Learning mechanisms in nocebo hyperalgesia: The role of conditioning and extinction processes. Thomaidou et al. Appendix 1. The TENS handout (translated from Dutch)Effectivity of electrical nerve stimulation (ENS) in increasing pain.Electrical nerve stimulation (ENS) is the administration of an electrical current produced by a

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.

Nocebo effects may occur when we learn to expect some thing bad will happen, such as our itch getting worse, and then, like a "self-fulfilling prophecy", the itch really does get worse because we expected it would. This study investiga ted 2 different ways in which such nocebo effects can oc cur in healthy participants: learning expectations through direct experience (classical conditioning) and learning expectations through observation (observational learning). While learning through direct experience led to nocebo effects on itch, there were no indications for observatio nal learning having this effect. This suggests that nocebo effects on itch can arise through first-hand, negative expe riences with itch treatments.To investigate learning processes underlying nocebo effects on itch, this study measured the efficacy of classical conditioning and observational learning for inducing nocebo effects on cowhage-evoked itch and scratching behaviour. A total of 58 healthy female participants were assigned to classical conditioning, observational learning, or sham conditioning groups. In the classical conditioning group, experimenters associated the application of an inert gel with increased itch intensity themselves. In the observational learning group, a video of the conditioning paradigm was shown. Nocebo effects were measured as the difference in itch or scratching between control and nocebo test phase trials, compared between learning and control groups. Compared with sham conditioning, classical conditioning induced a significant nocebo effect on itch, while observational learning did not. No nocebo effect on scratching was detected. These results highlight the role that learning through direct experiences plays in pruritic symptoms. Future research should investigate how a patient's history of unsuccessful treatments shapes treatment outcomes.

Placebo effects, positive treatment outcomes that go beyond treatment processes, can alter sensations through learning mechanisms. Understanding how methodological factors contribute to the magnitude of placebo effects will help define the mechanisms by which these effects occur. We conducted a systematic review and meta-analysis of experimental placebo studies in cutaneous pain and itch in healthy samples, focused on how differences in methodology contribute to the resulting placebo effect magnitude. We conducted meta-analyses by learning mechanism and sensation, namely, for classical conditioning with verbal suggestion, verbal suggestion alone, and observational learning, separately for pain and itch. We conducted subgroup analyses and meta-regression on the type of sensory stimuli, placebo treatment, number of acquisition and evocation trials, differences in calibrated intensities for placebo and control stimuli during acquisition, age, and sex. We replicated findings showing that a combination of classical conditioning with verbal suggestion induced larger placebo effects on pain (k 5 68, g 5 0.59) than verbal suggestion alone (k 5 39, g 5 0.38) and found a smaller effect for itch with verbal suggestion alone (k 5 7, g 5 0.14). Using sham electrodes as placebo treatments corresponded with larger placebo effects on pain than when topical gels were used. Other methodological and demographic factors did not significantly affect placebo magnitudes. Placebo effects on pain and itch reliably occur in experimental settings with varied methods, and conditioning with verbal suggestion produced the strongest effects. Although methods may shape the placebo effect to some extent, these effects appear robust overall, and their underlying learning mechanisms may be harnessed for applications outside the laboratory.

This study aimed to identify electrophysiological biomarkers of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) was induced in 36 healthy participants through classical conditioning and negative suggestions. In a baseline phase, participants received high thermal pain stimulations. During acquisition, participants learned to associate an inert gel applied to their forearm with high pain, relative to a moderate intensity control stimulus administered without gel. During evocation, nocebo and control stimuli were both accompanied by moderate pain to measure nocebo responses. Electroencephalography was recorded during rest (pre and post nocebo acquisition) and during pain stimulation (baseline, nocebo acquisition and evocation). Nocebo hyperalgesia led to pre- to post-acquisition increases in long-range temporal correlations (LRTC), with beta-band alterations being negatively associated with nocebo magnitudes. Moreover, individuals with strong LRTC at rest showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. By involving LRTC, these findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing. This study provides novel insights into neural underpinnings of nocebo hyperalgesia, a phenomenon that greatly impacts the experience of pain.