When do placebo and nocebo work? The role of time on placebo analgesia and nocebo hyperalgesia.

Verbal suggestions are strong modulators of one\u2019s expectations and they can be used to induce placebo and nocebo responses. Research so far has investigated the magnitude (i.e. stronger or weaker) and the direction (i.e. increase or decrease of pain) of verbal suggestions, while no attention has been given to the dimension of time. Relying on three main experiments, which investigated the influence of temporal verbal suggestions in modulating the onset of action of placebo analgesia and nocebo hyperalgesia, this thesis seeks to address this shortcoming. In Study 1, pain was induced experimentally on healthy participants via short- lasting, medium-to-low intensity electrical stimuli. After each noxious stimulus participants rated their pain from 0 (no pain) to 10 (unbearable pain). Partic- ipants were assigned to one of three placebo groups, three nocebo groups, a no expectancy (NE) group, or a natural history (NH) group. An inert cream was ad- ministered to all participants, except from those in the NH group, while different verbal suggestions were given according to group allocation. Participants in the placebo groups were told that the cream had analgesic properties setting in after 5 (Placebo Group 5, P5), 15 (Placebo Group 15, P15) and 30 (Placebo Group 30, P30) minutes from cream application. Participants in the nocebo groups were told that the cream had hyperalgesic properties setting in after 5 (Nocebo Group 5, N5), 15 (Nocebo Group 15, N15) and 30 (Nocebo Group 30, N30) minutes from cream application. Participants in the NE group were told that the cream only had hydrating properties and that would not influence pain perception, while those in the NH group did not receive the cream and served to control for pain natural fluctuations over time. Participants repeated the pain test at baseline, after 10, 20 and 35 minutes after the cream application. Mixed-method analysis of variance showed a significant interaction between group and time, indicating that pain ratings varied between time-points and between groups. As expected, post hoc comparisons revealed that placebo and nocebo groups began to show a significant change in pain ratings than the NE group at the expected time point but not earlier. Interestingly, once triggered, the analgesic effect remained stable over time, while the hyperalgesic effect increased over time. In Study 2 and 3, the influence of temporal suggestions on placebo analgesia (Study 2) and nocebo hyperalgesia (Study 3) onset was investigated using a long lasting, high-intensity, tonic pain model, induced with the Cold Pressor Test (CPT). Heart Rate (HR) was measured to assess whether it correlated with placebo analgesia and nocebo hyperalgesia. In Study 2, participants were assigned to one of two placebo groups, or to the No Expectations (NE) group. In Study 3, participants were allocated to one of two nocebo groups, while the control group (NE) was taken from the previous study (Study 2). In this case participants also received an inert cream and those in the placebo groups were told that the cream had analgesic properties that would set in after 5 (placebo 5, P5) and 30 (placebo 30, P30) minutes from its application. Participants in the nocebo groups were told that the cream had hyperalgesic properties setting in after 5 (nocebo 5, P5) and 30 (nocebo 30, N30) minutes from application, while those in the NE group were told that the cream only had hydrating properties. All the participants repeated the CPT at baseline and after 10 and 35 minutes from cream application. Percentage change in exposure time (pain tolerance) from baseline to Test 10 ( 0610) and to test 35 ( 0635) and changes in HR during CPT were compared between the three groups. In both studies, data were non- parametric and non-parametric statistics were used accordingly. In Study 2, 0610 was greater in P5 than in NE and P30, indicating analgesia only in the group expecting cream early onset effect. 0635 was greater in P5 and P30 compared to NE, showing a delayed onset of analgesia in P30 and maintained analgesia in P5. The same results, but in the opposite direction, were reported in Study 3, where hyperalgesia onset followed the temporal verbal suggestions that partici- pants received. HR differences between groups were not significant in Study 2 nor 3. In conclusion, the experiments demonstrated that both placebo analgesia and nocebo hyperalgesia follow the temporal information provided. In addition, it was shown that once triggered, both placebo analgesia and nocebo hyperalgesia endure over time (at least for the duration of the experimental session). These data apply to experimentally induced pain both of a phasic nature with medium- low intensity and of a tonic nature, reaching high intensities. The important role of verbal suggestions in modulating the onset of action of a given (inert-) intervention could not only aid the clinical use of placebo treatment (e.g., in open-label placebo), but also support the efficacy of active drugs. Indeed, further research is needed to extend these results from healthy participants to patients and from placebos to active interventions

What is the relative contribution of biological and psychosocial factors to the generation of hypoxia headache?

ABSTRACTBackground: The biopsychosocial model claims that illness is generated by both biological and psychosocial factors. Accordingly, several studies have shown that both factors contribute to the generation of pain.Aims: The aim of the present study is to manipulate biological, psychological, and social factors in hypobaric hypoxia headache in order to understand their relative contribution to the generation of headache pain.Methods: Healthy subjects were subdivided into three groups and brought to our high-altitude labs for the assessment of hypoxia-induced headache, blood oxygen saturation (SO2), prostaglandins, and cortisol during the first 24 h after arrival. The first group did not undergo any manipulation. The second group (negative expectation) was told that severe headache would occur if SO2 dropped to less than 80% and their oximeters were set to display a saturation of 75%, even though real SO2 was much higher. The third group (negative expectation and social interaction) underwent the same ..

Explicit and implicit own’s body and space perception in painful musculoskeletal disorders and rheumatic diseases: a systematic scoping review

Background: Pain and body perception are essentially two subjective mutually influencing experiences. However, in the field of musculoskeletal disorders and rheumatic diseases we lack of a comprehensive knowledge about the relationship between body perception dysfunctions and pain or disability. We systematically mapped the literature published about the topics of: a) somatoperception; b) body ownership; and c) perception of space, analysing the relationship with pain and disability. The results were organized around the two main topics of the assessment and treatment of perceptual dysfunctions. Methods: This scoping review followed the six-stage methodology suggested by Arksey and O’Malley. Ten electronic databases and grey literature were systematically searched. The PRISMA Extension for Scoping Reviews was used for reporting results. Two reviewers with different background, independently performed study screening and selection, and one author performed data extraction, that was checked by a second reviewer. Results: Thirty-seven studies fulfilled the eligibility criteria. The majority of studies (68%) concerned the assessment methodology, and the remaining 32% investigated the effects of therapeutic interventions. Research designs, methodologies adopted, and settings varied considerably across studies. Evidence of distorted body experience were found mainly for explicit somatoperception, especially in studies adopting self-administered questionnaire and subjective measures, highlighting in some cases the presence of sub-groups with different perceptual features. Almost half of the intervention studies (42%) provided therapeutic approaches combining more than one perceptual task, or sensory-motor tasks together with perceptual strategies, thus it was difficult to estimate the relative effectiveness of each single therapeutic component. Conclusions: To our knowledge, this is the first attempt to systematically map and summarize this research area in the field of musculoskeletal disorders and rheumatic diseases. Although methodological limitations limit the validity of the evidence obtained, some strategies of assessment tested and therapeutic strategies proposed represent useful starting points for future research. This review highlights preliminary evidence, strengths, and limitations of the literature published about the research questions, identifying key points that remain opened to be addressed, and make suggestions for future research studies. Body representation, as well as pain perception and treatment, can be better understood if an enlarged perspective including body and space perception is considered

Explicit and implicit own’s body and space perception in painful musculoskeletal disorders and rheumatic diseases: a systematic scoping review

Background: Pain and body perception are essentially two subjective mutually influencing experiences. However, in the field of musculoskeletal disorders and rheumatic diseases we lack of a comprehensive knowledge about the relationship between body perception dysfunctions and pain or disability. We systematically mapped the literature published about the topics of: a) somatoperception; b) body ownership; and c) perception of space, analysing the relationship with pain and disability. The results were organized around the two main topics of the assessment and treatment of perceptual dysfunctions. Methods: This scoping review followed the six-stage methodology suggested by Arksey and O’Malley. Ten electronic databases and grey literature were systematically searched. The PRISMA Extension for Scoping Reviews was used for reporting results. Two reviewers with different background, independently performed study screening and selection, and one author performed data extraction, that was checked by a second reviewer. Results: Thirty-seven studies fulfilled the eligibility criteria. The majority of studies (68%) concerned the assessment methodology, and the remaining 32% investigated the effects of therapeutic interventions. Research designs, methodologies adopted, and settings varied considerably across studies. Evidence of distorted body experience were found mainly for explicit somatoperception, especially in studies adopting self-administered questionnaire and subjective measures, highlighting in some cases the presence of sub-groups with different perceptual features. Almost half of the intervention studies (42%) provided therapeutic approaches combining more than one perceptual task, or sensory-motor tasks together with perceptual strategies, thus it was difficult to estimate the relative effectiveness of each single therapeutic component. Conclusions: To our knowledge, this is the first attempt to systematically map and summarize this research area in the field of musculoskeletal disorders and rheumatic diseases. Although methodological limitations limit the validity of the evidence obtained, some strategies of assessment tested and therapeutic strategies proposed represent useful starting points for future research. This review highlights preliminary evidence, strengths, and limitations of the literature published about the research questions, identifying key points that remain opened to be addressed, and make suggestions for future research studies. Body representation, as well as pain perception and treatment, can be better understood if an enlarged perspective including body and space perception is considered

Incorporating methods and findings from neuroscience to better understand placebo and nocebo effects in sport

Placebo and nocebo effects are a factor in sports performance. However, the majority of published studies in sport science are descriptive and speculative regarding mechanisms. It is therefore not unreasonable for the sceptic to argue that placebo and nocebo effects in sport are illusory, and might be better explained by variations in phenomena such as motivation. It is likely that, in sport at least, placebo and nocebo effects will remain in this empirical grey area until researchers provide stronger mechanistic evidence. Recent research in neuroscience has identified a number of consistent, discrete and interacting neurobiological and physiological pathways associated with placebo and nocebo effects, with many studies reporting data of potential interest to sport scientists, for example relating to pain, fatigue and motor control. Findings suggest that placebos and nocebos result in activity of the opioid, endocannabinoid and dopamine neurotransmitter systems, brain regions including the motor cortex and striatum, and measureable effects on the autonomic nervous system. Many studies have demonstrated that placebo and nocebo effects associated with a treatment, for example an inert treatment presented as an analgesic or stimulant, exhibit mechanisms similar or identical to the verum or true treatment. Such findings suggest the possibility of a wide range of distinct placebo and nocebo mechanisms that might influence sports performance. In the present paper, we present some of the findings from neuroscience. Focussing on fatigue as an outcome and caffeine as vehicle, we propose three approaches that researchers in sport might incorporate in their studies in order to better elucidate mechanisms of placebo/nocebo effects on performance

Enhancing primary school children's knowledge of online safety and risks with the CATZ cooperative cross-age teaching intervention: results from a pilot study

Children are heavy users of the internet and prior studies have shown that many of them lack a good understanding of the risks of doing so and how to avoid them. This study examined if the Cross-Age Teaching Zone (CATZ) intervention could help children acquire important knowledge of online risks and safety. It allowed older students to act as CATZ tutors to design and deliver a lesson to younger schoolmates (tutees), using content material about online risks and safety provided by adults. Students in Year 6 (mean age = 11.5 years) were randomly assigned to act as either CATZ tutors (n= 100) or age-matched controls (n = 46) and students in Year 4 (mean age = 9.5 years) acted as either CATZ tutees (n = 117) or age-matched controls (n = 28) (total N = 291). CATZ tutors but not matched controls scored significantly higher on objective measures of knowledge of both online risks and safety, and CATZ tutees but not matched controls did so for online safety. Effect sizes were moderate or large. CATZ was highly acceptable to participants. The results suggest that CATZ is a viable way to help school students learn about online dangers and how to avoid them

Consensus statement on placebo effects in sports and exercise: the need for conceptual clarity, methodological rigour, and the elucidation of neurobiological mechanisms.

In June 2017 a group of experts in anthropology, biology, kinesiology, neuroscience, physiology, and psychology convened in Canterbury, UK, to address questions relating to the placebo effect in sport and exercise. The event was supported exclusively by Quality Related (QR) funding from the Higher Education Funding Council for England (HEFCE). The funder did not influence the content or conclusions of the group. No competing interests were declared by any delegate. During the meeting and in follow-up correspondence, all delegates agreed the need to communicate the outcomes of the meeting via a brief consensus statement. The two specific aims of this statement are to encourage researchers in sport and exercise science to: 1. Where possible, adopt research methods that more effectively elucidate the role of the brain in mediating the effects of treatments and interventions. 2. Where possible, adopt methods that factor for and/or quantify placebo effects that could explain a percentage of inter-individual variability in response to treatments and interventio

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain

Background: The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain. Methods: Fifty-one healthy participants were allocated to one of three groups. Participants received an inert cream and were instructed that the agent had either hyperalgesic properties setting in after 5 (Nocebo 5, N5) or 30 (Nocebo 30, N30) minutes from cream application, or hydrating properties (No Expectation Group, NE). Pain was induced by the Cold Pressure Test (CPT) which was repeated before cream application (baseline) and after 10 (Test10) and 35 (Test35) minutes. Changes in pain tolerance and in HR at each test point in respect to baseline were compared between the three groups. Results: Tolerance change at Test 10 (Δ10) was greater in N5 (MED = −36.8; IQR = 20.9) compared to NE (MED = −5.3; IQR = 22.4; p < 0.001) and N30 (MED = 0.0; IQR = 23.1; p < 0.001), showing that hyperalgesia was only present in the group that expected the effect of the cream to set in early. Tolerance change at Test 35 (Δ35) was greater in N5 (MED = −36.3; IQR = 35.3; p = 0.002) and in N30 (MED = −33.3; IQR = 34.8; p = 0.009) compared to NE, indicating delayed onset of hyperalgesia in N30, and sustained hyperalgesia in N5. No group differences were found for HR. Conclusions: Our study demonstrated that temporal expectations shift nocebo response onset in a model of sustained pain

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain

Background: The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain.Methods: Fifty-one healthy participants were allocated to one of three groups. Participants received an inert cream and were instructed that the agent had either hyperalgesic properties setting in after 5 (Nocebo 5, N5) or 30 (Nocebo 30, N30) minutes from cream application, or hydrating properties (No Expectation Group, NE). Pain was induced by the Cold Pressure Test (CPT) which was repeated before cream application (baseline) and after 10 (Test10) and 35 (Test35) minutes. Changes in pain tolerance and in HR at each test point in respect to baseline were compared between the three groups.Results: Tolerance change at Test 10 (Δ10) was greater in N5 (MED = −36.8; IQR = 20.9) compared to NE (MED = −5.3; IQR = 22.4; p < 0.001) and N30 (MED = 0.0; IQR = 23.1; p < 0.001), showing that hyperalgesia was only present in the group that expected the effect of the cream to set in early. Tolerance change at Test 35 (Δ35) was greater in N5 (MED = −36.3; IQR = 35.3; p = 0.002) and in N30 (MED = −33.3; IQR = 34.8; p = 0.009) compared to NE, indicating delayed onset of hyperalgesia in N30, and sustained hyperalgesia in N5. No group differences were found for HR.Conclusions: Our study demonstrated that temporal expectations shift nocebo response onset in a model of sustained pain