<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03793790</url>
  </required_header>
  <id_info>
    <org_study_id>CEP18-0816/318</org_study_id>
    <nct_id>NCT03793790</nct_id>
  </id_info>
  <brief_title>The Role of Learning in Nocebo Hyperalgesia</brief_title>
  <official_title>Learning Mechanisms in Nocebo Hyperalgesia: the Role of Conditioning and Extinction Processes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Leiden University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Universiteit Leiden</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Leiden University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Nocebo effects are adverse effects induced by patients' expectations. Nocebo effects on pain&#xD;
      may underlie several clinical conditions, such as chronic pain. These effects can be learned&#xD;
      via classical conditioning mechanisms. In the lab, nocebo effects are commonly studied via&#xD;
      conditioning with continuous reinforcement (CRF) during which 100 percent of unconditioned&#xD;
      pain stimuli are paired to conditioned stimuli (i.e., the activation of a mock medical&#xD;
      device). Partial reinforcement (PRF) provides a more uncertain pairing during conditioning,&#xD;
      where less than 100 percent of unconditioned pain stimuli are paired to conditioned stimuli.&#xD;
      This method provides a potentially more clinically relevant learning platform to study how&#xD;
      nocebo effects on pain are induced. In this study, the efficacy of conditioning with PRF,&#xD;
      CRF, and sham-conditioning in inducing nocebo effects on pain will be compared. Furthermore,&#xD;
      a counterconditioning method will be compared to an extinction method for the attenuation of&#xD;
      nocebo effects on pain. Given the relevance of nocebo effects for patients, it is important&#xD;
      to ascertain effective &amp; clinically relevant methods to understand how nocebo effects may be&#xD;
      formed and attenuated. This study is conducted by Leiden University.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Main planned analyses:&#xD;
&#xD;
      Primary Outcome; Comparing the effectivity of conditioning with PRF, conditioning with CRF,&#xD;
      and sham conditioning, in inducing nocebo effects on pain:&#xD;
&#xD;
      The magnitude of the induced nocebo effect during the first evocation phase (dependent&#xD;
      variable), will be compared between induction groups (independent variable). The pain ratings&#xD;
      for the first control trial will be measured against the pain ratings for the first&#xD;
      reinforced trial, yielding the magnitude of the nocebo effect. A 3x2 mixed model Analysis of&#xD;
      Variance (ANOVA) will be used, treating group as the between-subjects factor with three&#xD;
      levels (PRF, CRF, sham) and magnitude of the nocebo effect on pain as a within-subjects&#xD;
      measure with two levels (first control and first reinforced trial). Planned contrasts will be&#xD;
      conducted.&#xD;
&#xD;
      Secondary Outcome; Comparing the effectivity of counterconditioning and extinction in&#xD;
      attenuating nocebo effects on pain:&#xD;
&#xD;
      The nocebo effect still present in the second evocation phase (dependent variable) will be&#xD;
      compared between attenuation groups (independent variable). This effect will be measured as&#xD;
      the change in pain ratings reported in the first reinforced trial of the first evocation&#xD;
      phase (after induction) and pain ratings reported in the first reinforced trial of the second&#xD;
      evocation phase (after attenuation). This effect will be further analysed by measuring any&#xD;
      change in pain reports for the control trials (second dependent variable) in the same way.&#xD;
      The effect of induction group will also be further explored. A 2x2 mixed model ANOVA will be&#xD;
      conducted, with attenuation group as the between-subjects factor (counterconditioning and&#xD;
      extinction) and the degree to which the nocebo effect has been attenuated as the&#xD;
      within-subjects measure with two levels (first and second evocation phase for the first&#xD;
      reinforced trials). Further secondary analyses will be conducted.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 20, 2018</start_date>
  <completion_date type="Actual">April 30, 2019</completion_date>
  <primary_completion_date type="Actual">April 30, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_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.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>A double-blind randomization list (stratified for gender) was created by an independent statistician. Complete blinding of the researchers during the experiment is not possible due to the nature of conditioning paradigms. However, in this study blinding is optimized: the researchers are informed of the (conditioning) group to which participants are allocated after their final inclusion to the study, and after all questionnaires and pain calibration procedures have been completed on the testing day.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF, CRF, or sham conditioning.</measure>
    <time_frame>Testing day 1, in the 1st evocation phase</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) still present after counterconditioning or extinction.</measure>
    <time_frame>Testing day 1, in the 2nd evocation phase</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Possible resistance to extinction of induced nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF as compared to after CRF.</measure>
    <time_frame>Testing day 1, in the attenuation phase and the 2nd evocation phase</time_frame>
    <description>Exploring whether participants in the PRF group will exhibit higher resistance to extinction during attenuation, as compared to participants in the CRF group. This will be assessed by analyzing the time-course of extinction of the previously induced nocebo effects on pain (rated on a 0-10 numeric rating scale) during the attenuation phase and the 2nd evocation phase</description>
  </other_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">140</enrollment>
  <condition>Nocebo Effects</condition>
  <condition>Hyperalgesia</condition>
  <condition>Chronic Pain</condition>
  <condition>Pain Syndrome</condition>
  <arm_group>
    <arm_group_label>Group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Conditioning nocebo effects on pain with a partial reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Conditioning nocebo effects on pain with a partial reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Conditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Conditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 5</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham conditioning of nocebo effects on pain (induction) and extinction (attenuation).</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Conditioning with partial reinforcement</intervention_name>
    <description>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.</description>
    <arm_group_label>Group 1</arm_group_label>
    <arm_group_label>Group 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Conditioning with continuous reinforcement</intervention_name>
    <description>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.</description>
    <arm_group_label>Group 3</arm_group_label>
    <arm_group_label>Group 4</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Counterconditioning</intervention_name>
    <description>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.</description>
    <arm_group_label>Group 1</arm_group_label>
    <arm_group_label>Group 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Extinction</intervention_name>
    <description>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).</description>
    <arm_group_label>Group 2</arm_group_label>
    <arm_group_label>Group 4</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Sham Conditioning</intervention_name>
    <description>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.</description>
    <arm_group_label>Group 5</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged 18 - 35 years&#xD;
&#xD;
          -  Good understanding of the Dutch language&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe or chronic physical morbidity (e.g., heart and lung diseases, diabetes)&#xD;
&#xD;
          -  Psychiatric disorders (DSM diagnosis; e.g., depression, autism)&#xD;
&#xD;
          -  Chronic pain complaints (≥ 6 months) at present or in the past&#xD;
&#xD;
          -  Current pain&#xD;
&#xD;
          -  Current use of analgesic medication&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  After inclusion, participants who do not reach a sensation of high pain with the&#xD;
             highest temperature administered or participants who appear unable to distinguish&#xD;
             between moderate and high pain stimuli will also be excluded&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Participants whose gender identity, gender expression, and lived gender is male, will be included as male. Participants whose gender identity, gender expression, and lived gender is female, will be included as female.</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrea WM Evers, Prof. Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Leiden University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Leiden University</name>
      <address>
        <city>Leiden</city>
        <state>South Holland</state>
        <zip>2333 AL</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>December 29, 2018</study_first_submitted>
  <study_first_submitted_qc>January 2, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 4, 2019</study_first_posted>
  <last_update_submitted>August 12, 2019</last_update_submitted>
  <last_update_submitted_qc>August 12, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Universiteit Leiden</investigator_affiliation>
    <investigator_full_name>AWMEvers</investigator_full_name>
    <investigator_title>Prof. Dr.</investigator_title>
  </responsible_party>
  <keyword>Nocebo</keyword>
  <keyword>Pain</keyword>
  <keyword>Conditioning</keyword>
  <keyword>Counterconditioning</keyword>
  <keyword>Partial reinforcement</keyword>
  <keyword>Learning</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyperalgesia</mesh_term>
    <mesh_term>Chronic Pain</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>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.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>Data will become available immediately after publication of the study and will be retained for 15 years.</ipd_time_frame>
    <ipd_access_criteria>Data can be shared with scientists in relevant fields for the purpose of future studies such as replication or meta-analysis (or with designated persons for monitoring purposes).</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03793790
org study id: CEP18-0816/318
nct id: NCT03793790
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention 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.
primary purpose: Basic Science
masking: Double (Participant, Investigator)
masking description: A double-blind randomization list (stratified for gender) was created by an independent statistician. Complete blinding of the researchers during the experiment is not possible due to the nature of conditioning paradigms. However, in this study blinding is optimized: the researchers are informed of the (conditioning) group to which participants are allocated after their final inclusion to the study, and after all questionnaires and pain calibration procedures have been completed on the testing day.
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
description: 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.
measure: 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
description: 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.
measure: Possible resistance to extinction of induced nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF as compared to after CRF.
time frame: Testing day 1, in the attenuation phase and the 2nd evocation phase
description: Exploring whether participants in the PRF group will exhibit higher resistance to extinction during attenuation, as compared to participants in the CRF group. This will be assessed by analyzing the time-course of extinction of the previously induced nocebo effects on pain (rated on a 0-10 numeric rating scale) during the attenuation phase and the 2nd evocation phase
arm group label: Group 1
arm group type: Experimental
description: Conditioning nocebo effects on pain with a partial reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation).
arm group label: Group 2
arm group type: Experimental
description: Conditioning nocebo effects on pain with a partial reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation).
arm group label: Group 3
arm group type: Experimental
description: Conditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation).
arm group label: Group 4
arm group type: Experimental
description: Conditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation).
arm group label: Group 5
arm group type: Sham Comparator
description: Sham conditioning of nocebo effects on pain (induction) and extinction (attenuation).
intervention type: Behavioral
intervention name: Conditioning with partial reinforcement
description: 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.
arm group label: Group 1
arm group label: Group 2
intervention type: Behavioral
intervention name: Conditioning with continuous reinforcement
description: 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.
arm group label: Group 3
arm group label: Group 4
intervention type: Behavioral
intervention name: Counterconditioning
description: 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.
arm group label: Group 1
arm group label: Group 3
intervention type: Behavioral
intervention name: Extinction
description: 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).
arm group label: Group 2
arm group label: Group 4
intervention type: Behavioral
intervention name: Sham Conditioning
description: 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.
arm group label: Group 5
criteria: 
gender: All
gender based: Yes
gender description: Participants whose gender identity, gender expression, and lived gender is male, will be included as male. Participants whose gender identity, gender expression, and lived gender is female, will be included as female.
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Andrea WM Evers, Prof. Dr.
role: Principal Investigator
affiliation: Leiden University Medical Center
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Universiteit Leiden
investigator full name: AWMEvers
investigator title: Prof. Dr.
mesh term: Hyperalgesia
mesh term: Chronic Pain
sharing ipd: Yes
ipd description: 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.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Analytic Code
ipd time frame: Data will become available immediately after publication of the study and will be retained for 15 years.
ipd access criteria: Data can be shared with scientists in relevant fields for the purpose of future studies such as replication or meta-analysis (or with designated persons for monitoring purposes).