Contextual factors, placebo and nocebo effects in physical therapy: clinical relevance and impact on research

A brief overview on placebo and nocebo effects Placebo and nocebo effects represent one of the most fascinating topics in the healthcare field. They represent complex and distinct psychoneurobiological phenomena where behavioural and neurophysiological changes occur during an interaction between the patient and the healthcare context (1). Placebo effects (Latin “I shall please”) are produced by a psychosocial context that is capable of positively affecting the patient's brain and therapeutic outcomes (2-4). On the contrary, nocebo effects (Latin “I shall harm”) are consequences of the negative perception of the ritual and therapeutic act on the patient's mind and body, so much so that it generates unwanted effects and side effects (5-7). Throughout the history of medicine, placebo and nocebo have been traditionally viewed as bothersome variables to check for in a clinical trial. In the last four decades, in light of some significant clinical and laboratory findings, they have become a source of research interest. Indeed, placebo and nocebo have been adopted as a conceptual model to examine the body-mind interaction and the human body systems, exploring their connection with different systems, mechanisms, diseases and therapeutic interventions (8, 9). In particular, placebo and nocebo effects have been studied in mood (10), cardiovascular, respiratory (11), gastrointestinal (12, 13), motor (14), immune and endocrine (15), and pain systems (16-18). Clinically, not all improvement or aggravation of patients’ symptoms is due to placebo and nocebo effects. It is necessary to rule out the patients’ modifications created by placebo and nocebo effects from the changes of outcomes related to other confounding elements. The elements which could create misinterpretations of the patients’ clinical picture are: the spontaneous remission of the disease and symptom fluctuation (also called the natural history), the regression to the mean (a statistical phenomenon caused by selection biases), the patient’s and clinician’s biases during the reports of clinical conditions, and unidentified effects of concomitant co-interventions (8, 9). Different psychoneurobiological findings allowed the scientific community to begin to understand the underlying mechanisms of placebo and nocebo effects. From a theoretical perspective, two main psychological subjective constructs have been suggested to explain how placebo or nocebo effects act: the expectation and the conditioning. The social learning, reward, anxiety reduction, desire, motivation, memory, somatic focus, genetic and personality traits also represent alternative theories (19-25). “Alternative” however does not mean that these psychological mechanisms are mutually exclusive: they can interact simultaneously (26). Regarding the actual findings, placebo and nocebo interact with the brain modulatory systems at a neurochemical level, through the release of specific neurotransmitters. For instance, considering pain outcome as a model, the endogenous opioids, dopamine, cannabinoids, oxytocin and vasopressin are involved in placebo analgesia, while cholecystokinin, dopamine, opioid deactivation and cyclooxygenaseprostaglandins activation are implicated in nocebo hyperalgesia (27-29). Furthermore, recent advances in neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), suggest an involvement of specific neural correlates during placebo and nocebo effects, mainly the pain one. In fact, placebo and nocebo are able to activate or deactivate the four key brain regions commonly associated with the descending pain processing pathway: the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the periaqueductal gray and the dorsal horn of spine (16). Nevertheless, they represent only a part of brain areas showing a change in their activity during placebo or nocebo (30-32). Therefore, the previously described evidence suggests that placebo and nocebo effects are concrete and genuine phenomena, triggered by different contexts, and capable of impacting the patients’ brain. It is necessary to define what the context is, and why its parts are important from a clinical perspective (33). The healthcare context as a trigger of placebo and nocebo effects In 1955 Balint described the context as the “whole atmosphere around the therapy” (34). The context is not a vacuum, but it embodies a healing space composed by internal, external and relational elements capable of interacting with the patient’s disease (35). The internal elements consist of memories, emotions, expectations and psychological characteristics of the patient. The external elements include the physical aspects of therapy, such as the kind of treatment (pharmacological or manual) and the place in which the treatment is delivered. Relational elements are represented by all the social cues that characterize the patient-clinician relationship, such as the verbal information that the clinicians give to the patient, the communication style or the body language (36). In 2001, Di Blasi et al. defined these elements as “contextual factors”. These factors have been grouped, from a clinical practice point of view, in five categories: a) clinician features, b) patient features, c) patient-clinician relationship, d) intervention features, and e) healthcare setting features (37). As a whole, contextual factors constitute the therapeutic ritual and healing symbols surrounding the patient-clinician encounter, capable of producing changes in the patient at perceptual, neurophysiological and cognitive levels (38). Indeed, contextual factors convey a hidden meaning, actively detected and analysed by the patient, which is essential for the perception of care and the interpretation of the therapeutic intervention (39, 40). When these contextual stimuli and cues are filtered by the patient’s perspective and mind-set (41), they are translated into a complex cascade of psycho-neuroimmunoendocrine events, thus triggering placebo and nocebo effects and influencing the course of illness (42, 43). From a clinical perspective, the contextual factors pervade every healthcare action (history taking, physical examination, therapy and prognosis) and directly affect the quality of the health-related outcome (44-46). A positive context, that is characterized by the presence of positive contextual factors, can improve therapeutic outcome by producing placebo effects, while a negative context, characterized by the presence of negative contextual factors, can aggravate therapeutic outcome by creating nocebo effects(47, 48). For example, during the same treatment delivery (e.g. painkillers), the use of positive verbal suggestion (e.g. “This therapy will help you and it will decrease pain”) can improve musculoskeletal pain, while the adoption of verbal suggestion of uncertainty (e.g. “This therapy could help you and sometimes it decrease pain”) can aggravate patient’s pain (49). The presented studies offer a starting point for reflection about the role of the contextual factors surrounding the administration of a healthcare treatment: they can be a source of improvement of the efficacy of the therapy or implicated in the manifestation of adverse effects. The logical consequence is to wonder whether context, placebo and nocebo effects have been taken into consideration in a specific healthcare field, such as physical therapy. The link between placebo, nocebo effects and physical therapy Throughout the history of physical therapy and rehabilitation, placebo and nocebo effects have been considered as problematic phenomena for two main reasons. From a research point of view, they have represented confounding factors capable of limiting the internal validity of the study design and reducing the external validity of the findings (50). From a clinical point of view, they have embodied troublesome and nonspecific variables able to attenuate the therapeutic role of specific therapies such as massage, joint mobilization and therapeutic exercise (51, 52). As a consequence, for many years the role of placebo and nocebo effects was debated worldwide by clinicians and researchers (53-55). At the end of the first decade of the twenty-first century the scientific community began to investigate the mechanisms of action of joint, soft tissue and neural therapeutic intervention, consequently revaluing the role of placebo and nocebo effects in physiotherapy (56). Recent studies have suggested a mechanical and neurophysiological mechanism (peripheral, spinal and supraspinal) linked to the therapeutic strategies adopted by physical therapists (57). Among the supraspinal mechanisms, the placebo and nocebo effects have assumed an important top-down role in inducing changes in patient’s symptoms (58), thus becoming elements that clinicians should adopt in clinical practice (59). Recently, also the context in which interventions are delivered has been suggested as a moderator of clinical effects (60). A new line of research has indicated the context as responsible for a larger non-specific component of treatment efficacy in physical therapy (61). Despite these promising advances, the following issues remain unexplored: 1) What are the contextual factors? 2) How can the contextual factors trigger placebo and nocebo effects? 3) Which therapeutic outcomes can be influenced by the contextual factors? 4) Are the physical therapists aware of the use of contextual factors in clinical practice? 5) What is the role of contextual factors in research? General organization of the research project The main goal of this PhD research project is to investigate the relevance of the contextual factors as triggers of placebo/nocebo effects and their impact on therapeutic outcomes in physiotherapy. Different studies were conducted during the 3-year period of PhD training (2015-2018). The results, relative discussions and implications are reported in the chapters of the present dissertation as follows: • Chapter I: a conceptual model regarding the role of the contextual factors as triggers of placebo, nocebo responses and influencers of physical therapy outcomes; • Chapter II: the model of contextual factors regarding musculoskeletal pain, which is a common outcome encountered by physical therapists; • Chapter III: the link between the determinants of patient satisfaction in outpatient musculoskeletal physiotherapy clinics and the contextual factors; • Chapter IV: the knowledge, attitude and behaviour of Italian physiotherapists specialized in manual therapy towards contextual factors; • Chapter V: the translational value of contextual factors and their relevance for physical therapy research.