Context Matters: Psychoneurobiological Determinants of Placebo, Nocebo, and Context-Related Effects in Physiotherapy (2020) PDF

Rossettini et al. Archives of Physiotherapy (2020) 10:11 https://doi.org/10.1186/s40945-020-00082-y REVIEW Open Access Context matters: the psychoneu...

Rossettini et al. Archives of Physiotherapy (2020) 10:11 https://doi.org/10.1186/s40945-020-00082-y REVIEW Open Access Context matters: the psychoneurobiological determinants of placebo, nocebo and context-related effects in physiotherapy Giacomo Rossettini1* , Eleonora Maria Camerone1,2, Elisa Carlino2, Fabrizio Benedetti2,3 and Marco Testa1 Abstract Background: Placebo and nocebo effects embody psychoneurobiological phenomena where behavioural, neurophysiological, perceptive and cognitive changes occur during the therapeutic encounter in the healthcare context. Placebo effects are produced by a positive healthcare context; while nocebo effects are consequences of negative healthcare context. Historically, placebo, nocebo and context-related effects were considered as confounding elements for clinicians and researchers. In the last two decades this attitude started to change, and the understanding of the value of these effects has increased. Despite the growing interest, the knowledge and the awareness of using the healthcare context to trigger placebo and nocebo effects is currently limited and heterogeneous among physiotherapists, reducing their translational value in the physiotherapy field. Objectives: To introduce the placebo, nocebo and context-related effects by: (1) presenting their psychological models; (2) describing their neurophysiological mechanisms; (3) underlining their impact for the physiotherapy profession; and (4) tracing lines for future researches. Conclusion: Several psychological mechanisms are involved in placebo, nocebo and context-related effects; including expectation, learning processes (classical conditioning and observational learning), reinforced expectations, mindset and personality traits. The neurophysiological mechanisms mainly include the endogenous opioid, the endocannabinoid and the dopaminergic systems. Neuroimaging studies have identified different brain regions involved such as the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the periaqueductal gray and the dorsal horn of spine. From a clinical perspective, the manipulation of the healthcare context with the best evidence-based therapy represents an opportunity to trigger placebo effects and to avoid nocebo effects respecting the ethical code of conduct. From a managerial perspective, stakeholders, organizations and governments should encourage the assessment of the healthcare context aimed to improve the quality of physiotherapy services. From an educational perspective, placebo and nocebo effects are professional topics that should be integrated in the university program of health and medical professions. From a research perspective, the control of placebo, nocebo and context-related effects offers to the scientific community the chance to better measure the impact of physiotherapy on different outcomes and in different conditions through primary studies. Keywords: Contextual factors, Placebo effect, Nocebo effect, Physical therapy modalities, Pain, Expectation, Conditioning, Rehabilitation, Therapeutic outcome, Learning * Correspondence: [email protected] 1 Department of Neuroscience, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, University of Genova, Campus Universitario di Savona, via Magliotto 2, 17100 Savona, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Archives of Physiotherapy (2020) 10:11 Page 2 of 12 Background of time with their patients in numerous sessions, Placebo and nocebo effects embody complex and dis- intervening on different disorders (e.g., motor, cardio- tinct psychoneurobiological phenomena where behav- respiratory, gastrointestinal, urogynecological or neuro- ioural, neurophysiological, perceptive and cognitive logical), and therefore easily establishing an empathetic changes occur during therapeutic encounter, between therapeutic relationship [24, 25]. Moreover, physiothera- the (physio) therapist and the patient, in the healthcare pists, more than medical doctors, interact with their context. Specifically, placebos and nocebos can be patients using verbal (e.g., encouraging words) and non- defined as inert treatments or active treatments that are verbal (e.g., communicative, non-therapeutic touch) not therapeutically effective for the disease or condition elements [26, 27]. Every physiotherapy intervention, be- under cure (active placebo or nocebo). These treatments, ing it manual treatment, exercises or modalities, is nat- if administered in a therapeutic and healthcare context, urally enriched by different contextual factors that can can produce remarkable effects, known as “placebo influence the trajectory of outcomes towards a positive effects” or “nocebo effects”. “Placebo effects” are pro- or a negative result, depending on how they are man- duced by a positive healthcare context that can amelior- aged by the physiotherapist (Fig. 1). ate the patient’s symptoms [1, 3]. Conversely, “nocebo Throughout the history of physiotherapy, placebo, effects” are produced by a negative healthcare context nocebo and contextual-related effects have always that can elevate the patient’s symptoms [4–6]. These ef- been considered a challenging phenomena for two fects can also occur when an active and therapeutically main reasons. From a research perspective, these effective treatment is administered: indeed, any health- represented possible confounders capable of decreas- care treatment (active or inert) that is administered in ing both internal and external validity of the studies any healthcare contexts (e.g., medical, rehabilitative) can conducted [29, 30]. From a clinical perspective, con- trigger contextual-related effects. Placebo, nocebo and textual factors symbolise troublesome and non- contextual-related effects have been used as models to specific variables that can attenuate the therapeutic examine the body-mind interaction by investigating the role of the specific interventions such as manual impact of these phenomena on different bodily pro- treatments, therapeutic exercise and modalities ad- cesses, diseases and individual behaviour [7, 8]. ministration [31, 32]. Indeed, the healthcare context is not a vacuum, but it It was at the end of the first decade of the twenty- is an enriched relational space created by several ele- first century that this attitude started to change. In- ments [9–15] – defined as contextual factors – such as: deed, the scientific community began to investigate (1) the physiotherapist’s professionalism, mindset and the mechanisms of action of different therapeutic in- appearance; (2) the patient’s beliefs, experiences and ex- terventions like exercise and manual treatment of pectation about the disease and the therapy; (3) the joint, soft and neural tissue, enlightening the weight words, gestures and behaviour presented in the of placebo and nocebo effects in such mechanisms physiotherapist-patient relationship during the thera- and therefore their relevant role in physiotherapy [33, peutic encounter; (4) the rituality, the invasiveness and 34]. Emergent studies have suggested a mechanical the overt application of the intervention; (5) the furni- and neurophysiological mechanism (peripheral, spinal ture, the architectural design and the overall impression and supraspinal) as the base of the effects induced by of the clinic. These contextual factors have been the therapeutic interventions adopted by the physio- suggested as responsible for a large non-specific compo- therapists [35–37]. Considering the supraspinal mech- nent of treatment efficacy, directly affecting the quality anisms, placebo and nocebo effects were indicated as of patient’s health-related outcomes (e.g., pain, disability, important top-down modulators of patient’s symp- satisfaction, and experience) [16–20]. For instance, the toms, mainly pain and motor performance [38–44], same treatment (e.g., exercise) if associated with physio- thus becoming elements that physiotherapists should therapist’s positive verbal suggestion (e.g., “This exercise attentively consider in their clinical practice. will ameliorate your symptoms”) can reduce the pain Despite the growing interest in the physiotherapy field and increase the strength of a patient. Whereas, if asso- [16, 17], the knowledge and the awareness of using con- ciated with verbal suggestion of uncertainty (e.g., “This textual factors to enhance placebo and avoid nocebo ef- exercise sometimes might reduce symptoms”), could fects is still limited among physiotherapists. The even worsen pain and strength [17, 21, 22]. same unawareness has also been shown among other If compared with other healthcare professionals, the healthcare providers such as nurses and physicians [46, physiotherapist’s clinical action is deeply pervaded by 47]. Moreover, the lack of a clear education about this placebo and nocebo effects for several reasons strongly professional topic in physiotherapy university courses re- related to the characteristics of physiotherapy adminis- duces their perceived translational value and their rele- tration. Physiotherapists spend a significant amount vance for physiotherapy practice [16, 48]. Rossettini et al. Archives of Physiotherapy (2020) 10:11 Page 3 of 12 Fig. 1 Contextual factors in clinical practice. The following contextual factors were accepted as effective modifiers of physiotherapy outcomes. For a review of this topic see reviews [16, 17, 19]. a Physiotherapist’s features: professionalism (expertise, qualification, reputation, education, trining); mindset (behaviour, beliefs, expectation, previous experience); appearance (attire, uniform, white coat, trustworthiness). b Patient’s features: mindset (expectation, previous experience, history of treatment, preference, desire, and emotion); baseline (level of symptoms, comorbidity, health condition, gender, age). c Patient-physiotherapist relationship: verbal communication (positive message, tone of voice, active listening, suggestions of support and encouragement, language reciprocity, warmth, attention, care, empathetic interaction); non-verbal communication (eye contact, facial caring expression, smiling, posture, gestures, head nodding, forward leaning, open body orientation). d Treatment features: therapeutic touch (emotional, empathetic, affective); modality (level of invasiveness, open/overt application, observational/ social learning); posology (personalized treatment, treatment delivered by the same physiotherapist, cleanliness, adequate length of the consultation, punctuality, flexibility with patient’s appointments, timely and efficient treatment, adequate frequency, duration and follow-up of therapy); marketing (brand, prize, novelty, rituality). e Healthcare setting features: positive distractors (natural lighting, low noise levels, relaxing and soft music, pleasing aromas, adequate temperature); supportive indications (highly visible and easy to read signs, parking information, accessible entrances, clear and consistent verbal or written directions, information desks and accessible electronic information); comfort element (windows and skylights, private therapeutic settings, good access to services, convenient clinic hours, location, parking, and available and approachable support staff); decorations and ornaments (nature artworks, green vegetation, flowers, water, plants, garden, colour) The aim of this narrative review is to offer a general Main text overview of placebo, nocebo and contextual factors ef- The psychobiological determinants of placebo, nocebo fects by: (1) presenting the psychological models behind and context-related effects their effects; (2) describing the neurophysiological mech- There are several psychological mechanisms involved in anisms involved; (3) underlining the impact for the placebo, nocebo and context-related effects including: physiotherapy profession (clinical, managerial and edu- expectation, learning processes such as classical condi- cational); and (4) tracing lines for future researches. tioning and observational learning, reinforced expecta- To this end, the narrative review style has been se- tions, mindset and personality traits (Fig. 2). lected, citing both primary studies (e.g., clinical trial) Expectation refers to one’s anticipation of a future and secondary studies (e.g., systematic review, narra- event. The expectations of individuals are a powerful tive review) on placebo and nocebo effects from modulator of their cognitive, emotional and physical different healthcare fields (e.g., medicine, nursing, experiences. These are continuously shaped and physiotherapy) as previously reported [16, 17, 19]. updated according to the inputs coming from the sur- Some studies specifically focus on the role of inert rounding environment. Contextual factors summa- substances in producing positive (placebo) or negative rized in Fig. 1 represent the key elements that are likely (nocebo) effects, whereas others refer to the effect of to influence patients’ expectations within the healthcare the therapeutic context when an active treatment is setting. Verbal suggestions are the simplest and administered (context-related effects). most direct way to shape expectations, therefore, a large Rossettini et al. Archives of Physiotherapy (2020) 10:11 Page 4 of 12 Fig. 2 Psychobiological determinants of placebo, nocebo and context-related effects. Principal psychobiological determinants of placebo, nocebo and context related effects body of evidence has used either positive or negative together with other classical conditioning studies [56, verbal information to modulate expectations and elicit 60, 61], have demonstrated that verbally induced expec- placebo and nocebo responses. For example, Kam- tations alone have no effect on autonomous physio- Hansen et al. (2014) demonstrated that placebo labelled logical processes such as hormonal plasma production as active treatment (positive context expectation) and and the immune system. However, a positive context active treatment labelled as placebo (drug effect) had created by a placebo administration after real drug pre- comparable healing effects on migraine attacks. conditioning can elicit autonomic responses. Similar findings were reported on post-surgical pain of Conditioning can also function as an expectation thoracotomized patients and on patients suffering booster, leading to reinforced expectations. To this end, from irritable bowel syndrome. A recent study con- a conditioning procedure can be used to create an asso- ducted on chronic neck pain patients has shown neck ciation between an inert treatment and pain amelior- pain modulation according to contextual changes. Spe- ation by reducing the intensity of the stimulation during cifically, when positive verbal suggestions were associ- the learning phase. During the recall phase, stimuli in- ated with the neck manipulation, patients reported a tensity is set back to baseline but is generally perceived significant reduction in pain. This was the case for both as less painful. Montgomery and Kirsch (1997) fur- the real or the sham neck handling. A similar, but ther investigated conditioning response when partici- weaker effect was shown in relation to neutral informa- pants were overtly told the nature of the placebo and of tion, whereas pain worsened when negative information the preconditioning. Interestingly, analgesic and hyper- was given. algesic responses were no longer present. This suggests Pavlovian classical conditioning represents an- that conditioning alone was insufficient to elicit placebo other mechanism that is strongly involved in placebo and nocebo effects and that conscious expectations were and nocebo effects, and associated positive and negative necessary; indicating that conditioning served as a re- contexts [56–58]. Benedetti et al. (2003) showed that inforcer to enhance expectation. placebo administration (saline injection) after real drug Observational learning represents another mechanism preconditioning (sumatriptan injection) mimicked the associated with placebo responsiveness. Colloca and effects of the drug on growth hormone (GH) secretion. Benedetti (2009) explored observational learning mecha- In contrast, positive expectations alone without prior nisms in electric shock induced pain. At first, par- conditioning led to no effect on GH. These findings, ticipants observed a demonstrator taking part in the Rossettini et al. Archives of Physiotherapy (2020) 10:11 Page 5 of 12 experiment and whom was instructed to shown anal- effects have begun to be extensively identified, using dif- gesic and hyperalgesic effects when the painful stimuli ferent approaches ranging from pharmacology to neuro- were preceded by a green and by a red light, respectively. imaging [17, 48, 77–79]. Pain and Parkinson Disease Then, participants underwent the same procedure they (PD) have been used as main models to understand the had observed and, as expected, they reported analgesia neurobiology of positive (placebo), negative (nocebo) (pain decrease) and hyperalgesia (pain increase) in and context-related effects [80, 81]. So far, three major response to green and red cues accordingly. The same questions have been addressed: (1) which are the neuro- experiment was conducted using classical conditioning biological pathways activated by inert substances; (2) procedure as well as verbal suggestions alone. The which are the brain regions that trigger these effects; magnitudes of placebo and nocebo effects were compar- and (3) which are the dynamical and temporal changes able between classical conditioning and observational that occur in the brain before and after the administra- learning procedures. On the contrary, the effect was tion of a placebo treatment (Fig. 3). much smaller for verbal suggestions alone. The role of Pharmacological studies have demonstrated that the observational learning in both positive social context administration of an inert substance activates the en- (placebo) [65, 66] and negative social context (nocebo) dogenous opioid system and the endocannabinoid sys- [65–68] has been reiterated in later studies. tem. The observation that μ-opioid antagonists (e.g., Up to date evidence has introduced a new mechanism naloxone) [56, 82, 83] and CB1-antagonist (e.g., rimona- involved in placebo and nocebo effects, namely operant bant) block some types of placebo analgesia has conditioning. This new paradigm consisted in re- been documented by conditioning protocols using opi- warding and punishing participants when they oid drugs like morphine or cannabinoid drugs like ketor- responded ‘correctly’ to painful stimuli. Coloured cues olac, respectively. Indirect confirmation of the preceded each stimulus, and dependently on the cue involvement of the opioid system has been confirmed by colour, the experimenter wanted the subjects to respond the study of the anti-opioid action of cholecystokinin either with analgesia or hyperalgesia. Participants were (CCK). Indeed, it has been demonstrated that CCK an- rewarded or punished, via positive and negative writings tagonist (e.g., proglumide) and CCK-2 agonist (e.g., displayed on the screen, accordingly on whether they pentagastrin) produce opposite effects on pain: the responded as desired by the experimenter. When stimuli former enhances placebo analgesic effects while the lat- were presented in the absence of rewards and ‘punish- ter disrupts them [85–89]. Also nocebo hyperalgesia ments’, analgesia and hyperalgesia phenomena persisted, seems to be modulated by the activation of the opioid suggesting that operant conditioning functions as a learn- system as it can be reversed by CCK antagonist. More- ing process eliciting placebo and nocebo effects. over, placebos and nocebos also modulate the synthesis Other factors may interact with placebo and nocebo of prostaglandins, an important target of analgesic drugs effects, including mindset and personality traits. Here,. On the whole, these pharmacological studies sup- mindset refers to a broad set of viewpoints that compose port the notion that inert substances and drugs may one’s outlook on life. Multiple studies revealed that in- share common biochemical pathways. creasing the level of optimism in one’s mindset can posi- Neuroimaging studies have identified different brain tively change both subjective and objective measures of regions that contribute to placebo, nocebo and context one’s health and wellbeing [70–72]. related effects [91–99]. Different brain regions are acti- Concerning personality traits, suggestibility appears to vated during the “expectation phase”, when a positive or make individuals more or less susceptible to the positive negative effect is foreseen, and during the “perception and/or negative context, leading to stronger placebo and phase”, when analgesic or hyperalgesic effects are experi- nocebo responses. Similarly, optimistic and pessim- enced. In particular, when a positive beneficial effect is istic personality seems to facilitate placebo and nocebo expected, activation of anterior cingulate cortex (ACC), effects, respectively. Whereas, high trait and state precentral and lateral prefrontal cortex and periaqueduc- anxiety tend to promote nocebo responses [75, 76]. With tal gray (PAG) has been documented. On the other this knowledge in mind, no personality trait has yet been hand, when placebo analgesia is experienced deactivation identified that can reliably predict if someone will re- has been found in different brain regions such as the spond to placebo (placebo responder) or not (placebo mid- and posterior cingulate cortex, superior temporal non responder). and precentral gyri, the anterior and posterior insula, the claustrum and putamen, and the thalamus and caudate The neurophysiological mechanisms of placebo, nocebo body. As for nocebo effects, when hyperalgesia is and context-related effects expected and experienced, an increased activity in differ- Over the past decade, the neurophysiological mecha- ent brain regions involved in pain processing and emo- nisms underlying placebo, nocebo and context-related tion regulation, such as prefrontal cortex (PFC), ACC Rossettini et al. Archives of Physiotherapy (2020) 10:11 Page 6 of 12 Fig. 3 Neurophysiological mechanisms of placebo, nocebo and context-related effects. Principal neurobiological mechanisms of placebo, nocebo and context related effects. a Pharmacological studies. The opioid and cannabinoid systems are involved in placebo and nocebo effects. In some circumstances, placebo analgesia occurs through the activation of the opioid system and can be reversed by naloxone. In other circumstances, placebo analgesia occurs through the activation of the cannabinoid system and can be reversed by rimonabant. Anticipatory anxiety can activate the pro-nociceptive cholecystokinin (CCK) system, leading to nocebo hyperalgesia. The pro-nociceptive CCK effect can be reversed by proglumide and agonized by pentagastrin. b Neuroimaging studies. The activation and deactivation of different brain regions during placebo analgesia and nocebo hyperalgesia have been described trough different brain imaging studies. c Electrophysiological studies. Electroencephalographic (EEG) studies showed the dynamical studies showed the dynamical and temporal changes that occur in the brain before and after the administration of inert treatments and insula, has been documented [101–106]. Context- placebo administration, a large amount of dopamine was related effects have been extensively documented using released in the dorsal motor striatum, suggesting a rela- the so-called “open-hidden” design, in which patients re- tionship between the amount of dorsal striatal dopamine ceive a real analgesic drug but they are either aware release and clinical benefit. On the whole, these studies (open condition) or unaware (hidden condition) of re- demonstrate that a complex network of brain regions is ceiving it. In these studies, it has been demonstrated that activated when placebos or nocebos are expected and the open condition, that is a condition that maximizes positive or negative effects are experienced [111–113]. the context-related effects, produced analgesic effect Recently, high temporal resolution techniques, such as along with deactivation of the pain matrix and activation electroencephalographic (EEG), has been used to deter- of dorsolateral prefrontal cortex (DLPFC) and rostral mine changes in brain activity when placebo and nocebo Anterior Cingulate Cortex (rACC). On the contrary, pa- phenomena arise. Studies on pain have revealed insights tients in the hidden condition, that is a condition that into the time-by-time and fast changes that occur before dramatically reduces the context-related effects, exhib- and after the administration of a sham treatment. Inter- ited no changes in pain perception and no pain matrix estingly, as already documented by neuroimaging stud- deactivation. ies, placebos and nocebos change EEG brain activity Furthermore, the involvement of the dopaminergic during both the expectation and the perception phases. system has been documented in pain [108, 109] and PD For example, the expectation of receiving no painful or patients. In placebo analgesia, an increase in dopa- painful stimuli respectively decrease or increase the mine binding to D2/D3 receptors and in opioid binding amplitude of the contingent negative variation (CNV), to μ-opioid receptors occurs in the nucleus accumbens, an EEG slow negative wave that represents an objective whereas a decreased binding to the same receptors is measure of expectation of a specific incoming event present in nocebo hyperalgesia [108, 109]. In PD, when (e.g., expectation of analgesia or hyperalgesia). patients experienced a motor improvement after a Considering the “perception phase”, placebo treatments Rossettini et al. Archives of Physiotherapy (2020) 10:11 Page 7 of 12 produce a decrease in laser-evoked potential (LEP), that during a joint manipulation , or an empathetic thera- represents an early measure of nociceptive processes, peutic relationship during a modalities administration since it occurs after 200–250 ms after a painful stimula- ), can ameliorate patients’ clinical outcomes by trig- tion. Also motor electrophysiological potentials re- gering placebo effects. Instead a negative context (e.g., a lated to motor preparation and fatigue, such as the detrimental verbal indication delivered during a joint readiness potential (RP), can be affected by a placebo ad- manipulation or during a muscle strength test [121, ministration in healthy volunteers and PD patients 122]), can worsen patients’ symptoms by stimulating , demonstrating that the brain changes that occur nocebo effects. Examples of clinical application of con- when a placebo is administered can be triggered in dif- textual factors are presented in Table 1. ferent ways and in different times. From a clinical point of view, it is imperative to distin- Even if modern brain imaging techniques have been guish between the changes in patients’ symptoms result- fundamental in the understanding of the placebo and ing from placebo and nocebo effects, and those rising nocebo effects, further researches are needed to fully from other variables. Possible confounders include understand the underpinnings of these phenomena and the natural history (the spontaneous relief of the dys- the clinical implications and application of these function and symptom modifications) and the regression findings. to the mean (a statistical event caused by selection biases). Moreover, the patient’s and clinician’s confirm- Clinical, managerial and educational implications for ation biases during the description of clinical symptoms physiotherapy profession as well as unrevealed effects of simultaneous treatments In accordance with the evidence reported in this review, have been reported as other confounders [1, 124]. the analysis of placebo, nocebo and context-related ef- From a managerial perspective, placebo, nocebo and fects may lead to new therapeutic strategies that are cap- context-related effects could help policy decision-makers able of improving the professional action of the during the design of the healthcare setting [16, 17]. Tak- physiotherapist and of influencing management and ing into account contextual factors offers the opportun- education. ity to significantly improve patients’ perception of From a clinical perspective, the integration of the con- physiotherapy services in terms of quality and overall textual factors with the best evidence-based therapy rep- satisfaction [16, 17]. Thus, at multiple levels (e.g., private resents an opportunity to stimulate placebo effects and or public services, inpatients or outpatients units), stake- to prevent nocebo effects; boosting therapy effectiveness. holders, organizations and governments should encour- This would be done in accordance with the ethical and age assessment and management of contextual factors deontological code of conduct [118, 119]. Indeed, con- [125, 126]. The positive context around the treatment textual factors pervade every clinical action (e.g., history (e.g., respect of timetable of physiotherapy treatment, a taking, physical examination, therapy administration, quiet setting) can impact the overall patients’ satisfaction prognosis communication and revaluation) and directly and perception of their health care experiences by en- affect the quality of health-related outcomes [16, 17]. A hancing the attractiveness of a specific physiotherapy positive context (e.g., an encouraging verbal suggestion service [20, 127]. A positive healthcare context invites Table 1 Clinical application of contextual factors. The table presents examples of use of contextual factors aimed to enhance placebo effects and avoid nocebo effects. Adapted from [16, 17, 19] Contextual factors Actions to enhance (placebo effects) Actions to avoid (nocebo effects) (A) Physiotherapist’s features improve physiotherapist’s professionalism; overlook physiotherapist’s professionalism; be aware of physiotherapist’s mindset; be unaware of physiotherapist’s mindset; promote physiotherapist’s appearance; disregard physiotherapist’s appearance; (B) Patient’s features examine patients’ mindset; neglect patients’ mindset; analyse patients’ baseline; ignore patients’ baseline; (C) Patient-physiotherapist manage verbal communication; neglect verbal communication; relationship optimise non-verbal communication; ignore non-verbal communication; (D) Treatment features amplify the rituality of treatments; limit the rituality of treatments; be aware of therapeutic touch; be unaware of therapeutic touch; consider the modality/posology of treatment; omit the modality/posology of treatment; use marketing of treatment; neglect marketing of treatment; (E) Healthcare setting features adopt positive distractors and supportive avoid positive distractors and supportive indications; indications; use comfort elements, decorations and ornaments; omit comfort elements, decorations and ornaments; Rossettini et al. Archives of Physiotherapy (2020) 10:11 Page 8 of 12 patients to choose, return to and recommend the physio- on various patient’s clinical outcomes and in various therapy service. Moreover, it increases the adherence to health conditions. Using randomized clinical trials, there prescribed treatments and follow-ups [20, 127]. Instead, a is a need to compare the same physiotherapy treatment negative healthcare context (e.g., a noisy environment, an performed in a neutral and enriched context ; overcrowded setting) improves the likelihood of patients’ measuring the change of subjective (e.g., pain, disability, dissatisfaction, the abandonment of the service and the expectation and satisfaction) and objective (e.g., heart withdrawing from the treatment plan [20, 127]. rate variability, salivary cortisol, electromyographic activ- From an educational perspective, contextual factors ity) outcomes. (e.g., patient-clinician relationship) are underestimated Thirdly, researchers should examine the patient’s per- during the majority of physiotherapy degrees. Awareness ception of contextual factors. Although the patient’s and practice of these professional topics should be viewpoint on placebo interventions has been investigated strengthened and steadily integrated in teaching pro- through surveys and qualitative interviews [47, 147], only grams (e.g., core curriculum and core competence) and study in this field has accounted for the influence of the activities (e.g., skill-labs, role-playing), aiming to prepare patient’s viewpoint so far; it investigated contextual fac- the students for a better management of the psycho- tors in patients with musculoskeletal pain. More- social component in the clinical practice [16, 128]. In over, an item bank of contextual factors has been physiotherapy education, contextual factors help stu- presented to evaluate the patient’s viewpoint regarding dents to consider the therapeutic outcome as a complex, the overall healthcare experience. This preliminary not predictable and nonlinear result of multiple interac- finding represents an initial phase for the creation of a tions between different variables (e.g., clinicians, patients questionnaire that: classifies patients based on their pre- and healthcare setting) that evolve during the thera- ferred contextual factors; and helps clinicians to enrich peutic encounter in a positive or negative way the physiotherapy treatment with specific contextual through placebo and nocebo effects. Emerging evidence elements. has suggested that awareness of contextual factors corre- sponds to good diagnostic skills and therapeutic reason- Conclusions ing [130–134], thus suggesting to academics and In summary (Table 2), this narrative review provides a lecturers an additional teaching instrument for the de- stimulus for reflection on the role and strength of pla- velopment of students’ clinical ability. cebo, nocebo and context-related effects surrounding Emerging lines for future research Table 2 Key points on placebo, nocebo and context-related With an increased understanding of contextual factors, effects and placebo and nocebo effects, the physiotherapy Take-home message scientific community can measure the impact of phy- Placebo and nocebo effects are psychoneurobiological phenomena siotherapeutic interventions with greater precision in respectively produced by a positive and a negative healthcare context primary studies. around the treatment; The healthcare context is composed by contextual factors such as In contrast to the simplicity of creating a pharmaceut- the feature of: the physiotherapist; the patient; the patient- ical placebo (where the active component of the treat- physiotherapist relationship; the treatment; and the healthcare setting. ment is removed), devising physiotherapy placebos is a The psychological determinants of placebo and nocebo effects include: expectation; learning (classical conditioning and observational significant challenge. At first, the aim should be to iden- learning); reinforced expectations; mindset; and personality traits. tify the best physiotherapy placebos for existing treat- The neurophysiological mechanisms of placebo and nocebo effects ments. Various studies tried to develop [135, 136] and involve different systems (the endogenous opioid, the endocannabinoid, and the dopaminergic) and brain regions (dorsolateral prefrontal cortex, validate [137–139] a sham placebo technique. The the rostral anterior cingulate cortex, the periaqueductal gray, and the principle obstacles are the needs to assess the patients’ dorsal horn of spine). blinding, their expectations and their priori (real) inert- From a clinical perspective, the manipulation of the healthcare context with the best evidence-based therapy represents an opportunity ness [140–142]. However, a novel sham procedure has to trigger placebo effects and to avoid nocebo effects respecting the recently been validated and applied in clinical set- ethical and deontological code of conduct. tings; both to patients with migraines and those From a managerial perspective, stakeholders, organizations and governments should encourage the assessment of the healthcare with cervicogenic headache , thus paving the way context aimed to improve the quality of physiotherapy services. for a series of further studies. From an educational perspective, placebo and nocebo effects are Secondly, the impact of contextual factors on patient professional topics that should be integrated in the university program of health and medical professions. outcomes should be examined. The task of designing a From a research perspective, the control of placebo, nocebo and proper trial continues to be inconclusive among scholars context-related effects offers to the scientific community the chance to [78, 146]. Primary studies should follow a research better measure the impact of physiotherapy on different outcomes and in different conditions through primary studies. agenda aimed to estimate the effect of contextual factors Rossettini et al. Archives of Physiotherapy (2020) 10:11 Page 9 of 12 the administration of a physiotherapy treatment. On one 9. Ongaro G, Kaptchuk TJ. Symptom perception, placebo effects, and the hand, a positive healthcare context can significantly im- Bayesian brain. Pain. 2019;160:1–4. 10. Geuter S, Koban L, Wager TD. The cognitive neuroscience of placebo prove therapeutic effectiveness. On the other hand, a effects: concepts, predictions, and physiology. Annu Rev Neurosci. negative context can manifest adverse effects. 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Lancet. 2001;357:757–62. GH: growth hormone; PD: Parkinson disease; CCK: Cholecystokinin; 16. Testa M, Rossettini G. Enhance placebo, avoid nocebo: how contextual ACC: Anterior cingulate cortex; PAG: Periaqueductal gray; PFC: Prefrontal factors affect physiotherapy outcomes. Man Ther. 2016;24:65–74. cortex; DLPFC: Dorsolateral prefrontal cortex; rACC: Rostral anterior cingulate 17. Rossettini G, Carlino E, Testa M. Clinical relevance of contextual factors as cortex; EEG: Electroencephalographic; LEP: Laser-evoked potential; triggers of placebo and nocebo effects in musculoskeletal pain. BMC CNV: Contingent negative variation; RP: Readiness potential Musculoskelet Disord. 2018;19:27. 18. Geri T, Viceconti A, Minacci M, Testa M, Rossettini G. Manual therapy: Acknowledgements exploiting the role of human touch. Musculoskelet Sci Pract. 2019;44: The authors want to thank Samuele Graffiedi and Mattia Mirandola for their 102044. valuable advices during the advancement of this manuscript. 19. Palese A, Rossettini G, Colloca L, Testa M. The impact of contextual factors on nursing outcomes and the role of placebo/nocebo effects: a discussion Authors’ contributions paper. Pain Rep. 2019;4(3):e716. All authors conceived, designed, drafted and approved the final manuscript. 20. Rossettini G, Latini TM, Palese A, Jack SM, Ristori D, Gonzatto S, Testa M. Determinants of patient satisfaction in outpatient musculoskeletal Funding physiotherapy: a systematic, qualitative meta-summary, and meta-synthesis. The authors declare that they have no funding for this review. Disabil Rehabil. 2020;42:460–72. 21. Colloca L, Corsi N, Fiorio M. The interplay of exercise, placebo and nocebo Availability of data and materials effects on experimental pain. Sci Rep. 2018;8:14758. Not applicable. 22. Rossettini G, Emadi Andani M, Dalla Negra F, Testa M, Tinazzi M, Fiorio M. The placebo effect in the motor domain is differently modulated by the Ethics approval and consent to participate external and internal focus of attention. Sci Rep. 2018;8:12296. Not applicable. 23. Miciak M, Gross DP, Joyce A. A review of the psychotherapeutic 'common factors' model and its application in physical therapy: the need to consider general Consent for publication effects in physical therapy practice. Scand J Caring Sci. 2012;26:394–403. Not applicable. 24. Miciak M, Mayan M, Brown C, Joyce AS, Gross DP. The necessary conditions of engagement for the therapeutic relationship in physiotherapy: an Competing interests interpretive description study. Arch Physiother. 2018;8:3. The authors declare that they have no competing interests. 25. Miciak M, Mayan M, Brown C, Joyce AS, Gross DP. A framework for establishing connections in physiotherapy practice. Physiother Theory Pract. 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