Nocebo EffectsNCT03793790
The Role of Learning in Nocebo Hyperalgesia
A study testing Conditioning with partial reinforcement, Conditioning with continuous reinforcement and Counterconditioning in people with Nocebo Effects and Hyperalgesia, run by Leiden University Medical Center at 1 site in Netherlands.
Trial summary
Nocebo effects are adverse effects induced by patients' expectations. Nocebo effects on pain may underlie several clinical conditions, such as chronic pain. These effects can be learned via classical conditioning mechanisms. Read more about this study
- Who is it for?
- Ages 18 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Nocebo Effects, Hyperalgesia, Chronic Pain
- What is being tested?
- Conditioning with partial reinforcement, Conditioning with continuous reinforcement and Counterconditioning
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 140 participants
- Where
- 1 siteNetherlands
- Study dates
- 20 Sep 2018to 30 Apr 2019
- Phase
- Interventional
- 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 18 to 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Aged 18 - 35 years
- Good understanding of the Dutch language
Who cannot join
- Severe or chronic physical morbidity (e.g., heart and lung diseases, diabetes)
- Psychiatric disorders (DSM diagnosis; e.g., depression, autism)
- Chronic pain complaints (≥ 6 months) at present or in the past
- Current pain
- Current use of analgesic medication
- Pregnancy
- After inclusion, participants who do not reach a sensation of high pain with the highest temperature administered or participants who appear unable to distinguish between moderate and high pain stimuli will also be excluded
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Learning Mechanisms in Nocebo Hyperalgesia: the Role of Conditioning and Extinction Processes
Nocebo effects are adverse effects induced by patients' expectations. Nocebo effects on pain may underlie several clinical conditions, such as chronic pain. These effects can be learned via classical conditioning mechanisms. In the lab, nocebo effects are commonly studied via conditioning with continuous reinforcement (CRF) during which 100 percent of unconditioned pain stimuli are paired to conditioned stimuli (i.e., the activation of a mock medical device). Partial reinforcement (PRF) provides a more uncertain pairing during conditioning, where less than 100 percent of unconditioned pain stimuli are paired to conditioned stimuli. This method provides a potentially more clinically relevant learning platform to study how nocebo effects on pain are induced. In this study, the efficacy of conditioning with PRF, CRF, and sham-conditioning in inducing nocebo effects on pain will be compared. Furthermore, a counterconditioning method will be compared to an extinction method for the attenuation of nocebo effects on pain. Given the relevance of nocebo effects for patients, it is important to ascertain effective \& clinically relevant methods to understand how nocebo effects may be formed and attenuated. This study is conducted by Leiden University.
Read the detailed description
Main planned analyses:
Primary Outcome; Comparing the effectivity of conditioning with PRF, conditioning with CRF, and sham conditioning, in inducing nocebo effects on pain:
The magnitude of the induced nocebo effect during the first evocation phase (dependent variable), will be compared between induction groups (independent variable). The pain ratings for the first control trial will be measured against the pain ratings for the first reinforced trial, yielding the magnitude of the nocebo effect. A 3x2 mixed model Analysis of Variance (ANOVA) will be used, treating group as the between-subjects factor with three levels (PRF, CRF, sham) and magnitude of the nocebo effect on pain as a within-subjects measure with two levels (first control and first reinforced trial). Planned contrasts will be conducted.
Secondary Outcome; Comparing the effectivity of counterconditioning and extinction in attenuating nocebo effects on pain:
The nocebo effect still present in the second evocation phase (dependent variable) will be compared between attenuation groups (independent variable). This effect will be measured as the change in pain ratings reported in the first reinforced trial of the first evocation phase (after induction) and pain ratings reported in the first reinforced trial of the second evocation phase (after attenuation). This effect will be further analysed by measuring any change in pain reports for the control trials (second dependent variable) in the same way. The effect of induction group will also be further explored. A 2x2 mixed model ANOVA will be conducted, with attenuation group as the between-subjects factor (counterconditioning and extinction) and the degree to which the nocebo effect has been attenuated as the within-subjects measure with two levels (first and second evocation phase for the first reinforced trials). Further secondary analyses will be conducted.
- Conditions
- Nocebo Effects, Hyperalgesia, Chronic Pain, Pain Syndrome
- Being tested
- Conditioning with partial reinforcement, Conditioning with continuous reinforcement, Counterconditioning, Extinction, Sham Conditioning
- Keywords
- Nocebo, Pain, Conditioning, Counterconditioning, Partial reinforcement, Learning
- Medical subject headings
- Hyperalgesia, Chronic Pain, Somatoform Disorders, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Conditioning with partial reinforcementBehavioural
Conditioning with partial reinforcement (PRF) provides an uncertain pairing of unconditioned high pain stimuli and conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device). During PRF only 70 percent of unconditioned stimuli are paired to conditioned stimuli. Pain of only moderate intensity is used for control stimuli that are paired to the deactivation of the mock device and are also used in the 30 percent of unreinforced trials.
Conditioning with continuous reinforcementBehavioural
During conditioning with continuous reinforcement (CRF) unconditioned high pain stimuli are paired to conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) in 100 percent of conditioning trials. Pain of only moderate intensity is used for control stimuli that are paired to the deactivation of the mock device.
CounterconditioningBehavioural
During counterconditioning, the previously conditioned nocebo effects on pain are attenuated by pairing the same conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) to thermal pain stimuli of low intensity.
ExtinctionBehavioural
During extinction, the previously conditioned nocebo effects on pain are attenuated by pairing the same conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) only to control stimuli of moderate intensity (previously paired to the deactivation of the mock device).
Sham ConditioningBehavioural
In the sham group, participants receive different instructions (namely, that the activation of the device is not expected to affect their pain sensitivity). Additionally, during sham conditioning unconditioned stimuli are not consistently paired to conditioned stimuli, thereby preventing the formation of an association between high pain stimuli and the activation of the mock medical device. In the attenuation phase participants undergo an extinction procedure.
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | Experimental | Conditioning nocebo effects on pain with a partial reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation). Receives: Behavioral: Conditioning with partial reinforcement; Behavioral: Counterconditioning |
| Group 2 | Experimental | Conditioning nocebo effects on pain with a partial reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation). Receives: Behavioral: Conditioning with partial reinforcement; Behavioral: Extinction |
| Group 3 | Experimental | Conditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation). Receives: Behavioral: Conditioning with continuous reinforcement; Behavioral: Counterconditioning |
| Group 4 | Experimental | Conditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation). Receives: Behavioral: Conditioning with continuous reinforcement; Behavioral: Extinction |
| Group 5 | Sham comparator | Sham conditioning of nocebo effects on pain (induction) and extinction (attenuation). Receives: Behavioral: Sham Conditioning |
What is being measured
The primary outcome is the main question the study is designed to answer.
Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF, CRF, or sham conditioning.
This will be calculated in the first evocation phase, by analysing the pain ratings for the first reinforced trial against the pain ratings for the first control trial.
Measured: Testing day 1, in the 1st evocation phase
Secondary outcomes (1)
Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) still present after counterconditioning or extinction.
This will be calculated by analysing the pain ratings for the first reinforced trial in the second evocation phase against the pain ratings for the first reinforced trial in the first evocation phase.
Measured: Testing day 1, in the 2nd evocation phase
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jan 2019
- Study start20 Sep 2018
- Primary completion30 Apr 2019
- Study completion30 Apr 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Nocebo EffectsStudies 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
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This study employs a 2-by-2 design (i.e.,2 conditioning induction groups and 2 attenuation groups), with an additional control group (i.e., sham conditioning). Participants are thus allocated in 1 out of 5 groups.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 140 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, Universiteit Leiden
- Investigators
- Andrea WM Evers, Prof. Dr., Principal investigator, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03793790
- Sponsor's protocol ID
- CEP18-0816/318
- Status last verified
- Aug 2019
- First submitted
- 29 Dec 2018
- Last updated
- 13 Aug 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All data are collected pseudonymised thus no personal data are stored or shared. Consent forms are the only sources containing personal data and will not be shared, but are monitored by the department's Data Monitor.
Study at a glance
From the registry record, last updated by the sponsor on 13 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Learning Mechanisms in Nocebo Hyperalgesia: the Role of Conditioning and Extinction Processes
- ClinicalTrials.gov ID
- NCT03793790
- Acronym / sponsor ID
- CEP18-0816/318
- Conditions
- Nocebo Effects, Hyperalgesia, Chronic Pain, Pain Syndrome
- Keywords
- Nocebo, Pain, Conditioning, Counterconditioning, Partial reinforcement, Learning
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 140 participants (actual)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Collaborators
- Universiteit Leiden
- Study start
- 20 Sep 2018 (actual)
- Primary completion
- 30 Apr 2019 (actual)
- Study completion
- 30 Apr 2019 (actual)
- First posted
- 4 Jan 2019 (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.
Nocebo effects are adverse effects induced by patients' expectations. Nocebo effects on pain may underlie several clinical conditions, such as chronic pain. These effects can be learned via classical conditioning mechanisms. In the lab, nocebo effects are commonly studied via conditioning with continuous reinforcement (CRF) during which 100 percent of unconditioned pain stimuli are paired to conditioned stimuli (i.e., the activation of a mock medical device). Partial reinforcement (PRF) provides a more uncertain pairing during conditioning, where less than 100 percent of unconditioned pain stimuli are paired to conditioned stimuli. This method provides a potentially more clinically relevant learning platform to study how nocebo effects on pain are induced. In this study, the efficacy of conditioning with PRF, CRF, and sham-conditioning in inducing nocebo effects on pain will be compared. Furthermore, a counterconditioning method will be compared to an extinction method for the attenuation of nocebo effects on pain. Given the relevance of nocebo effects for patients, it is important to ascertain effective \& clinically relevant methods to understand how nocebo effects may be formed and attenuated. This study is conducted by Leiden University.
Detailed description
Main planned analyses:
Primary Outcome; Comparing the effectivity of conditioning with PRF, conditioning with CRF, and sham conditioning, in inducing nocebo effects on pain:
The magnitude of the induced nocebo effect during the first evocation phase (dependent variable), will be compared between induction groups (independent variable). The pain ratings for the first control trial will be measured against the pain ratings for the first reinforced trial, yielding the magnitude of the nocebo effect. A 3x2 mixed model Analysis of Variance (ANOVA) will be used, treating group as the between-subjects factor with three levels (PRF, CRF, sham) and magnitude of the nocebo effect on pain as a within-subjects measure with two levels (first control and first reinforced trial). Planned contrasts will be conducted.
Secondary Outcome; Comparing the effectivity of counterconditioning and extinction in attenuating nocebo effects on pain:
The nocebo effect still present in the second evocation phase (dependent variable) will be compared between attenuation groups (independent variable). This effect will be measured as the change in pain ratings reported in the first reinforced trial of the first evocation phase (after induction) and pain ratings reported in the first reinforced trial of the second evocation phase (after attenuation). This effect will be further analysed by measuring any change in pain reports for the control trials (second dependent variable) in the same way. The effect of induction group will also be further explored. A 2x2 mixed model ANOVA will be conducted, with attenuation group as the between-subjects factor (counterconditioning and extinction) and the degree to which the nocebo effect has been attenuated as the within-subjects measure with two levels (first and second evocation phase for the first reinforced trials). Further secondary analyses will be conducted.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 5
- Model description
- This study employs a 2-by-2 design (i.e.,2 conditioning induction groups and 2 attenuation groups), with an additional control group (i.e., sham conditioning). Participants are thus allocated in 1 out of 5 groups.
| Arm | Type | Receives |
|---|---|---|
| Group 1 | Experimental | Behavioral: Conditioning with partial reinforcement, Behavioral: CounterconditioningConditioning nocebo effects on pain with a partial reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation). |
| Group 2 | Experimental | Behavioral: Conditioning with partial reinforcement, Behavioral: ExtinctionConditioning nocebo effects on pain with a partial reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation). |
| Group 3 | Experimental | Behavioral: Conditioning with continuous reinforcement, Behavioral: CounterconditioningConditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation). |
| Group 4 | Experimental | Behavioral: Conditioning with continuous reinforcement, Behavioral: ExtinctionConditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation). |
| Group 5 | Sham comparator | Behavioral: Sham ConditioningSham conditioning of nocebo effects on pain (induction) and extinction (attenuation). |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Aged 18 - 35 years
- Good understanding of the Dutch language
Key exclusion criteria (7 listed)
- Severe or chronic physical morbidity (e.g., heart and lung diseases, diabetes)
- Psychiatric disorders (DSM diagnosis; e.g., depression, autism)
- Chronic pain complaints (≥ 6 months) at present or in the past
- Current pain
- Current use of analgesic medication
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 |
|---|---|---|
| Conditioning with partial reinforcementConditioning with partial reinforcement (PRF) provides an uncertain pairing of unconditioned high pain stimuli and conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device). During PRF only 70 percent of unconditioned stimuli are paired to conditioned stimuli. Pain of only moderate intensity is used for control stimuli that are paired to the deactivation of the mock device and are also used in the 30 percent of unreinforced trials. | Behavioural | Group 1, Group 2 |
| Conditioning with continuous reinforcementDuring conditioning with continuous reinforcement (CRF) unconditioned high pain stimuli are paired to conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) in 100 percent of conditioning trials. Pain of only moderate intensity is used for control stimuli that are paired to the deactivation of the mock device. | Behavioural | Group 3, Group 4 |
| CounterconditioningDuring counterconditioning, the previously conditioned nocebo effects on pain are attenuated by pairing the same conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) to thermal pain stimuli of low intensity. | Behavioural | Group 1, Group 3 |
| ExtinctionDuring extinction, the previously conditioned nocebo effects on pain are attenuated by pairing the same conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) only to control stimuli of moderate intensity (previously paired to the deactivation of the mock device). | Behavioural | Group 2, Group 4 |
| Sham ConditioningIn the sham group, participants receive different instructions (namely, that the activation of the device is not expected to affect their pain sensitivity). Additionally, during sham conditioning unconditioned stimuli are not consistently paired to conditioned stimuli, thereby preventing the formation of an association between high pain stimuli and the activation of the mock medical device. In the attenuation phase participants undergo an extinction procedure. | Behavioural | Group 5 |
Primary outcome
Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF, CRF, or sham conditioning.
Time frame: Testing day 1, in the 1st evocation phase
This will be calculated in the first evocation phase, by analysing the pain ratings for the first reinforced trial against the pain ratings for the first control trial.
1 secondary outcome
Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) still present after counterconditioning or extinction.
Time frame: Testing day 1, in the 2nd evocation phase
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 13 Aug 2019.
- Individual participant dataSharing planned: Yes. All data are collected pseudonymised thus no personal data are stored or shared. Consent forms are the only sources containing personal data and will not be shared, but are 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?
A study testing Conditioning with partial reinforcement, Conditioning with continuous reinforcement and Counterconditioning in people with Nocebo Effects and Hyperalgesia, 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 7 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 13 Aug 2019. 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. Some participants in this study may receive a placebo. 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?
Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF, CRF, or sham conditioning. (time frame: Testing day 1, in the 1st evocation phase). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 13 Aug 2019; AzTrials last refreshed its copy on 6 Nov 2026.