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.

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.

Anonymized data can be made accessible to interested researchers upon request

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.