermore, the same MT intervention may lack efficacy when compared
to a sham MT that is similar in context
to the studied MT and for which participants have higher expectations. Subsequently, the superiority, or failure to
demonstrate superiority, of the studied
MT intervention to a placebo treatment
may be related to the expectations attributed to each.
Potentially, even more challenging
and problematic is blinding the provider to whether he or she is providing the
“real” or the placebo intervention. Provider blinding has implications for outcomes due to the known effect of provider
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-controlled trials of MT may not be optimally
designed to determine clinical effectiveness, and carefully designed studies with
appropriate placebo comparators and
rigorous blinding may result in repeated
null findings or clinically meaningless effect sizes. Manual therapy efficacy studies
that include placebo comparators should
account for blinding, as well as participant 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 response and changes occurring in response
to no treatment (ie, the natural history of
the disorder), within an experimental design that can account for influences such
as natural history of the disorder and regression to the mean.3 Imagine the scene
from Raiders of the Lost Ark as a randomized controlled trial, with the swordsman,
in this example, considered as the placebo. Half the participants are assigned
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 outperform the swordsman. Equivocal findings
between Indiana Jones and the swordsman (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 Indiana 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 seeking care in terms of their expectations for
treatment (patients do not enter treatment 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-mechanism 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 enthusiastic practitioners instructing the patient
of the likely effectiveness. Placebo analgesia is greater in placebo-mechanism
studies than in placebo-control studies,27
and similar approaches may result in a
more accurate representation of the magnitude of the placebo effect size of MT in
clinical practice. Furthermore, placebocontrolled 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
in clinical care. Carefully designed studies 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 Placebo and MT? Randomized controlled
trials assume an additive effect, implying
that the treatment effect is the difference
between the response to the studied intervention and the response to the placebo 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) mechanisms.19 For Indiana Jones, a gun without
fanfare was effective. In the case of MT,
however, the “ritual” may be the active ingredient or may be necessary for the intervention 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 differing underlying mechanisms, as well as
the degree to which the dance interacts
with the sword to enhance its effectiveness, is imperative to our understanding
of the mechanisms of MT.
Reframing the Placebo Mechanism
Manual therapy is diverse, encapsulating differing approaches with markedly
different theoretical mechanisms. Headto-head comparisons consistently observe 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 neurophysiological effects generated and influenced by
the expectations and experience of receiving skilled treatment from a rigorously
journal
journal
of orthopaedic
of orthopaedic
& sports
& sports
physical
physical
therapy
therapy
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| volume
40 |47number
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8 | 5august
| may 2010
2017 | 303
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[ viewpoint ]
trained professional. Approaches such
as transcranial direct-current stimulation and repetitive transcranial magnetic
stimulation,25 intermittent hypoxia,14
and ischemic conditioning5 may prime
the nervous system to enhance the effectiveness of rehabilitation interventions.
Similarly, placebo mechanisms may
prime the nervous system to augment
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 patients, we must stop considering placebo
as the benchmark of an ineffective intervention and accept placebo mechanisms
as part of any treatment for pain. Would
we more readily embrace “priming neurophysiological capacity for endogenous
pain modulation” or “active central nervous system effects” as an explanation for
why our patients get better? t
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