(1) A. Strumpf et al.,2 2016/GERMANY | Closed-label; Randomized | N = 100; Healthy volunteers | 1) Nocebo-like control I: a) NaCl Application; b) Noted: “does not cause itch in most people”. 2) Nocebo-like control II: a) Histamine Application; b) Noted: “causes some itch in most people”. 3) Nocebo-like effect II: a) Histamine Application; b) Noted: “causes an enormous itch in most people”. 4) Nocebo-like effect I: c) NaCl Application; d) Noted: “causes an enormous itch in most people”. | Larger wheal developed, significantly higher itch intensities, and increased unpleasantness under the nocebo-like condition I, when compared to under nocebo-like control condition I (received NaCl; p = 0.001, p = 0.003, p = 0.003). Larger flare size and itch intensity ratings differed between the nocebo-like experimental condition and nocebo-like control condition II (received histamine; p = 0.02, p = 0.007). The differences were not significantly different between males and females. | Itch and even skin reactions can be induced and intensified by suggestions and instructions, but these are not significantly impacted by gender. |
(2) A. Van Laarhoven et al.,3 2011/NETHERLANDS | Part 1: Verbal suggestions regarding various somatosensory stimuli that can evoke itch/pain. Part 2: Suggestions of a decrease or neutral response related to the application of histamine. Groups related to placebo impact on pain were also part of the study - outside the scope of the review. | Part 1: N = 56. Part 2: N = 36 (only those in the high expectation group from Part 1). | Part 1: 1) Itch Nocebo Condition (high expectation); 2) Itch Nocebo Control Condition (low expectation). Measured the effect of different somatosensory stimuli (mechanical, electrical, and chemical stimuli). Part 2: 1) Itch placebo; 2) Itch placebo control condition. | Part 1: Itch levels were significantly higher in the high expectation group, when compared to controls (p < 0.001). This was true for each type of stimulus. Higher expectations of itch were associated with higher levels of experienced itch. Part 2: The decrease in itch was larger in the itch placebo group, when compared to the controls (p < 0.05). | Nocebo effects can be indicated on itch by manipulating expectations through verbal suggestions. Verbal suggestions designed to induce a placebo effect resulted in a decrease in itch. |
(3) D. Bartels et al.,4 2014/NETHERLANDS | Multi-arm parallel group; Single-blind; Randomized | N = 95 | 1) Verbal Suggestion - noted that the third electrode would impact itch intensity based on the color on the screen (an actual sham electrode - all medium intensity stimuli); 2) Conditioning – noted that the color changes represent the change in intensity (low, medium, and high intensity stimuli were used); 3) Conditioning and verbal suggestion; 4) Control – the colors were not associated with change in stimuli intensity, no verbal suggestions were given. | Significant nocebo effect in the conditioning with verbal suggestion group (3), when compared to controls (p = 0.02). Borderline significant nocebo effect in the verbal suggestion group (1), when compared to controls (p = 0.063). No significant difference between the conditioning group (2) and controls. Significant placebo effect in the conditioning group (3), when compared to controls (p = 0.009). This was not observed in the other groups. | The combination of conditioning and verbal suggestion can induce significant nocebo and placebo effects on itch. |
(4) D. Bartels, et al.,5 2017/NETHERLANDS | Multi-arm parallel group; Single-blind; Randomized | N = 129 | Part 1: negative verbal suggestions “receive a series of electrical itch stimuli with and without the activation of the third electrode that influenced intensity” third electrode = sham electrode = placebo, screen turned different color when third electrode was “activated”. Part 2: Group 1: Positive expectation group “the third electrode will now decrease itch intensity”. Group 2: Same procedure as Part 1; Group 3: Extinction Group - no instructions were given. Part 3: Same groups as Part 2, histamine iontophoresis was used | Part 1: Significantly higher itch score for the conditioned trials, when compared to that for the neutral trials (p < 0.001). Part 2: Change in itch score: group 1: −0.4 ± 1; Group 2: 0.5 ± 0.8; Group 3: 0.3 ± 0.9; (p < 0.001, p < 0.01). Part 3: Significantly lower itch scores in the positive versus negative expectation groups (p < 0.01). | The study demonstrates that nocebo effects can be effectively minimized by positive expectation induction, and that these may even result in placebo effects. |
(5) D. Bartels et al.,6 2018/NETHERLANDS | Additional analysis of D. Bartels, et al., 2017/NETHERLANDS | N = 129 | Refer to D. Bartels, et al., 2017/NETHERLANDS | Part 1: Localized scratching with greater frequency and duration in the conditioned trials, when compared to the neutral trials (p < 0.001), total body scratching with greater frequency (p = 0.056) and duration (p < 0.001) in the conditioned trials. Part 2: No significant change in scratching episodes in the positive expectation group versus controls. | No conclusive evidence was identified for the generalization of nocebo effects on itch to scratching - further research is needed. |
(6) M. Darrah et al.,7 2013/NEW ZEALAND | Single blinded; Randomized | N = 58: Healthy college student volunteers | Written information was provided along with verbal explanation of skin reaction and antihistamine effect. Baseline administration: Aqueous cream applied (placebo). Histamine administered. Second administration: 1) Control group: Same as the baseline protocol; 2) Expectancy group: Verbal instructions were provided on the effectiveness expected from the antihistamine (placebo cream). | Expected wheal area: Significant between group difference in the change in expected wheal area with the expectancy group, expecting a greater reduction (p = 0.005). Wheal Area: No significant difference (p = 0.64). Heart rate (HR): A greater reduction in HR from baseline to second administration in the expectancy group, when compared to the control group (p = 0.45). | The wheal area was not impacted by the participants’ expectation based on verbal instructions - participants in the expectancy group did expect greater reduction in wheal size, and experienced a greater reduction in heart rate. |
(7) M. Darragh et al.,8 2015/NEW ZEALAND | Closed label; Cross-over; Randomized | N = 50: Healthy volunteers | 1) Group 1: Session 1 – Control; Session 2 – Treatment. 2) Group 2: Session 1 – Treatment; Session 2 – Control. For the treatment session - watched video explaining that an anti-histamine treatment cream would be applied to reduce itchiness and the size of the weal. In the control session - informed the subjects that the purpose was to get an indication of skin reactivity without treatment. The placebo cream was applied in all treatment sessions, followed by histamine. | Reduction of itch in the treatment group was noted after one minute (p = 0.009), three minutes (p < 0.001), and five minutes (p < 0.05). There was no difference in itch at seven minutes (p = 0.23), and no difference in weal size (p = 0.39). | Demonstrates the placebo effect in the context of inflammatory skin reactions using verbal suggestions alone. |
(8) S. Meeuwis et al.,9 2018/NETHERLANDS: Study 1 | Open label; Randomized | N = 92: Healthy volunteers | 1) Open-label positive VS; 2) Control no VS. VS = verbal suggestion. | The positive verbal suggestion group had significantly lower itch expectations, when compared to the control group (p < 0.001). No statistically significant difference between groups in mean self-reported itch during iontophoresis. (p = 0.24). The self-reported skin condition scores were lower in the experimental group (p = 0.059). No difference in physical parameters (p > 0.14) | The proof-of-principle study demonstrated that the open-label positive verbal suggestions were successful in reducing the level of itch the participants were expected to experience, but not in reducing the itch that was actually experienced. |
(9) S. Meeuwis et al.,10 June 2019/NETHERLANDS: Study 2 | Placebo controlled Crossover study. Open and closed label groups. Randomized | N = 92: Healthy volunteers | 1) Open-label positive VS; 2) Closed-label positive VS; 3) Open-label negative VS; 4) Closed-label negative VS. VS = verbal suggestion. Positive VS = “tonic has an itch reducing effect”. Negative VS = “tonic has an itch increasing effect”. Open label = “tonic is a placebo, but people still have a response in their brain, impacting itch even if they know they received a placebo”. Closed label = no additional information given. | The area under the curve (AUC) for itch during histamine iontophoresis: the combined positive VS groups and negative VS groups revealed a small sized non-significant difference (p = 0.19). The open and closed label analysis revealed similar findings. Maximum itch during iontophoresis: the combined and separate groups had no significant difference (p > 0.24). AUC for itch during the follow-up iontophoresis: significant and medium sized difference in changes for scores during the four-minute follow-up for the positive VS groups (p = 0.16), but not the negative VS groups (p = 0.98). No differences in subjective or physical skin response among the groups. | Both open-label and closed-label verbal suggestions were able to influence itch expectations, with closed label suggestions having more effect in reducing itch during follow-up. However, experienced itch during histamine iontophoresis was not influenced by suggestions. |
(10) S. Meeuwis et al.,11 Nov/Dec 2019/NETHERLANDS | Placebo controlled Crossover study. Open and closed label groups. Randomized | N = 92: Healthy volunteers | Two-phase conditioning paradigm: 1) Open-Label Conditioned Group: a) CS + UCS with explanation of conditioning and expected effects; b) CS + placebo. 2) Closed-label conditioned group: a) CS + UCS no explanation given; b) CS + placebo. 3) Conditioned not evoked control group: a) CS + UCS; b) water + placebo. 4) Non-conditioned control group: a) CS + placebo; b) CS + placebo. CS = conditioned stimulus - flavored beverage; UCS = unconditioned stimulus - H1 antihistamine | No differences in expected itch, remembered itch, or expected medication efficacy were identified (p > 0.11). No significant differences were found for mean self-reported itch, clinical skin response to histamine iontophoresis, spirometry, heart rate, or skin conductance level. When the groups were combined for comparison, conditioning was identified to be marginally effective in reducing itch (p = 0.076). | The study provides preliminary support for the behavioral conditioning of antipruritic effects. The findings suggest that this conditioning may be effective when it is known that a learning paradigm is being used. Further investigation in the open-label setting may help facilitate the utilization of placebos in clinical practice. |
(11) S. Meeuwis et al.,12 Jan 2021/NETHERLANDS: Study 3 | Closed and open label arms; Randomized | N = 112: Healthy volunteers | 1) Open-label positive VS; 2) Closed-label positive VS; 3) Open-label negative VS; 4) Closed-label negative VS. VS = verbal suggestion, Positive VS = “caffeine-containing patch to shoulder, influence both cognitive abilities and sensitivity to stimuli such as itch”. Negative VS = “caffeine-containing patch made the itch worse”. Open Label = the participants noted that the patch does not contain caffeine, test effects of positive suggestions, studies have shown that this reduces itch, even if it is known that this is a placebo. | Expected itch/Expected patch efficacy: the expected itch in the positive VS groups was significantly lower, when compared to the negative VS groups (p < 0.001), larger effect size in the open-label group, the differences in expected patch efficacy were small (p = 0.059). Self-rated mean itch: Significantly lower in the positive VS groups (p < 0.001). Self-rated skin response: Reported as less severe in the positive VS group (p < 0.001). Clinical skin response: No difference between groups | Both open and closed label positive suggestions related to a sham transdermal patch were able to influence the expectations for itch, mean itch experienced, and self-reported skin response in the experimental setting, when compared to negative suggestions. |
(12) S. Meeuwis et al.,13 Dec 2021/NETHERLANDS | Data used from previous studies (refer to the study details above). Study 1: S. Meeuwis et al. 2018; Study 2: S. Meeuwis et al. June 2019; Study 3: S. Meeuwis et al. January 2021. | N = 295 in total from three studies | Data used from previous studies (refer to the study details above). Study 1: S. Meeuwis et al. 2018; Study 2: S. Meeuwis et al. June 2019; Study 3: S. Meeuwis et al. January 2021. | Effects of VS on mean itch as mediated by expectations: For open-label participants: Positive VS indirectly reduced post-VS mean itch through mediation of expectation (p < 0.001). The lower pre-VS expected itch was significantly associated with lower post-VS expected itch (p < 0.001, p = 0.032). Closed label participants: Positive VS reduced expected itch, when compared to negative VS (p < 0.001). Post-VS expected that the itch was not associated with the post-VS mean itch (p = 0.9), while positive VS was directly associated with lower post-VS mean itch (p = 0.014). Post VS expected that the itch did not mediate the effects of CS on mean itch in the closed label context. Interindividual differences in the relationship between verbal suggestions, expectations, and itch: BAS (behavioral activation system) and body ignorance may play a role in the effect of VS. VS = verbal suggestion. | Innovative statistical methods were used to obtain detailed mechanistic information on the influence of interindividual differences on how placebo effects are formed. The effects of open-label positive and negative VS on itch may be more dependent on mediation by expectations, while closed-label suggestions directly influence itch. Low BAS sensitivity (sensitivity to rewards) was associated with increased impact of expectation on itch response. High ignorance of bodily signals is associated with increased placebo response to VS. |