Learning Mechanisms for Placebo and Nocebo Studies on Somatosensory Sensations: a Systematic Review and Meta-analysis.

Placebo and nocebo effects are defined as the positive and negative effects occurring after the (supposed) administration of an inert treatment, which, through a given learning process, is believed to have positive or negative effects. The objective of this study is to summarize the available knowledge on experimental inductions of placebo and nocebo effects on somatosensory sensations, specifically pain and itch. The aim isto investigate the extent to which learning processes (such as conditioning and verbal suggestions) induce placebo and nocebo effects on pain and itch in healthy humans. The researchers intent to examine expectancy induction methods for placebo and nocebo effects on somatosensory sensations, describe methodological attributes of the research and propose practical and theoretical implications as well as future directions for research investigating placebo and nocebo effects on somatosensory sensations.

Research questions include:

1. What is the average magnitude of placebo or nocebo effects on pain and on itch, across included studies?
2. Across studies that tested multiple learning processes for placebo and nocebo effects on pain, is the magnitude of a placebo or nocebo effect on pain different based on the learning process used to induce the effect?
3. Does the magnitude of placebo or nocebo effects differ between the sensations of pain and itch?
4. Are nocebo effects on pain and itch stronger than placebo effects on pain and itch, as measured by their relative magnitude?

Dependent upon search results, the researchers intend to answer questions 1 and 2 with meta-analysis, and questions 3 and 4 with systematic review.

Search Strategy:

PubMed, PsycINFO, EMBASE, and the Cochrane CENTRAL Methodology Library will be searched. Languages are restricted to English, Dutch, and German. Publication period is not restricted. Searches were initially conducted on March 18th, 2019. The detailed key-worded search strategy will not be made publicly available until this review is complete.

Condition or domain being studied:

Experimental induction of placebo or nocebo effects on somatosensory sensations (i.e., pain and/or itch). For the purposes of in- and exclusion, studies are considered to have induced a placebo or nocebo effect if the (supposed) administration of an inert treatment, is paired with a given learning process attempt to induce positive or negative outcome-effects

Participants/population:

Healthy, adult human volunteers. Patient samples will not be included to improve homogeneity of the results.

Data extraction:

Titles and abstracts of articles retrieved using the search strategy and those from additional sources will be screened by two independent reviewers to identify studies that potentially meet the inclusion criteria outlined above. The full text of these articles and articles about which doubts exist based on the title and/or abstract will be retrieved and assessed for eligibility by two independent reviewers. Full texts that are considered to be possibly eligible for inclusion or about which doubts exist will also be assessed for eligibility by a third reviewer. Two independent reviewers will use a standardized form to extract data from the included studies to derive study characteristics, assess study quality, and for data analysis. Extracted information will include details of the intervention, control condition, study population, sensation type and how sensations were measured (e.g. self-report), type of experimental induction (i.e., learning method used), type of expectancy (i.e., placebo or nocebo), information for quality assessment, and outcome data for meta-analysis (e.g., sample size, mean, and standard deviation). Doubts regarding data-extraction will be resolved through discussion with a second review author. Missing data will be requested from the study authors.

Risk of bias assessment:

Risk of bias will be assessed using the method developed by Marcuzzi and colleagues in 2013 specifically for quantitative sensory testing studies. This method assesses 1) whether the sample was clearly described, 2) whether the sample is representative of the population, 3) whether the somatosensory assessment methods are standardized, validated, and well described, 4) adequate blinding if relevant, and 5) whether potential confounders were taken into account.

Strategy for data synthesis:

A quantitative synthesis, using aggregate data, of the data is planned. The (standardized) mean difference (with a 95% confidence interval) will be calculated for all included studies for which sufficient data are available. Both between and within subject designs will be included; sensitivity analyses will be conducted to test for a difference in design type (within/between). If significant differences are detected, design type will be included in the analyses as a moderator variable). Subsequently, the pooled effects for each of the experimental induction will be analyzed using a random-effects model. The effects of experimental inductions will also be compared between placebo and nocebo effects. If sufficient data are available, the effects of the experimental inductions will be compared between different somatosensory sensations (see below). Where statistical pooling is not possible, the findings of the systematic review will be presented in narrative form. Heterogeneity will be assessed with the I2 statistic, by visual inspection of the forest plot(s), and by subset analyses (see below). The presence of publication bias will also be assessed (e.g., via inspection of a funnel plot).

Eligibility Criteria:
Inclusion Criteria:

* Studies using experimental induction of placebo and/or nocebo effects on somatosensory sensations (i.e., pain and/or itch), which necessitates the (supposed) administration of an inert treatment, which, through a given learning process, is believed to have positive or negative effects.
* This review will include original, controlled experimental studies on healthy participants that employed learning-based inductions of placebo and/or nocebo effects on somatosensory sensations. The studies should be written in English, German or Dutch, available full-text, and published in a peer-reviewed journal. No year restrictions on publication date will be imposed.