Placebo and nocebo effects on itch: A review of experimental methods

Itch is a commonly experienced symptom of acute and chronic dermatological and systemic conditions. Placebo and nocebo effects, positive and negative effects experienced after both real and sham interventions, putatively due to positive or negative outcome expectancies, can have a significant impact on the experience of itch and its treatment. Experimental methods to induce and study placebo and nocebo effects on itch have been developed, utilizing various combinations of expectancy-induction methods (eg, conditioning, verbal suggestions) and short-acting itch-evoking stimuli (eg, histamine, electrical, or mechanical stimulation). The aim of this review is to describe the current research methods used to induce placebo and nocebo effects on itch, and the results of these studies. The benefits and drawbacks of different expectancy-induction methods and itch-evoking stimuli are described, and future directions for research and clinical application are discussed.Health and self-regulatio

Exploring the process of itch and its dimensionality : investigations using transcranial magnetic stimulation

This thesis explored three main areas of acute itch: firstly, how to reliably measure it; secondly, whether it is of a multi-dimensional nature, and lastly, which brain regions are crucial in the process. Chapter 2 reports an experiment that directly compared the re-test reliability of three commonly used measurement scales (pVAS, tVAS and gLMS). The general Labelled Magnitude Scale (gLMS) generated the least variance in itch intensity ratings between testing sessions and was therefore taken as the most reliable and administered for the following experiments. Chapter 3 and 4 explored the dimensionality of histamine and cowhage induced itch. The aims of these chapters were, (1) to explore any changes in the time-course and peak of itch intensity/unpleasantness, induced by varying stimuli doses, (2) to examine any dissociation between itch intensity and unpleasantness, which would indicate that they are dissociable dimensions. The results demonstrated that there was a significant linear trend for both intensity and unpleasantness, however there was no significant difference between the dimensions. Based on these results, it was decided that only the intensity should be measured in the following transcranial magnetic stimulation (TMS) experiment, as the unpleasantness dimension did not appear to add any additional information. Chapter 5 describes a TMS study, investigating which brain areas have a necessary function in the process of histamine and cowhage induced itch. The aim was to explore any differences in the perceived itch intensity, after brain stimulation to the somatosensory cortices (S1 and S2) and the inferor frontal gyrus (IFG), in comparison to the control area (superior parietal lobe; SPL). The results demonstrated that only TMS to S1 significantly reduced the itch intensity when administered via the histamine prick test. There was also a significant reduction of the wheal induced in the S1 and IFG condition. There was however, no significant reduction of the flare for any condition. There was also no significant difference in itch intensity or skin response, for any of the brain regions stimulated when cowhage was administered. In summary, the results indicate that S1 has a crucial role in the processing of itch intensity, and that the histamine prick test and TMS are ideal for exploring this. More investigation is necessary however, to explore the role of S2 and the IFG in itch perception

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

The neurobiology of acute pain

The mechanisms by which noxious stimuli produce the sensation of pain in animals are complex. Noxious stimuli are transduced at the periphery and transmitted to the CNS, where this information is subject to considerable modulation. Finally, the information is projected to the brain where it is perceived as pain. Additionally, plasticity can develop in the pain pathway and hyperalgesia and allodynia may develop through sensitisation both peripherally and centrally. A large number of different ion channels, receptors, and cell types are involved in pain perception, and it is hoped that through a better understanding of these, new and refined treatments for pain will result

Cortico-spinal imaging to study pain

ABSTRACT: Functional magnetic resonance imaging of the brain has helped to reveal mechanisms of pain perception in health and disease. Recently, imaging approaches have been developed that allow recording neural activity simultaneously in the brain and in the spinal cord. These approaches offer the possibility to examine pain perception in the entire central pain system and in addition, to investigate cortico-spinal interactions during pain processing. Although cortico-spinal imaging is a promising technique, it bears challenges concerning data acquisition and data analysis strategies. In this review, we discuss studies that applied simultaneous imaging of the brain and spinal cord to explore central pain processing. Furthermore, we describe different MR-related acquisition techniques, summarize advantages and disadvantages of approaches that have been implemented so far and present software that has been specifically developed for the analysis of spinal fMRI data to address challenges of spinal data analysis

Placebo and nocebo effects in itch : from conditioning to psychophysiological effects

This dissertation investigated placebo and nocebo effects in itch. Placebo and nocebo effects are positive and negative treatment outcomes respectively, that cannot be attributed to active treatment ingredients. Consistent with previous research, the dissertation shows that these effects play an important role in itch. The studies moreover illustrate that placebo effects can still occur when people are informed about them.The results described in this dissertation show that expectations about itch can be formed in various ways. People's expectations of treatment outcomes have been found underlie placebo and nocebo effects. For instance, the information that is given about how much itch an experimental test elicits (i.e., verbal suggestions) can influence expectations and lead to placebo or nocebo effects. The results also show that placebo effects can be automatically induced for itch by associative learning (through pharmacological conditioning). In addition, these effects may also occur when people know they are placebo effects. These results illustrate the importance of expectations and the psychosocial context in the treatment of somatic symptoms complaints such as itch. The results of this thesis may help improve existing treatments for itch. For example, medicine use can potentially be reduced by applying pharmacological conditioning, existing treatment can be improved by providing optimal treatment information, and the importance of expectations for treatment outcomes can be discussed with patients.The research was funded by a Consolidator Grant from the European Research Council (ERC), granted to A.W.M. Evers.Health and self-regulatio

The underestimated significance of conditioning in placebo hypoalgesia and nocebo hyperalgesia

Placebo and nocebo effects are intriguing phenomena in pain perception with important implications for clinical research and practice because they can alleviate or increase pain. According to current theoretical accounts, these effects can be shaped by verbal suggestions, social observational learning, and classical conditioning and are necessarily mediated by explicit expectation. In this review, we focus on the contribution of conditioning in the induction of placebo hypoalgesia and nocebo hyperalgesia and present accumulating evidence that conditioning independent from explicit expectation can cause these effects. Especially studies using subliminal stimulus presentation and implicit conditioning (i.e., without contingency awareness) that bypass the development of explicit expectation suggest that conditioning without explicit expectation can lead to placebo and nocebo effects in pain perception. Because only few studies have investigated clinical samples, the picture seems less clear when it comes to patient populations with chronic pain. However, conditioning appears to be a promising means to optimize treatment. In order to get a better insight into the mechanisms of placebo and nocebo effects in pain and the possible benefits of conditioning compared to explicit expectation, future studies should carefully distinguish both methods of induction