Measuring the Effects of Complementary Therapies in Chronic Neuropathic Pain

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

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.

Study Overview

• Status: Recruiting
• Conditions: Neuropathic Pain
• Intervention / Treatment: Behavioral: Hypnosis; Behavioral: Open label placebo

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

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.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chantal Berna Renella, MD PhD; Phone Number: +41 795564744; Email: chantal.berna-renella@chuv.ch
• Study Contact Backup: Name: Aurore Fernandez, MA; Phone Number: +4179 556 66 91; Email: aurore.fernandez@chuv.ch

Study Locations

• Switzerland
  • Lausanne, Switzerland, 1011
    • Recruiting
    • Lausanne University Hospital (CHUV)
    • Contact: Chantal Berna Renella, MD PhD; Phone Number: +41 79 556 47 44; Email: chantal.berna-renella@chuv.ch
    • Contact: Aurore Fernandez, MA; Phone Number: +41 79 556 66 91; Email: aurore.fernandez@chuv.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
second phase cross-over choice	patients are offered to choose a second treatment at 8 weeks	8 weeks
Long term outcomes on the Brief Pain Inventory (BPI)	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)	24 weeks
expectations regarding treatment effects	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).	8 weeks, 24 weeks
Hypnotisability according to the Carleton University Responsiveness to Suggestion Scale (CURSS)	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.	8 weeks

Collaborators and Investigators

• Sponsor: Chantal Berna

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: July 10, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 21, 2018

Study Record Updates

• Last Update Posted (Actual): December 22, 2023
• Last Update Submitted That Met QC Criteria: December 20, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: stress; HRV; hypnosis; open label placebo; neurocognitive measures; induced pain
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia
• Other Study ID Numbers: CER-VD 2017- 00924

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Anonymized data can be made accessible to interested researchers upon request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No