<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/NCT03783624</url>
  </required_header>
  <id_info>
    <org_study_id>CER-VD 2017- 00924</org_study_id>
    <nct_id>NCT03783624</nct_id>
  </id_info>
  <brief_title>Measuring the Effects of Complementary Therapies in Chronic Neuropathic Pain</brief_title>
  <official_title>A Randomized-controlled Clinical Trial of Hypnosis Versus Open Label Placebo for Chronic Neuropathic Pain With an Investigation of Neuro-cognitive Dysfunctions as Maintaining Factors and Therapeutic Targets</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chantal Berna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Lausanne Hospitals</source>
  <oversight_info>
    <has_dmc>Yes</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>
      The objective of the study is to a) assess the presence of a maladaptive stress response, a&#xD;
      decreased pain modulation and any cognitive impairment in patients with chronic neuropathic&#xD;
      pain in comparison to healthy controls. and b) evaluate the efficacy of a treatment of&#xD;
      hypnosis and of an open label placebo on these neuro-cognitive factors and on clinical pain.&#xD;
&#xD;
      This will be done through a) a prospective observational comparative study of patients (base&#xD;
      line measures) with Healthy Controls (HC) and b) an Open label; randomised, hypnosis vs. open&#xD;
      label placebo (OLP) vs. treatment as usual control design; with a second phase of exploratory&#xD;
      cross-over.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The current study, through two sub-studies, aims to investigate through clinical,&#xD;
      psychophysical and biological methodology in a population of patients with chronic&#xD;
      neuropathic pain (i.e. involving a peripheral or CNS lesion), A) signs of a maladaptive&#xD;
      stress response, correlates of decreased pain modulation, and of cognitive impairment, B)&#xD;
      test hypnosis vs. open label placebo as potential mechanistic treatments of these suspected&#xD;
      maintaining factors.&#xD;
&#xD;
      Patients will be recruited at the CHUV's Pain Center and via collaborating physicians&#xD;
      treating patients with neuropathic pain (general practitioner, neurologist…). Controls will&#xD;
      be recruited via advertisements posted in public places such as the CHUV, or the University&#xD;
      of Lausanne's website and compounds.&#xD;
&#xD;
      Participants will be informed, in a clear and comprehensible way, of the nature of the study,&#xD;
      its purpose, the procedures involved, the expected duration, the potential risks and benefits&#xD;
      and any discomfort it may entail.&#xD;
&#xD;
      Participants (patients and volunteers) will be first phone or live pre-screened by the study&#xD;
      team to ensure they fulfil the inclusion criteria (except the MMSE). Then, eligible&#xD;
      participants will be invited to the pain centre for the first study visit. During this visit&#xD;
      informed will first be collected by the PI. Following this, a screening of the cognitive&#xD;
      function of the participant will be performed through the MMSE test. Participants with a&#xD;
      score lower than 24/30 will be excluded and informed of their exclusion and its cause.&#xD;
      Pre-screening and/or screening data of non-included participants will be archived anonymously&#xD;
      at the pain center in order to document the CONSORT diagram. All other consented participants&#xD;
      will then take part in the first study procedures, which consist in a psychophysical&#xD;
      assessment to determine their baseline performance. These will be compared between patients&#xD;
      and matched volunteers without chronic pain, as well as longitudinally across treatment&#xD;
      groups. This assessment lasts approximately 3h and includes physiological recording (cardiac&#xD;
      rhythm, pulse-oxymetry, respiratory frequency), cognitive functions evaluation (Wisconsin&#xD;
      cards sorting test, Trail Making Test, Complex Figure Copy) and questionnaires (Brief Pain&#xD;
      Inventory, Hospital Anxiety and Depression Scale, Tampa Scale of Kinesiophobia, Pain&#xD;
      Catastrophizing Scale, WHO-BREF quality of Life, Brief Resilience Scale, Pain coping, scale&#xD;
      and sleep index). During this visit, patients will also undergo sensory testing to evaluate&#xD;
      their abilities to modulate pain perception. Moderately painful 10s.heat stimuli will be&#xD;
      applied on the forearm with a thermode (Medoc TSA, Israel). In pseudo-random order,&#xD;
      participants are instructed to pay attention to the stimulus, vs. use distraction or focused&#xD;
      mental imagery (i.e. reappraisal of the sensation). A peripheral blood plasma sample will&#xD;
      also be collected for metabolomic analysis, in collaboration with the Metabolomics platform&#xD;
      of the University of Lausanne. The day before the psychophysical assessment, participants&#xD;
      will receive instructions for saliva collection in order to determine the variation of&#xD;
      cortisol levels during the day (4 time points) and metabolomic signature. They will receive&#xD;
      kits either directly or by mail. Participants will bring the samples along with them to the&#xD;
      study visit.&#xD;
&#xD;
      Healthy volunteers will only participate in this unique visit. Patients will be randomized in&#xD;
      equal proportions into the &quot;Hypnosis&quot;, &quot;Open Label Placebo&quot; or the &quot;treatment as usual&quot; arm.&#xD;
&#xD;
      After 4 weeks, brief questionnaires will be filled regarding pain levels. After 8 weeks, all&#xD;
      the patients will participate in the same psychophysical assessment as described above.&#xD;
      Patients will also participate in the assessment of their hypnotisability. Afterward, we will&#xD;
      proceed with an exploratory, patient-choice cross-over i.e. patients randomized in the&#xD;
      &quot;standard of care&quot; arm will choose between the &quot;hypnosis&quot; or &quot;open label placebo&quot; arm. Those&#xD;
      that initially received hypnosis treatment will be free to practice self hypnosis as taught&#xD;
      during the treatment sessions, or switch to &quot;open label placebo&quot;. Those in the &quot;open label&#xD;
      placebo&quot; can choose to continue OLP or switch to hypnosis. All participants can also choose&#xD;
      no further intervention.&#xD;
&#xD;
      After 16 and 24 weeks a follow-up questionnaire will evaluate the longer-term efficacy of the&#xD;
      intervention and its impact on daily life, as well as adherence to treatment and&#xD;
      satisfaction. Questionnaires will be filled online, from home.&#xD;
&#xD;
      The intervention consists in&#xD;
&#xD;
        1. . Hypnosis. This represents 6 individual script-based sessions lasting 1h, distributed&#xD;
           over 8 weeks, administered by a certified expert in therapeutic hypnosis. A set of&#xD;
           standardized recordings are provided to use at home for self-hypnosis. Suggestions&#xD;
           address deep relaxation, sensory substitution or transformation, pain intensity&#xD;
           reduction, decreased pain unpleasantness and intensity, sense of control. A brief&#xD;
           example of such suggestions: &quot;in this deeply relaxed state, you can imagine that your&#xD;
           feet are covered in anesthetic… a deep layer of a powerful anesthetic medication,&#xD;
           creating protective, soothing socks with which you can walk again…&quot;.&#xD;
&#xD;
        2. . Open label placebo. This consists in information provided with a placebo pill.&#xD;
           Patients are asked to take the placebo pills as a self-healing ritual. The information&#xD;
           relies on 4 points of explanation, i.e. (1) the placebo effect can be powerful, (2) the&#xD;
           body automatically can respond to taking placebo pills like Pavlov dogs who salivated&#xD;
           when they heard a bell, (3) a positive attitude can be helpful but is not necessary, and&#xD;
           (4) taking the pills faithfully for the full duration of treatment is critical.&#xD;
&#xD;
      The active treatments are compared treatment as usual. Treatment as usual involves&#xD;
      medications, interventional pain therapy, physical therapy, and psychotherapy as needed,&#xD;
      provided by the patient's current physicians. Patients are required to be on stable&#xD;
      medication 1 month prior to enrollment, and have no novel medication or procedures introduced&#xD;
      during the 2 first months of the trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 1, 2018</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">March 2023</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Investigator, Outcomes Assessor)</masking>
    <masking_description>due to the nature of the treatment (Open label placebo, hypnosis)patients and care providers will be in an open label setting, however the investigators and outcomes assessors will be blinded to the conditions.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Interference due to pain (BPI interference)</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Brief Pain Inventory, mean interference with function score (score 0-10), with higher scores meaning higher interference.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>pain severity (BPI pain scale)</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Brief Pain Inventory, mean pain intensity score over last 2 weeks (score 0-10) with higher scores meaning higher pain</description>
  </primary_outcome>
  <primary_outcome>
    <measure>fMRI of pain regulating circuitry (BOLD signal changes)</measure>
    <time_frame>8 weeks</time_frame>
    <description>BOLD signal will be measured during pain perception</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Stress response measured through Cortisol awakening response</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Four sequential salivary samples at awakening will be collected and allow dosing of salivary cortisol levels (Cortisol Awakening Response curve).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stress response measured through Heart rate variability (HRV)</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>ECG collection over times of rest and induced stress will allow to calculate HRV (based mainly on the RR interval)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain modulation: modulation of induced pain through mental imagery and expectations. The outcome measure is on pain Visual Analogue Scale (VAS) for unpleasantness</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>induced heat pain will be modulated through different instructions provided with visual cues: e.g. participants will be asked to imagine the stimulus is delivered in different contexts (more or less pleasant). The responses are given on a Pain unpleasantness Visual analogue Scale (VAS) ranging from 0 (not at all unpleasant: better outcome) to 10 (as much as can be unpleasant: worse outcome).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain modulation: modulation of induced pain through mental imagery and expectations. The outcome measure is on pain Visual Analogue Scale (VAS) for intensity</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>induced heat pain will be modulated through different instructions provided with visual cues: e.g. participants will be asked to imagine the stimulus is delivered in different contexts (more or less pleasant). The responses are given on a Pain intensity Visual analogue Scale (VAS) ranging from 0 (not at all intense- better outcome) to 10 (as much as can be intense- worse outcome).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trail making test (outcomes in time, seconds)</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Neuro-cognitive functioning testing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Wisconsin card sorting task</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Standardized cognitive flexibility task</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rey-Osterrieth figure test</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Prospective thinking task</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital Anxiety and Depression Scale (HADS)</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Hospital Anxiety and Depression Scale (HADS), which measures anxiety and depression symptoms in patients with somatic medical diagnosis. This scale ranges from 0-42 points, where higher scores indicate more depression/Anxiety. There are 2 sub-scales, each with 21 points, one for depression, teh other one for anxiety. The global scale score is calculated as a total</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tampa Scale of Kinesiophobia</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Tampa scale of fear of movement (i.e. Kinesiophobia): A scale with results ranging from 11-44 points, with teh higher points suggesting more severe kinesiophobia (worse fear of movement, worse outcome).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Catastrophizing Scale (PCS)</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>This scale measures the Catastrophizing thinking regarding pain scale. The score ranges between 0-52 with the higher scores indicating more severe catastrophizing, i.e. worse negative thinking regarding pain.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Coping Strategies Questionnaire</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Scale measuring the cognitive coping strategies used to deal with pain, with scores ranging from 0 to 78 points total, with higher scores indicating higher coping skills</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>patient satisfaction with care</measure>
    <time_frame>4 and 8 weeks</time_frame>
    <description>Subjective measure of satisfaction with the treatment, on a VAS scale: How satisfied are you with your attributed treatment? VAS 0: not at all; 10: very much satisfied</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of patient compliance</measure>
    <time_frame>4 and 8 weeks</time_frame>
    <description>Subjective measures of compliance: adequate adherence to treatment recommendations: question : &quot;were you able to follow the treatment plan as instructed? &quot; Yes/no&quot; if no: why. NUmber of patients reporting adequate compliance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood metabolomics</measure>
    <time_frame>8 weeks</time_frame>
    <description>Metabolomics is the analysis of the metabolic state (metabolites in the blood, saliva or other bodily fluid) at a given time. It is a growing technology that allows to analyse the biological response from a broader perspective and offers a sensitive way to investigate poorly-explored biochemical pathways in disease. The analysis of metabolites may provide a technically and bioinformatically tractable, physiologically relevant, chemically comprehensive method to better understand complex chronic diseases. For example, a recent study on chronic fatigue syndrome (CFS) showed an objectively identifiable chemical signature in both men and women with CFS distinct from healthy controls. Metabolomics showed that CFS is a highly concerted hypometabolic response to environmental stress that traces to the mitochondria.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>second phase cross-over choice</measure>
    <time_frame>8 weeks</time_frame>
    <description>patients are offered to choose a second treatment at 8 weeks</description>
  </other_outcome>
  <other_outcome>
    <measure>Long term outcomes on the Brief Pain Inventory (BPI)</measure>
    <time_frame>24 weeks</time_frame>
    <description>brief pain inventory, which measures the average pain score (pain VAS 0: no pain to 10: worst pain, and pain interference = no interference on daily activities by pain, 10 = full interference (see outcomes 1-2)</description>
  </other_outcome>
  <other_outcome>
    <measure>expectations regarding treatment effects</measure>
    <time_frame>8 weeks, 24 weeks</time_frame>
    <description>measured at Baseline: Question: how well do you expect this treatment to work for you (VAS: 0: no effect at all to 10: full relief).</description>
  </other_outcome>
  <other_outcome>
    <measure>Hypnotisability according to the Carleton University Responsiveness to Suggestion Scale (CURSS)</measure>
    <time_frame>8 weeks</time_frame>
    <description>This scale The Carleton scale yields 3 suggestibility scores for each S: objective (CURSS-O) scores reflect overt response to suggestion, subjective scores reflect experiential response to suggestion. Objective scores range from 0-7 , subjective scores from 0-21. The higher the score, the more hypnotizable the people are.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">72</enrollment>
  <condition>Neuropathic Pain</condition>
  <arm_group>
    <arm_group_label>Hypnosis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This represents 6 individual script-based sessions lasting 1h, distributed over 8 weeks, administered by a certified expert in therapeutic hypnosis. A set of standardized recordings are provided to use at home for self-hypnosis. Suggestions address deep relaxation, sensory substitution or transformation, pain intensity reduction, decreased pain unpleasantness and intensity, sense of control. A brief example of such suggestions: &quot;in this deeply relaxed state, you can imagine that your feet are covered in anesthetic… a deep layer of a powerful anesthetic medication, creating protective, soothing socks with which you can walk again…&quot;.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Open Label placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This consists in information provided with a placebo pill. Patients are asked to take the placebo pills as a self-healing ritual. The information relies on 4 points of explanation, i.e. (1) the placebo effect can be powerful, (2) the body automatically can respond to taking placebo pills like Pavlov dogs who salivated when they heard a bell, (3) a positive attitude can be helpful but is not necessary, and (4) taking the pills faithfully for the full duration of treatment is critical.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Usual care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients continue with their usual treatments</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Hypnosis</intervention_name>
    <description>A 6 session course of individual hypnosis therapy will be offered.</description>
    <arm_group_label>Hypnosis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Open label placebo</intervention_name>
    <description>Ritual intake of 2 placebo capsules twice a day</description>
    <arm_group_label>Open Label placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Patients:&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          -  aged 18-90 years,&#xD;
&#xD;
          -  interested in complementary medicine&#xD;
&#xD;
          -  peripheral neuropathic pain lasting for more than 6 months,&#xD;
&#xD;
          -  pain intensity of at least 3/10 VAS over the last two weeks&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  cognitive deficit (MMSE&lt;24/30),&#xD;
&#xD;
          -  severe hearing impairment,&#xD;
&#xD;
          -  acute psychiatric (e.g. suicidality, psychotic symptoms) or somatic (e.g. unstable&#xD;
             cardiorespiratory condition) co-morbidity preventing full engagement in the 8-week&#xD;
             study intervention,&#xD;
&#xD;
          -  prior negative experience with hypnosis,&#xD;
&#xD;
          -  allergy or intolerance to mannitol.&#xD;
&#xD;
        Healthy controls:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  matching patients for age and gender,&#xD;
&#xD;
          -  no chronic pain condition no acute pain condition requiring daily intake of&#xD;
             analgesics,&#xD;
&#xD;
          -  no acute medical or psychiatric condition.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Chantal Berna Renella, MD PhD</last_name>
    <phone>+41 795564744</phone>
    <email>chantal.berna-renella@chuv.ch</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Aurore Fernandez, MA</last_name>
    <phone>+4179 556 66 91</phone>
    <email>aurore.fernandez@chuv.ch</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Lausanne University Hospital (CHUV)</name>
      <address>
        <city>Lausanne</city>
        <zip>1011</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chantal Berna Renella, MD PhD</last_name>
      <phone>+41 79 556 47 44</phone>
      <email>chantal.berna-renella@chuv.ch</email>
    </contact>
    <contact_backup>
      <last_name>Aurore Fernandez, MA</last_name>
      <phone>+41 79 556 66 91</phone>
      <email>aurore.fernandez@chuv.ch</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>July 10, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 21, 2018</study_first_posted>
  <last_update_submitted>June 28, 2022</last_update_submitted>
  <last_update_submitted_qc>June 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 30, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Lausanne Hospitals</investigator_affiliation>
    <investigator_full_name>Chantal Berna</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>hypnosis</keyword>
  <keyword>open label placebo</keyword>
  <keyword>neurocognitive measures</keyword>
  <keyword>stress</keyword>
  <keyword>induced pain</keyword>
  <keyword>HRV</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuralgia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Anonymized data can be made accessible to interested researchers upon request</ipd_description>
  </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/NCT03783624
org study id: CER-VD 2017- 00924
nct id: NCT03783624
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The objective of the study is to a) assess the presence of a maladaptive stress response, a
      decreased pain modulation and any cognitive impairment in patients with chronic neuropathic
      pain in comparison to healthy controls. and b) evaluate the efficacy of a treatment of
      hypnosis and of an open label placebo on these neuro-cognitive factors and on clinical pain.

      This will be done through a) a prospective observational comparative study of patients (base
      line measures) with Healthy Controls (HC) and b) an Open label; randomised, hypnosis vs. open
      label placebo (OLP) vs. treatment as usual control design; with a second phase of exploratory
      cross-over.
The current study, through two sub-studies, aims to investigate through clinical,
      psychophysical and biological methodology in a population of patients with chronic
      neuropathic pain (i.e. involving a peripheral or CNS lesion), A) signs of a maladaptive
      stress response, correlates of decreased pain modulation, and of cognitive impairment, B)
      test hypnosis vs. open label placebo as potential mechanistic treatments of these suspected
      maintaining factors.

      Patients will be recruited at the CHUV's Pain Center and via collaborating physicians
      treating patients with neuropathic pain (general practitioner, neurologist…). Controls will
      be recruited via advertisements posted in public places such as the CHUV, or the University
      of Lausanne's website and compounds.

      Participants will be informed, in a clear and comprehensible way, of the nature of the study,
      its purpose, the procedures involved, the expected duration, the potential risks and benefits
      and any discomfort it may entail.

      Participants (patients and volunteers) will be first phone or live pre-screened by the study
      team to ensure they fulfil the inclusion criteria (except the MMSE). Then, eligible
      participants will be invited to the pain centre for the first study visit. During this visit
      informed will first be collected by the PI. Following this, a screening of the cognitive
      function of the participant will be performed through the MMSE test. Participants with a
      score lower than 24/30 will be excluded and informed of their exclusion and its cause.
      Pre-screening and/or screening data of non-included participants will be archived anonymously
      at the pain center in order to document the CONSORT diagram. All other consented participants
      will then take part in the first study procedures, which consist in a psychophysical
      assessment to determine their baseline performance. These will be compared between patients
      and matched volunteers without chronic pain, as well as longitudinally across treatment
      groups. This assessment lasts approximately 3h and includes physiological recording (cardiac
      rhythm, pulse-oxymetry, respiratory frequency), cognitive functions evaluation (Wisconsin
      cards sorting test, Trail Making Test, Complex Figure Copy) and questionnaires (Brief Pain
      Inventory, Hospital Anxiety and Depression Scale, Tampa Scale of Kinesiophobia, Pain
      Catastrophizing Scale, WHO-BREF quality of Life, Brief Resilience Scale, Pain coping, scale
      and sleep index). During this visit, patients will also undergo sensory testing to evaluate
      their abilities to modulate pain perception. Moderately painful 10s.heat stimuli will be
      applied on the forearm with a thermode (Medoc TSA, Israel). In pseudo-random order,
      participants are instructed to pay attention to the stimulus, vs. use distraction or focused
      mental imagery (i.e. reappraisal of the sensation). A peripheral blood plasma sample will
      also be collected for metabolomic analysis, in collaboration with the Metabolomics platform
      of the University of Lausanne. The day before the psychophysical assessment, participants
      will receive instructions for saliva collection in order to determine the variation of
      cortisol levels during the day (4 time points) and metabolomic signature. They will receive
      kits either directly or by mail. Participants will bring the samples along with them to the
      study visit.

      Healthy volunteers will only participate in this unique visit. Patients will be randomized in
      equal proportions into the "Hypnosis", "Open Label Placebo" or the "treatment as usual" arm.

      After 4 weeks, brief questionnaires will be filled regarding pain levels. After 8 weeks, all
      the patients will participate in the same psychophysical assessment as described above.
      Patients will also participate in the assessment of their hypnotisability. Afterward, we will
      proceed with an exploratory, patient-choice cross-over i.e. patients randomized in the
      "standard of care" arm will choose between the "hypnosis" or "open label placebo" arm. Those
      that initially received hypnosis treatment will be free to practice self hypnosis as taught
      during the treatment sessions, or switch to "open label placebo". Those in the "open label
      placebo" can choose to continue OLP or switch to hypnosis. All participants can also choose
      no further intervention.

      After 16 and 24 weeks a follow-up questionnaire will evaluate the longer-term efficacy of the
      intervention and its impact on daily life, as well as adherence to treatment and
      satisfaction. Questionnaires will be filled online, from home.

      The intervention consists in

        1. . Hypnosis. This represents 6 individual script-based sessions lasting 1h, distributed
           over 8 weeks, administered by a certified expert in therapeutic hypnosis. A set of
           standardized recordings are provided to use at home for self-hypnosis. Suggestions
           address deep relaxation, sensory substitution or transformation, pain intensity
           reduction, decreased pain unpleasantness and intensity, sense of control. A brief
           example of such suggestions: "in this deeply relaxed state, you can imagine that your
           feet are covered in anesthetic… a deep layer of a powerful anesthetic medication,
           creating protective, soothing socks with which you can walk again…".

        2. . Open label placebo. This consists in information provided with a placebo pill.
           Patients are asked to take the placebo pills as a self-healing ritual. The information
           relies on 4 points of explanation, i.e. (1) the placebo effect can be powerful, (2) the
           body automatically can respond to taking placebo pills like Pavlov dogs who salivated
           when they heard a bell, (3) a positive attitude can be helpful but is not necessary, and
           (4) taking the pills faithfully for the full duration of treatment is critical.

      The active treatments are compared treatment as usual. Treatment as usual involves
      medications, interventional pain therapy, physical therapy, and psychotherapy as needed,
      provided by the patient's current physicians. Patients are required to be on stable
      medication 1 month prior to enrollment, and have no novel medication or procedures introduced
      during the 2 first months of the trial.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Investigator, Outcomes Assessor)
masking description: due to the nature of the treatment (Open label placebo, hypnosis)patients and care providers will be in an open label setting, however the investigators and outcomes assessors will be blinded to the conditions.
measure: Interference due to pain (BPI interference)
time frame: at 8 weeks
description: Brief Pain Inventory, mean interference with function score (score 0-10), with higher scores meaning higher interference.
measure: pain severity (BPI pain scale)
time frame: at 8 weeks
description: Brief Pain Inventory, mean pain intensity score over last 2 weeks (score 0-10) with higher scores meaning higher pain
measure: fMRI of pain regulating circuitry (BOLD signal changes)
time frame: 8 weeks
description: BOLD signal will be measured during pain perception
measure: Stress response measured through Cortisol awakening response
time frame: at 8 weeks
description: Four sequential salivary samples at awakening will be collected and allow dosing of salivary cortisol levels (Cortisol Awakening Response curve).
measure: Stress response measured through Heart rate variability (HRV)
time frame: at 8 weeks
description: ECG collection over times of rest and induced stress will allow to calculate HRV (based mainly on the RR interval)
measure: Pain modulation: modulation of induced pain through mental imagery and expectations. The outcome measure is on pain Visual Analogue Scale (VAS) for unpleasantness
time frame: at 8 weeks
description: induced heat pain will be modulated through different instructions provided with visual cues: e.g. participants will be asked to imagine the stimulus is delivered in different contexts (more or less pleasant). The responses are given on a Pain unpleasantness Visual analogue Scale (VAS) ranging from 0 (not at all unpleasant: better outcome) to 10 (as much as can be unpleasant: worse outcome).
measure: Pain modulation: modulation of induced pain through mental imagery and expectations. The outcome measure is on pain Visual Analogue Scale (VAS) for intensity
time frame: at 8 weeks
description: induced heat pain will be modulated through different instructions provided with visual cues: e.g. participants will be asked to imagine the stimulus is delivered in different contexts (more or less pleasant). The responses are given on a Pain intensity Visual analogue Scale (VAS) ranging from 0 (not at all intense- better outcome) to 10 (as much as can be intense- worse outcome).
measure: Trail making test (outcomes in time, seconds)
time frame: at 8 weeks
description: Neuro-cognitive functioning testing
measure: Wisconsin card sorting task
time frame: at 8 weeks
description: Standardized cognitive flexibility task
measure: Rey-Osterrieth figure test
time frame: at 8 weeks
description: Prospective thinking task
measure: Hospital Anxiety and Depression Scale (HADS)
time frame: at 8 weeks
description: Hospital Anxiety and Depression Scale (HADS), which measures anxiety and depression symptoms in patients with somatic medical diagnosis. This scale ranges from 0-42 points, where higher scores indicate more depression/Anxiety. There are 2 sub-scales, each with 21 points, one for depression, teh other one for anxiety. The global scale score is calculated as a total
measure: Tampa Scale of Kinesiophobia
time frame: at 8 weeks
description: Tampa scale of fear of movement (i.e. Kinesiophobia): A scale with results ranging from 11-44 points, with teh higher points suggesting more severe kinesiophobia (worse fear of movement, worse outcome).
measure: Pain Catastrophizing Scale (PCS)
time frame: at 8 weeks
description: This scale measures the Catastrophizing thinking regarding pain scale. The score ranges between 0-52 with the higher scores indicating more severe catastrophizing, i.e. worse negative thinking regarding pain.
measure: Coping Strategies Questionnaire
time frame: at 8 weeks
description: Scale measuring the cognitive coping strategies used to deal with pain, with scores ranging from 0 to 78 points total, with higher scores indicating higher coping skills
measure: patient satisfaction with care
time frame: 4 and 8 weeks
description: Subjective measure of satisfaction with the treatment, on a VAS scale: How satisfied are you with your attributed treatment? VAS 0: not at all; 10: very much satisfied
measure: Evaluation of patient compliance
time frame: 4 and 8 weeks
description: Subjective measures of compliance: adequate adherence to treatment recommendations: question : "were you able to follow the treatment plan as instructed? " Yes/no" if no: why. NUmber of patients reporting adequate compliance.
measure: Blood metabolomics
time frame: 8 weeks
description: Metabolomics is the analysis of the metabolic state (metabolites in the blood, saliva or other bodily fluid) at a given time. It is a growing technology that allows to analyse the biological response from a broader perspective and offers a sensitive way to investigate poorly-explored biochemical pathways in disease. The analysis of metabolites may provide a technically and bioinformatically tractable, physiologically relevant, chemically comprehensive method to better understand complex chronic diseases. For example, a recent study on chronic fatigue syndrome (CFS) showed an objectively identifiable chemical signature in both men and women with CFS distinct from healthy controls. Metabolomics showed that CFS is a highly concerted hypometabolic response to environmental stress that traces to the mitochondria.
measure: second phase cross-over choice
time frame: 8 weeks
description: patients are offered to choose a second treatment at 8 weeks
measure: Long term outcomes on the Brief Pain Inventory (BPI)
time frame: 24 weeks
description: brief pain inventory, which measures the average pain score (pain VAS 0: no pain to 10: worst pain, and pain interference = no interference on daily activities by pain, 10 = full interference (see outcomes 1-2)
measure: expectations regarding treatment effects
time frame: 8 weeks, 24 weeks
description: measured at Baseline: Question: how well do you expect this treatment to work for you (VAS: 0: no effect at all to 10: full relief).
measure: Hypnotisability according to the Carleton University Responsiveness to Suggestion Scale (CURSS)
time frame: 8 weeks
description: This scale The Carleton scale yields 3 suggestibility scores for each S: objective (CURSS-O) scores reflect overt response to suggestion, subjective scores reflect experiential response to suggestion. Objective scores range from 0-7 , subjective scores from 0-21. The higher the score, the more hypnotizable the people are.
arm group label: Hypnosis
arm group type: Experimental
description: This represents 6 individual script-based sessions lasting 1h, distributed over 8 weeks, administered by a certified expert in therapeutic hypnosis. A set of standardized recordings are provided to use at home for self-hypnosis. Suggestions address deep relaxation, sensory substitution or transformation, pain intensity reduction, decreased pain unpleasantness and intensity, sense of control. A brief example of such suggestions: "in this deeply relaxed state, you can imagine that your feet are covered in anesthetic… a deep layer of a powerful anesthetic medication, creating protective, soothing socks with which you can walk again…".
arm group label: Open Label placebo
arm group type: Placebo Comparator
description: This consists in information provided with a placebo pill. Patients are asked to take the placebo pills as a self-healing ritual. The information relies on 4 points of explanation, i.e. (1) the placebo effect can be powerful, (2) the body automatically can respond to taking placebo pills like Pavlov dogs who salivated when they heard a bell, (3) a positive attitude can be helpful but is not necessary, and (4) taking the pills faithfully for the full duration of treatment is critical.
arm group label: Usual care
arm group type: No Intervention
description: Patients continue with their usual treatments
intervention type: Behavioral
intervention name: Hypnosis
description: A 6 session course of individual hypnosis therapy will be offered.
arm group label: Hypnosis
intervention type: Behavioral
intervention name: Open label placebo
description: Ritual intake of 2 placebo capsules twice a day
arm group label: Open Label placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Chantal Berna Renella, MD PhD
phone: +41 795564744
email: chantal.berna-renella@chuv.ch
last name: Aurore Fernandez, MA
phone: +4179 556 66 91
email: aurore.fernandez@chuv.ch
facility: 
status: Recruiting
contact: 
contact backup: 
country: Switzerland
responsible party type: Sponsor-Investigator
investigator affiliation: University of Lausanne Hospitals
investigator full name: Chantal Berna
investigator title: Principal investigator
mesh term: Neuralgia
sharing ipd: Undecided
ipd description: Anonymized data can be made accessible to interested researchers upon request