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

Not Applicable

Completed

• Conditions: Complex Regional Pain Syndrome of Upper Limb (Disorder); Transcranial Magnetic Stimulation
• Interventions: Device: Active nrTMS and open phase; Device: Sham nrTMS and open phase

• Registration Number: NCT04439669
• Lead Sponsor: Helsinki University Central Hospital

Brief Summary

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

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.

Study Timeline

• Study Start: 2017-08-28
• Study First Submitted: 2020-03-31
• Study First Submitted QC: 2020-06-17
• Study First Posted: 2020-06-19
• Primary Completion: 2021-07-29
• Study Completion: 2022-08-25
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-01
• Last Update Posted: 2024-07-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 62

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Starts with active stimulation	Active nrTMS and open phase	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.
Starts with sham stimulation	Sham nrTMS and open phase	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.

Primary Outcome Measures

Name	Time	Method
15-item quality of life measure	Change from baseline at one month	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.

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Turku University Hospital, Pain Clinic; 🇫🇮 Turku, Varsinais-Suomi, Finland

Helsinki University Hospital, Pain Clinic; 🇫🇮 Helsinki, Uusimaa, Finland