[ viewpoint ] Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on April 26, 2025. For personal use only. No other uses without permission. Copyright © 2017 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. 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 Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on April 26, 2025. For personal use only. No other uses without permission. Copyright © 2017 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. [ viewpoint ] 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 Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on April 26, 2025. For personal use only. No other uses without permission. Copyright © 2017 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. 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 | volume | volume 40 |47number | number 8 | 5august | may 2010 2017 | 303 Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on April 26, 2025. For personal use only. No other uses without permission. Copyright © 2017 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. [ 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 REFERENCES 1. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectationactivated opioid systems versus conditioningactivated specific subsystems. 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