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Measuring the Effects of Complementary Therapies in Chronic Neuropathic Pain

Primary Purpose

Neuropathic Pain

Status
Recruiting
Phase
Not Applicable
Locations
Switzerland
Study Type
Interventional
Intervention
Hypnosis
Open label placebo
Sponsored by
Chantal Berna
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuropathic Pain focused on measuring hypnosis, open label placebo, neurocognitive measures, stress, induced pain, HRV

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Patients:

Inclusion criteria:

  • aged 18-90 years,
  • interested in complementary medicine
  • peripheral neuropathic pain lasting for more than 6 months,
  • pain intensity of at least 3/10 VAS over the last two weeks

Exclusion criteria:

  • cognitive deficit (MMSE<24/30),
  • severe hearing impairment,
  • acute psychiatric (e.g. suicidality, psychotic symptoms) or somatic (e.g. unstable cardiorespiratory condition) co-morbidity preventing full engagement in the 8-week study intervention,
  • prior negative experience with hypnosis,
  • allergy or intolerance to mannitol.

Healthy controls:

Inclusion Criteria:

  • matching patients for age and gender,
  • no chronic pain condition no acute pain condition requiring daily intake of analgesics,
  • no acute medical or psychiatric condition.

Sites / Locations

  • Lausanne University Hospital (CHUV)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

No Intervention

Arm Label

Hypnosis

Open Label placebo

Usual care

Arm 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…".

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.

Patients continue with their usual treatments

Outcomes

Primary Outcome Measures

Interference due to pain (BPI interference)
Brief Pain Inventory, mean interference with function score (score 0-10), with higher scores meaning higher interference.
pain severity (BPI pain scale)
Brief Pain Inventory, mean pain intensity score over last 2 weeks (score 0-10) with higher scores meaning higher pain
fMRI of pain regulating circuitry (BOLD signal changes)
BOLD signal will be measured during pain perception

Secondary Outcome Measures

Stress response measured through Cortisol awakening response
Four sequential salivary samples at awakening will be collected and allow dosing of salivary cortisol levels (Cortisol Awakening Response curve).
Stress response measured through Heart rate variability (HRV)
ECG collection over times of rest and induced stress will allow to calculate HRV (based mainly on the RR interval)
Pain modulation: modulation of induced pain through mental imagery and expectations. The outcome measure is on pain Visual Analogue Scale (VAS) for unpleasantness
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).
Pain modulation: modulation of induced pain through mental imagery and expectations. The outcome measure is on pain Visual Analogue Scale (VAS) for intensity
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).
Trail making test (outcomes in time, seconds)
Neuro-cognitive functioning testing
Wisconsin card sorting task
Standardized cognitive flexibility task
Rey-Osterrieth figure test
Prospective thinking task
Hospital Anxiety and Depression Scale (HADS)
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
Tampa Scale of Kinesiophobia
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).
Pain Catastrophizing Scale (PCS)
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.
Coping Strategies Questionnaire
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
patient satisfaction with care
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
Evaluation of patient compliance
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.
Blood metabolomics
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.

Full Information

First Posted
July 10, 2018
Last Updated
June 28, 2022
Sponsor
Chantal Berna
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1. Study Identification

Unique Protocol Identification Number
NCT03783624
Brief Title
Measuring the Effects of Complementary Therapies in Chronic Neuropathic Pain
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 1, 2018 (Actual)
Primary Completion Date
March 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Chantal Berna

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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 . 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…". . 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuropathic Pain
Keywords
hypnosis, open label placebo, neurocognitive measures, stress, induced pain, HRV

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
InvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Hypnosis
Arm Type
Experimental
Arm 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 Title
Open Label placebo
Arm Type
Placebo Comparator
Arm 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 Title
Usual care
Arm Type
No Intervention
Arm Description
Patients continue with their usual treatments
Intervention Type
Behavioral
Intervention Name(s)
Hypnosis
Intervention Description
A 6 session course of individual hypnosis therapy will be offered.
Intervention Type
Behavioral
Intervention Name(s)
Open label placebo
Intervention Description
Ritual intake of 2 placebo capsules twice a day
Primary Outcome Measure Information:
Title
Interference due to pain (BPI interference)
Description
Brief Pain Inventory, mean interference with function score (score 0-10), with higher scores meaning higher interference.
Time Frame
at 8 weeks
Title
pain severity (BPI pain scale)
Description
Brief Pain Inventory, mean pain intensity score over last 2 weeks (score 0-10) with higher scores meaning higher pain
Time Frame
at 8 weeks
Title
fMRI of pain regulating circuitry (BOLD signal changes)
Description
BOLD signal will be measured during pain perception
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
Stress response measured through Cortisol awakening response
Description
Four sequential salivary samples at awakening will be collected and allow dosing of salivary cortisol levels (Cortisol Awakening Response curve).
Time Frame
at 8 weeks
Title
Stress response measured through Heart rate variability (HRV)
Description
ECG collection over times of rest and induced stress will allow to calculate HRV (based mainly on the RR interval)
Time Frame
at 8 weeks
Title
Pain modulation: modulation of induced pain through mental imagery and expectations. The outcome measure is on pain Visual Analogue Scale (VAS) for unpleasantness
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).
Time Frame
at 8 weeks
Title
Pain modulation: modulation of induced pain through mental imagery and expectations. The outcome measure is on pain Visual Analogue Scale (VAS) for intensity
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).
Time Frame
at 8 weeks
Title
Trail making test (outcomes in time, seconds)
Description
Neuro-cognitive functioning testing
Time Frame
at 8 weeks
Title
Wisconsin card sorting task
Description
Standardized cognitive flexibility task
Time Frame
at 8 weeks
Title
Rey-Osterrieth figure test
Description
Prospective thinking task
Time Frame
at 8 weeks
Title
Hospital Anxiety and Depression Scale (HADS)
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
Time Frame
at 8 weeks
Title
Tampa Scale of Kinesiophobia
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).
Time Frame
at 8 weeks
Title
Pain Catastrophizing Scale (PCS)
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.
Time Frame
at 8 weeks
Title
Coping Strategies Questionnaire
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
Time Frame
at 8 weeks
Title
patient satisfaction with care
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
Time Frame
4 and 8 weeks
Title
Evaluation of patient compliance
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.
Time Frame
4 and 8 weeks
Title
Blood metabolomics
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.
Time Frame
8 weeks
Other Pre-specified Outcome Measures:
Title
second phase cross-over choice
Description
patients are offered to choose a second treatment at 8 weeks
Time Frame
8 weeks
Title
Long term outcomes on the Brief Pain Inventory (BPI)
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)
Time Frame
24 weeks
Title
expectations regarding treatment effects
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).
Time Frame
8 weeks, 24 weeks
Title
Hypnotisability according to the Carleton University Responsiveness to Suggestion Scale (CURSS)
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.
Time Frame
8 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Patients: Inclusion criteria: aged 18-90 years, interested in complementary medicine peripheral neuropathic pain lasting for more than 6 months, pain intensity of at least 3/10 VAS over the last two weeks Exclusion criteria: cognitive deficit (MMSE<24/30), severe hearing impairment, acute psychiatric (e.g. suicidality, psychotic symptoms) or somatic (e.g. unstable cardiorespiratory condition) co-morbidity preventing full engagement in the 8-week study intervention, prior negative experience with hypnosis, allergy or intolerance to mannitol. Healthy controls: Inclusion Criteria: matching patients for age and gender, no chronic pain condition no acute pain condition requiring daily intake of analgesics, no acute medical or psychiatric condition.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chantal Berna Renella, MD PhD
Phone
+41 795564744
Email
chantal.berna-renella@chuv.ch
First Name & Middle Initial & Last Name or Official Title & Degree
Aurore Fernandez, MA
Phone
+4179 556 66 91
Email
aurore.fernandez@chuv.ch
Facility Information:
Facility Name
Lausanne University Hospital (CHUV)
City
Lausanne
ZIP/Postal Code
1011
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chantal Berna Renella, MD PhD
Phone
+41 79 556 47 44
Email
chantal.berna-renella@chuv.ch
First Name & Middle Initial & Last Name & Degree
Aurore Fernandez, MA
Phone
+41 79 556 66 91
Email
aurore.fernandez@chuv.ch

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
Anonymized data can be made accessible to interested researchers upon request

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Measuring the Effects of Complementary Therapies in Chronic Neuropathic Pain

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