CRPS - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation

Study Overview
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Brief Summary
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This is a sham controlled, randomized, double-blind, navigated repetitive Transcranial Magnetic Stimulation (nrTMS) study for the treatment of complex regional pain syndrome (CRPS types 1 and 2). The investigators study factors that may contribute to development, maintenance, or treatment responses with clinical, sleep, and psychiatric questionnaires and clinical examinations, quantitative sensory testing and neurophysiologic recordings, genetics, and MRI techniques.

Detailed Description
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rTMS hypothetically disrupts the default networks related to chronic pain and renders the brain more susceptible to drugs, rehabilitation, or cognitive behavioral therapy. In addition, there is experimental evidence that rTMS releases factors that are involved in endogenous top-down modulation of pain and neural plasticity. Thus, the analgesic effect of rTMS may be mediated via enforcing endogenous pain control systems at the brain level, in addition to its effects on neuroplastic effects. For active, navigated stimulation targets the investigators have the parietal opercular cortex overlying the secondary somatosensory cortex (S2) and the primary motor cortex (M1). The investigators randomize participants to first receive nrTMS to the right S2 or sham stimulation. After ten sessions the investigators follow up the participants up to three months. At three months, if the average pain is ≥5/10 in numeric rating scale (NRS), the participant is offered an active, open nrTMS treatment phase depending on which treatment the participant first received. If the participant benefits from the open label treatment, a maintenance therapy is offered (6 months with gradually reducing nrTMS treatment frequency). The symptoms and quality of life are followed with questionnaires and diaries. After the maintenance period, the RN calls a structured interview at 1, 3, and 6 months.

Official Title
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Complex Regional Pain Syndrome - Diagnostics, Pathophysiological Mechanisms, and Response to Treatment With Noninvasive Brain Stimulation

Conditions
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Transcranial Magnetic Stimulation, Complex Regional Pain Syndrome of Upper Limb (Disorder)

Intervention / Treatment
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* Device: Sham nrTMS and open phase
* Device: Active nrTMS and open phase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CRPS 1 or 2 of the upper limb Duration ≥ 6 months Mean pain (NRS) intensity ≥5/10 Medical and other therapies have failed Exclusion Criteria: Other stimulation therapies apart from transcutaneous nerve stimulation psychotic disorder severe depression use of strong opioids epilepsy any contraindication for MRI abuse of alcohol or drugs ongoing insurance or other entitlement cases

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Interventional Model Description: The patients are first randomized to receive either sham stimulation or right S2 for three week period (10 stimulation sessions). Thereafter, a 3 month followup period (clinical checkup at a research visit at 1 month, RN structured telephone interviews at 2 and 3 months). If pain ≥5/10 at 3 month interview, the patient is offered an open label nrTMS treatment phase, in which the protocol depends on the first protocol of the RCT phase.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Starts with active stimulation<br>Active nrTMS is given to S2 at the right side (10 sessions in a three week period). Thereafter, a new, open label phase will start if the average pain at 3 month follow-up is ≥5/10. Then, the nrTMS will be targeted to M1 contralateral to the side of pain. After 5 stimulation sessions the response is evaluated. If pain is still ≥510, the investigators change the target to the S2 on the left side for five sessions. If there is response with pain relief, a maintenance therapy with this target is offered for 6 months with gradually reducing stimulation sessions. | Device: Active nrTMS and open phase<br>* Navigated repetitive TMS treatment (10 sessions during a three-week period) randomized to S2. In the following open phase stimulation the treatment targets are contralateral M1 and left S2. If the patient benefited from active S2 stimulation, but the treatment effect faded in follow-up, the open phase stimulation starts with right S2.<br>* Other names: Starts with active stimulation;|
| Placebo Comparator: Starts with sham stimulation<br>Sham nrTMS will be targeted to the S2 on the right side, but using a sham box/coil. Stimulation period is similar than for the active comparator. Similarly, thereafter, a new, open label phase will start if the average pain at 3 month follow-up is ≥5/10. Then, the nrTMS will be targeted to S2 at the right side. After 5 stimulation sessions the response is evaluated. If pain is still ≥5/10, the investigators change the target to M1 on the contralateral side of the pain and furthermore to S2 at the left side after 5 stimulation sessions, if pain is still ≥5/10. | Device: Sham nrTMS and open phase<br>* Navigated repetitive TMS treatment (10 sessions during a three-week period) randomized to sham. In the following open phase stimulation the treatment targets are the right S2-contralateral M1-left S2.<br>* Other names: Starts with sham stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 15-item quality of life measure | Quality of life (15D questionnaire) with 15 question items with 5 alternatives in each. The scores range between 15 to 75 with 15 the best and 75 the worst quality of life. | Change from baseline at one month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean pain intensity and interference | Numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable) | Baseline, during stimulation, and two weeks after the intervention | 
| Weekly pain intensity and interference | Pain questionnaires (numeric rating scale (NRS, 0= no pain and 10= the worst pain imaginable) | Up to 3 months after intervention | 
| Sleep interference and quality | Insonnia severity index (ISI). There are seven questions with scale 0 to 4 (0 with no symptoms and 4 with the worst symptoms). The scores are added up to get a total score ranging from 0 to 28. A higher score means a worse outcome. | Baseline and 1,2,and 3 months after intervention | 
| Clinical neurophysiology measures | Quantitative sensory testing (QST) with standardized reporting | Baseline and one week after intervention | 
| Cognitive assessment A | Cognitive function assessment by Cogstate, a computer based detection and identification task. Answers yes or no, standard reporting. | Baseline and one month after the intervention | 
| Hand strength | Hand motor function measured e.g. by Jamar (kg) | Baseline and one week after the intervention. | 
| Biochemical tests | Blood samples: inflammatory markers (e.g. high sensitivity CRP, proteomics). Standard reporting | At baseline | 
| Brain imaging: Default mode networks | Resting state fMRI | Baseline and one week after intervention | 
| CRPS symptom severity | CRPS severity scale (CSS, 0=no symptoms or signs, 17=maximum score with symptoms and signs) | Baseline and at one month | 
| Patient global impression of change | Global impression of change (GIC, 1=very much improved, 7= very much worse) | 1, 2, and 3 months and through study completion, an average of 1 year | 
| Screening of psychiatric symptoms and diagnostics | Psychiatric interveiw (SCID II) with symptom and diagnostic description. Nine questions, answers yes or no, standard reporting. The more yes-answers, the worse the outcome. | Up to 24 weeks | 
| Hand mobility | Angles of the joints in the hand (degrees) | Baseline and one week after intervention | 
| Cognitive assessment B | Wechsler Memory Scale III (WMS-III) subtest: digit span. Number of digits recalled. Standard reporting. | Baseline and one month after the intervention | 
| Cognitive assessment C | Wechsler Memory Scale III (WMS-III) subtest: word list. Number of words recalled. Standard reporting. | Baseline and one month after the intervention | 
| Cognitive assessment D | Bourdon-Wiersma (Attention and concentration): number of visual stimuli found. | Baseline and one month after the intervention | 
| Cognitive assesment E | Trail-Making Test (Parts A and B): time spent (seconds) for visual scanning task. Standard reporting. | Baseline and one month after the intervention | 
| DNA | DNA analysis. Standard reporting. | At baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TMS, CRPS, pain, fMRI, quality of life, mood, cognitive function, DNA