Measuring the Effects of Complementary Therapies in Chronic Neuropathic Pain

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Neuropathic Pain

Intervention / Treatment
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* Behavioral: Hypnosis
* Behavioral: Open label placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypnosis<br>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…. | Behavioral: Hypnosis<br>* A 6 session course of individual hypnosis therapy will be offered.<br>|
| Placebo Comparator: Open Label placebo<br>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. | Behavioral: Open label placebo<br>* Ritual intake of 2 placebo capsules twice a day<br>|
| No Intervention: Usual care<br>Patients continue with their usual treatments | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interference due to pain (BPI interference) | Brief Pain Inventory, mean interference with function score (score 0-10), with higher scores meaning higher interference. | at 8 weeks | 
| 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 | at 8 weeks | 
| fMRI of pain regulating circuitry (BOLD signal changes) | BOLD signal will be measured during pain perception | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | at 8 weeks | 
| 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) | at 8 weeks | 
| 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). | at 8 weeks | 
| 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). | at 8 weeks | 
| Trail making test (outcomes in time, seconds) | Neuro-cognitive functioning testing | at 8 weeks | 
| Wisconsin card sorting task | Standardized cognitive flexibility task | at 8 weeks | 
| Rey-Osterrieth figure test | Prospective thinking task | at 8 weeks | 
| 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 | at 8 weeks | 
| 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). | at 8 weeks | 
| 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. | at 8 weeks | 
| 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 | at 8 weeks | 
| 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 | 4 and 8 weeks | 
| 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. | 4 and 8 weeks | 
| 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. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypnosis, open label placebo, neurocognitive measures, stress, induced pain, HRV