PainNCT04387851
Learning Mechanisms for Placebo and Nocebo Studies on Somatosensory Sensations: a Systematic Review and Meta-analysis.
An observational study of Pain and Itch, run by Leiden University Medical Center at 1 site in Netherlands.
Trial summary
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. Read more about this study
- Who is it for?
- Any age
- What is being tested?
- Nocebo
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 130 participants
- Where
- 1 siteNetherlands
- Study dates
- 1 Mar 2019to 1 Dec 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Child, Adult, Older adult
Study population: Healthy, adult human volunteers. Patient samples will not be included to improve homogeneity of the results.
Who may be able to join
- 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.
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the detailed description
Research questions include:
- What is the average magnitude of placebo or nocebo effects on pain and on itch, across included studies?
- 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?
- Does the magnitude of placebo or nocebo effects differ between the sensations of pain and itch?
- 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).
- Being tested
- Placebo induction, Control, Nocebo
- Keywords
- Placebo, Nocebo, Pain, Itch, Somatosensory, Learning
- Medical subject headings
- Pain, Pruritus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Placebo inductionBehavioural
The placebo interventions of interest are experimental learning methods (e.g. verbal suggestion, conditioning), used to induce placebo effects on somatosensory sensations.
ControlBehavioural
Placebo and nocebo effects should be measured relative to a control group (between-subjects design). In the case of within-subjects designs, these will be included to the extent possible (in a separate analysis or descriptively depending on the number of results).
NoceboBehavioural
The nocebo interventions of interest are experimental learning methods (e.g. verbal suggestion, conditioning), used to induce nocebo effects on somatosensory sensations.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo effects are defined as the positive effects occurring after the (supposed) administration of an inert treatment, which, through a given learning process, is believed to have positive effects. Receives: Behavioral: Placebo induction; Behavioral: Control | |
| Nocebo | Nocebo effects are defined as the negative effects occurring after the (supposed) administration of an inert treatment, which, through a given learning process, is believed to have negative effects. Receives: Behavioral: Control; Behavioral: Nocebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Placebo magnitude
The magnitude of induced placebo effects, by measures including, but not limited to, self-report measures of perceived sensation intensity or unpleasantness (e.g., as rated on a visual analogue scale or numerical rating scale).
Measured: Through study completion, an average of 1 month
Nocebo magnitude
The magnitude of induced nocebo effects, by measures including, but not limited to, self-report measures of perceived sensation intensity or unpleasantness (e.g., as rated on a visual analogue scale or numerical rating scale).
Measured: Through study completion, an average of 1 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 May 2020
- Study start1 Mar 2019
- Primary completion1 Dec 2021
- Study completion1 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for PainStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Retrospective
- Enrolment
- 130 participants (actual)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Universiteit Leiden
- Responsible party
- Principal investigator, AWMEvers, Leiden University Medical Center
- Investigators
- Andrea WM Evers, Prof. Dr., Principal investigator, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04387851
- Sponsor's protocol ID
- META-BLOM-DD-2022
- Status last verified
- Jan 2022
- First submitted
- 11 May 2020
- Last updated
- 11 Jan 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: No personal data are collected, stored, or shared. Data collection is monitored by the department's Data Monitor.
Publications
Thomaidou MA, Blythe JS, Peerdeman KJ, van Laarhoven AIM, Van Schothorst MME, Veldhuijzen DS, Evers AWM. Learned Nocebo Effects on Cutaneous Sensations of Pain and Itch: A Systematic Review and Meta-analysis of Experimental Behavioral Studies on Healthy Humans. Psychosom Med. 2023 May 1;85(4):308-321. doi: 10.1097/PSY.0000000000001194. Epub 2023 Mar 23.
PubMed 36961347Blythe JS, Thomaidou MA, Peerdeman KJ, van Laarhoven AIM, van Schothorst MME, Veldhuijzen DS, Evers AWM. Placebo effects on cutaneous pain and itch: a systematic review and meta-analysis of experimental results and methodology. Pain. 2023 Jun 1;164(6):1181-1199. doi: 10.1097/j.pain.0000000000002820. Epub 2022 Nov 16.
PubMed 36718994
Study at a glance
From the registry record, last updated by the sponsor on 11 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Learning Mechanisms for Placebo and Nocebo Studies on Somatosensory Sensations: a Systematic Review and Meta-analysis.
- ClinicalTrials.gov ID
- NCT04387851
- Acronym / sponsor ID
- META-BLOM-DD-2022
- Keywords
- Placebo, Nocebo, Pain, Itch, Somatosensory, Learning
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 130 participants (actual)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Collaborators
- Universiteit Leiden
- Study start
- 1 Mar 2019 (actual)
- Primary completion
- 1 Dec 2021 (actual)
- Study completion
- 1 Dec 2021 (actual)
- First posted
- 14 May 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Research questions include:
- What is the average magnitude of placebo or nocebo effects on pain and on itch, across included studies?
- 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?
- Does the magnitude of placebo or nocebo effects differ between the sensations of pain and itch?
- 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).
Study design
- Observational model
- Other
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | – | Behavioral: Placebo induction, Behavioral: ControlPlacebo effects are defined as the positive effects occurring after the (supposed) administration of an inert treatment, which, through a given learning process, is believed to have positive effects. |
| Nocebo | – | Behavioral: Control, Behavioral: NoceboNocebo effects are defined as the negative effects occurring after the (supposed) administration of an inert treatment, which, through a given learning process, is believed to have negative effects. |
Who may qualify
- Sex
- All
- Age groups
- Child, Adult, Older adult
- Study population
- Healthy, adult human volunteers. Patient samples will not be included to improve homogeneity of the results.
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Placebo inductionThe placebo interventions of interest are experimental learning methods (e.g. verbal suggestion, conditioning), used to induce placebo effects on somatosensory sensations. | Behavioural | Placebo |
| ControlPlacebo and nocebo effects should be measured relative to a control group (between-subjects design). In the case of within-subjects designs, these will be included to the extent possible (in a separate analysis or descriptively depending on the number of results). | Behavioural | Nocebo, Placebo |
| NoceboThe nocebo interventions of interest are experimental learning methods (e.g. verbal suggestion, conditioning), used to induce nocebo effects on somatosensory sensations. | Behavioural | Nocebo |
Primary outcome
Placebo magnitude
Time frame: Through study completion, an average of 1 month
The magnitude of induced placebo effects, by measures including, but not limited to, self-report measures of perceived sensation intensity or unpleasantness (e.g., as rated on a visual analogue scale or numerical rating scale).
Nocebo magnitude
Time frame: Through study completion, an average of 1 month
The magnitude of induced nocebo effects, by measures including, but not limited to, self-report measures of perceived sensation intensity or unpleasantness (e.g., as rated on a visual analogue scale or numerical rating scale).
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jan 2022.
- Derived from this study: PubMed 36961347Thomaidou MA, Blythe JS, Peerdeman KJ, van Laarhoven AIM, Van Schothorst MME, Veldhuijzen DS, Evers AWM. Learned Nocebo Effects on Cutaneous Sensations of Pain and Itch: A Systematic Review and Meta-analysis of Experimental Behavioral Studies on Healthy Humans. Psychosom Med. 2023 May 1;85(4):308-321. doi: 10.1097/PSY.0000000000001194. Epub 2023 Mar 23.
- Derived from this study: PubMed 36718994Blythe JS, Thomaidou MA, Peerdeman KJ, van Laarhoven AIM, van Schothorst MME, Veldhuijzen DS, Evers AWM. Placebo effects on cutaneous pain and itch: a systematic review and meta-analysis of experimental results and methodology. Pain. 2023 Jun 1;164(6):1181-1199. doi: 10.1097/j.pain.0000000000002820. Epub 2022 Nov 16.
- Individual participant dataSharing planned: Yes. No personal data are collected, stored, or shared. Data collection is monitored by the department's Data Monitor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrea WM Evers, Prof. Dr. principal investigator
Leiden University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pain and Itch, run by Leiden University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Placebo magnitude (time frame: Through study completion, an average of 1 month). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04387851, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jan 2022.