Nocebo Effects on Cowhage-evoked Itch: A Randomized Controlled Trial of Classical Conditioning and Observational Learning

Abstract

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.

Can placebo and nocebo effects generalize within pain modalities and across somatosensory sensations?

“…Participants in our study also indicated to perceive a low similarity between pain and itch responses. Second, although a previous study 4 indicated that nocebo effects on cowhage-evoked itch could be induced by conditioning and verbal suggestions, it might be that cowhage-evoked itch is less prone to be altered by expectations than other types of itch, including histamine and electrical stimulation, that have been repeatedly studied in placebo and nocebo research. 2,5 Third, order effects should be considered as cowhage stimuli were tested after the first generalization effect (ie, from heat pain to pressure pain).…”

Learned Nocebo Effects on Cutaneous Sensations of Pain and Itch: A Systematic Review and Meta-analysis of Experimental Behavioral Studies on Healthy Humans

“…Learning has consistently been shown to underlie induced nocebo effects ( 5 – 7 , 9 , 25 ), and verbal suggestions seem to induce stronger nocebo responses when combined with conditioning ( 26 ). The positive counterpart to nocebo, placebo effects, also seem to be stronger when induced through a combination of conditioning with verbal suggestions, compared with conditioning alone, both on pain ( 27 ) and itch ( 4 , 12 ).…”

“…At the same time, other variables, such as the type of sensation (i.e., pain or itch), stimulus modality (e.g., thermal, electrical), the intensity of pain or itch stimulations, and the length of conditioning (learning) phases in different behavioral paradigms, also require a systematic examination across studies. For example, in experimental nocebo research, some nocebo conditioning paradigms include as few as four associative learning trials ( 5 ), whereas others use much longer paradigms ( 6 , 8 , 31 ). A diverse set of cutaneous (pain/itch) sensory induction methods are also used, such as thermal ( 25 ), electrical ( 6 , 12 ), or laser pain stimulations ( 32 ).…”

Induction and generalization of nocebo effects on itch

“…This has been studied using several pruritogens (eg histamine, electrical, and mechanical stimulation) 9,11,12 . So far, only one study indicated conditioning can induce nocebo hyperknesis using cowhage spicules (derived from the tropical bean mucuna pruriens) 13 . A single spicule can induce non‐histaminergic itch for several minutes and notably elicit cutaneous dysesthesia areas where tactile stimuli can evoke an alloknesis 14 .…”

“… 9 , 11 , 12 So far, only one study indicated conditioning can induce nocebo hyperknesis using cowhage spicules (derived from the tropical bean mucuna pruriens). 13 A single spicule can induce non‐histaminergic itch for several minutes and notably elicit cutaneous dysesthesia areas where tactile stimuli can evoke an alloknesis. 14 No studies to date have investigated whether merely verbal suggestion can evoke nocebo effects on cowhage‐evoked itch, neither did any studies assess nocebo effects on alloknesis areas.…”